Virtual Library

Background:
Immunotherapy and DNA damage repair inhibitors have the potential to play a role in the treatment of patients with extensive-disease small cell lung cancer (ED-SCLC), due to high mutation load and genomic instability in this disease setting. Durvalumab, a selective, high-affinity, engineered human IgG1 mAb blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb targeting CTLA-4. Durvalumab plus tremelimumab demonstrated clinical activity and manageable tolerability in a Phase 1b study in NSCLC (NCT02000947). AZD1775, a small-molecule inhibitor of DNA damage checkpoint kinase WEE1, potentiates genotoxic chemotherapies. AZD1775 plus carboplatin showed antitumor activity and acceptable safety in a Phase 2 study in platinum-refractory p53-mutated ovarian cancer (NCT01164995).

Method:
BALTIC (NCT02937818) is a Phase 2, open-label, multicenter, multi-arm, exploratory, signal-searching study to assess the preliminary activity of novel treatment combinations in patients with platinum-refractory/resistant ED-SCLC. Inclusion criteria include disease progression during, or within 90 days of completing, first-line platinum-based chemotherapy; WHO/ECOG performance status of 0/1; and life expectancy ≥8 weeks. Each study arm is independent and will open sequentially to enroll up to 20 patients. The study will open initially with two arms. Patients will receive durvalumab 1500 mg + tremelimumab 75 mg i.v. q4w for 4 doses, followed by durvalumab monotherapy 1500 mg i.v. q4w (Arm A); and oral AZD1775 225 mg bid for 2.5 days from Day 1 + carboplatin AUC 5 on Day 1 i.v. q3w (Arm B). Treatment will continue until confirmed disease progression or discontinuation. Further arms will be added to assess other combinations once tolerable dosing regimens have been established. The primary endpoint is investigator-assessed ORR (RECIST v1.1). Secondary endpoints include duration of response, disease control rate, time-to-response, PFS, OS, pharmacokinetics, safety and tolerability. Gene expression levels and biomarkers will also be explored. Recruitment is ongoing.Figure 1



Result:
Section not applicable

Conclusion:
Section not applicable

Background:
New therapies are urgently needed for patients with extensive-disease small cell lung cancer (ED-SCLC). High mutation burden in SCLC suggests a potential role for immune checkpoint blockade. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb against CTLA-4. Durvalumab ± tremelimumab in combination with chemotherapy has shown acceptable tolerability and evidence of clinical activity in a Phase 1b study (NCT02537418) in patients with advanced solid tumors, including NSCLC and SCLC.

Method:
CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study investigating the combination of first-line chemotherapy with durvalumab ± tremelimumab in Stage IV ED-SCLC. Treatment-naïve patients (N=795) will be randomized 1:1:1 to receive durvalumab 1500 mg + tremelimumab 75 mg i.v. q3w + chemotherapy (Arm 1); durvalumab 1500 mg i.v. q3w + chemotherapy (Arm 2); or chemotherapy alone (Arm 3). Durvalumab ± tremelimumab will be concurrently administered with chemotherapy in Arms 1 and 2 and will continue post chemotherapy (one further dose for tremelimumab; until disease progression for durvalumab). Chemotherapy (etoposide with either carboplatin or cisplatin) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. Co-primary endpoints are OS and PFS using blinded independent central review (RECIST v1.1; Arm 1 vs Arm 3). Secondary endpoints include OS and PFS (Arm 2 vs Arm 3, Arm 1 vs Arm 2); ORR; 18-month OS; proportion of patients alive and progression-free at 6 and 12 months; pharmacokinetics; immunogenicity; HRQoL; safety and tolerability. An independent data monitoring committee will meet at two early stages of enrolment to confirm the safety and tolerability of the proposed combination dosing regimen and will monitor safety every 6 months thereafter. Recruitment is ongoing. Figure 1



Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Crizotinib has been established as the standard first-line treatment for patients with ALK-rearranged non-small-cell lung cancer. However, despite its superiority to chemotherapy, resistance occurs within approximately 12 months. New ALK-inhibitors are needed to overcome the resistance to crizotinib and to increase drug penetration to CNS. X-396 (ensartinib) is a novel, potent ALK tyrosine kinase inhibitor (TKI). Its phase I/II study showed X-396 is well-tolerated with favorable anti-tumor activities in both ALK TKI-naïve and crizotinib-resistant NSCLC patients, as well as patients with CNS metastases. The recommended phase II dose (RP2D) was established at 225 mg, once daily.

Method:
A phase II, multi-center study is evaluating the efficacy and safety of single-agent X-396 in Chinese patients with ALK (+) non–small-cell lung cancer after progression on crizotinib. Eligible patients will have documentation of a positive ALK rearrangement and progression on crizotinib. X-396 225 mg is orally administered until disease progression or intolerable toxicity. The primary endpoint is RECIST 1.1 response rate. Secondary endpoints include PFS, duration of response, and safety. The sample size is calculated using the test for inequality method, assuming that X396 have an ORR of 50% in patients with ALK-positive NSCLC, 15% higher than that from existing second-line therapy. Therefore, up to 144 patients will be enrolled with a significance level and power of 5% and 90%, respectively. Recruitment will be started on September, 2017.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Atezolizumab is an anti–PD-L1 mAb that blocks PD-L1 from interacting with its receptors PD-1 and B7.1 and restores anti-cancer immunity. In patients with 2L/3L advanced NSCLC, the OAK trial showed improved mOS in the atezolizumab arm (13.8 mo) vs the docetaxel arm (9.6 mo), with survival benefit observed across all PD-L1 expression levels on tumor cells (TC) or tumor-infiltrating immune cells (IC). In patients with fully resected NSCLC (stages IB [tumors ≥ 4 cm]-IIIA), adjuvant chemotherapy remains the standard of care, but survival benefit is limited. Therefore, more effective therapies are still needed for patients with early-stage NSCLC. IMpower010 (NCT02486718) is a global Phase III, randomized, open-label trial conducted to evaluate the efficacy and safety of atezolizumab vs best supportive care (BSC) following adjuvant cisplatin–based chemotherapy in patients with resected stage IB (tumors ≥ 4 cm)-IIIA NSCLC.

Method:
Eligibility criteria include complete tumor resection 4-12 weeks prior to enrollment for pathological stage IB (tumors ≥ 4 cm)-IIIA NSCLC, adequate recovery from surgery, ability to receive cisplatin-based adjuvant chemotherapy and ECOG PS 0-1. Patients with other malignancies, autoimmune disease, hormonal cancer or radiation therapy within 5 years and prior chemotherapy or immunotherapy will be excluded. Approximately 1127 patients will be enrolled regardless of PD-L1 status. Patients will receive up to four 21-day cycles of cisplatin-based chemotherapy (cisplatin [75 mg/m[2] IV, day 1] + vinorelbine [30 mg/m[2] IV, days 1, 8], docetaxel [75 mg/m[2] IV, day 1] or gemcitabine [1250 mg/m[2] IV, days 1, 8], or pemetrexed [500 mg/m[2] IV, day 1; only non-squamous NSCLC]). Adjuvant radiation therapy is not permitted. Eligible patients will be randomized 1:1 to receive 16 cycles of atezolizumab 1200 mg q3w or BSC post-adjuvant chemotherapy. Stratification factors include sex, histology (squamous vs non-squamous), disease stage (IB vs II vs IIA) and PD-L1 status by IHC (TC2/3 [≥ 5% expressing PD-L1] and any IC vs TC0/1 [< 5%], and IC2/3 vs TC0/1 and IC0/1 [< 5%]). The primary endpoint is disease-free survival, and secondary endpoints include OS and safety. Exploratory biomarkers will be evaluated, including PD-L1 expression and immune- and tumor-related biomarkers before, during and after treatment with atezolizumab and at radiographic disease recurrence or confirmation of new primary NSCLC.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Amplification of MET leading to oncogenic signaling occurs in 3‒5% of newly diagnosed EGFR wild type (wt) non-small cell lung cancer (NSCLC) cases with decreasing incidence at higher levels of amplification. Mutations in MET leading to exon 14 deletion (METΔ[ex14]) also occur in 2–4% of adenocarcinoma and 1–2% of other NSCLC subsets. Capmatinib (INC280) is a potent and selective MET inhibitor that has shown strong evidence of antitumor activity in a phase I study in patients with EGFR wt advanced NSCLC harboring MET amplification and METΔ[ex14].

Method:
This phase II, multicenter study (NCT02414139) was designed to confirm the clinical activity of capmatinib in patients with advanced NSCLC by MET amplification and METΔ[ex14] status. Eligible patients (≥18 years of age, Eastern Cooperative Oncology Group Performance Status 0–1) must have ALK-negative, EGFR wt, stage IIIB/IV NSCLC (any histology). Centrally assessed MET amplification (gene copy number [GCN]) and mutation status is used to assign patients to one of the below cohorts: Pretreated with 1–2 prior systemic lines of therapy for advanced setting (cohorts 1–4): 1a: MET amplification GCN ≥10 (n=69) 1b: MET amplification GCN ≥6 and <10 (n=69) 2: MET amplification GCN ≥4 and <6 (n=69) 3: MET amplification GCN <4 (n=69) 4: METΔ[ex14] mutation regardless of MET GCN (n=69) Treatment naïve (cohorts 5a and 5b): 5a: MET amplification GCN ≥10 and no METΔ[ex14] mutation (n=27) 5b: METΔ[ex14] mutation regardless of MET GCN (n=27) Capmatinib 400 mg tablets are orally administered twice daily on a continuous dosing schedule 12 hours apart. Primary and key secondary endpoints are overall response rate (ORR) and duration of response (DOR), respectively (blinded independent review assessment). Other secondary endpoints include investigator-assessed ORR, DOR, time to response, disease control rate, progression-free survival (independent and investigator assessment), safety, and pharmacokinetics. Enrollment is ongoing in 25 countries. Cohorts 1b, 2, and 3 are now closed to enrollment; cohorts 1a and 4 continue to enroll patients who have received 1–2 prior lines of therapy in the advanced setting, and cohorts 5a and 5b are open for enrollment of treatment-naïve patients. Responses have been seen in both MET-amplified and MET-mutated patients irrespective of the line of therapy.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
EGFR-TKIs are standard first-line therapy in patients with EGFR sensitizing mutation (EGFRm)-positive advanced NSCLC. EGFR T790M resistance mutation is observed in >50% of patients with acquired resistance to EGFR-TKIs. Osimertinib is a third-generation, irreversible, CNS-active EGFR-TKI selective for EGFRm and T790M, recommended in patients with T790M-positive advanced NSCLC who have progressed on first-line EGFR-TKIs. In a recent study (NCT01405079), gefitinib treatment in patients with resected EGFRm-positive NSCLC significantly increased disease-free survival (DFS) vs vinorelbine+cisplatin: median 28.7 vs 18.0 months (hazard ratio 0.60 (95% CI 0.42–0.87), p=0.005), warranting further investigation of EGFR-TKIs in this setting (Wu et al, J Clin Oncol 2017;35:suppl;abs8500). Osimertinib may prolong DFS in adjuvant EGFRm-positive NSCLC.

Method:
Trial Design ADAURA (NCT02511106) is a global, Phase III, double-blind, randomized study, assessing efficacy and safety of osimertinib vs placebo in patients with stage IB–IIIA non-squamous EGFRm-positive NSCLC with complete tumor resection. Approximately 700 patients from 210 sites will be randomized. A planned 60% of patients will be recruited from Asia, 40% from non-Asian countries; 70% stage II–IIIA, 30% stage IB. Patients must be adults ≥18 years (Japan/Taiwan: ≥20) with primary NSCLC staged post-operatively as IB/II/IIIA, and central confirmation of Ex19del or L858R (alone or combined with other EGFR mutations including T790M). Complete surgical resection of the primary NSCLC is mandatory; patients will have baseline CT scans within 28 days prior to treatment confirming radiographic absence of residual disease. Complete surgical recovery is required for randomization; treatment to start at least 4 weeks following surgery. Patients who have received radiation therapy, pre-operative chemotherapy, prior anticancer therapy or neoadjuvant/adjuvant EGFR-TKI treatment are exempt. Standard post-operative adjuvant chemotherapy, consisting of a platinum-based doublet for 4 cycles maximum, is allowed; no more than 10 and 26 weeks may have elapsed between surgery and randomization for patients who have not or have received adjuvant chemotherapy, respectively. Patients will be randomized 1:1 to once-daily osimertinib 80 mg or placebo and stratified by stage (IB/II/IIIA), mutation type (Ex19Del/L858R) and race (Asian/non-Asian). Treatment may continue for 3 years in absence of discontinuation criteria including disease recurrence. Primary objective is to assess the efficacy of osimertinib vs placebo, measured by investigator-assessed DFS. Secondary objectives include assessment of the safety profile of osimertinib vs placebo; DFS rate at 2, 3, 5 years; overall survival (OS); 5-year OS rate; health-related quality of life; pharmacokinetics. Estimated primary completion date (final DFS data collection date): July 2021.

Result:
Section not applicable.

Conclusion:
Section not applicable.

Background:
Therapeutic options for small-cell lung cancer (SCLC) remain limited, with etoposide/platinum (EP) as the standard first-line chemotherapy regimen. However, patients with extensive-stage (ES)-SCLC experience high relapse rates within months after initial therapy. Pembrolizumab, a humanized monoclonal antibody against PD-1, has shown antitumor activity as monotherapy in heavily pretreated patients with PD-L1–positive SCLC in the phase 1b KEYNOTE-028 study. KEYNOTE-604 (ClinicalTrials.gov, NCT03066778) evaluates EP plus either pembrolizumab or placebo as first-line therapy for ES-SCLC.

Method:
Section not applicable

Result:
Section not applicable

Conclusion:
In this international, double-blind, phase 3 trial, adults with newly diagnosed ES-SCLC, ECOG PS ≤1, and no previous systemic therapy for SCLC are randomized 1:1 to receive either EP plus a 200-mg fixed dose of pembrolizumab intravenously (IV) once every 3 weeks (Q3W) or EP plus placebo IV Q3W. Randomization is stratified by the chosen platinum therapy (carboplatin vs cisplatin), ECOG PS (0 vs 1), and baseline lactate dehydrogenase concentration (≤ upper limit of normal [ULN] vs > ULN). Study treatment includes a total of 4 cycles of EP and 2 years of pembrolizumab/placebo and continues until documented PD, intolerable toxicity, or withdrawal of consent. Patients with a response after 4 cycles of EP plus placebo or pembrolizumab may receive prophylactic cranial irradiation. Patients who complete 2 years of pembrolizumab treatment or stop pembrolizumab for reasons other than PD/intolerability, but subsequently have documented PD confirmed by blinded independent review, may receive an additional 1 year of pembrolizumab provided that no other systemic therapy has been administered. Patients must meet the eligibility criteria for retreatment; patients in the placebo arm are not eligible for treatment with pembrolizumab at the time of PD. Tumor response is assessed every 6 weeks for 48 weeks, and every 9 weeks thereafter by RECIST version 1.1 by blinded independent central review. AEs occurring during treatment and 30 days thereafter (90 days for serious AEs) are graded per Common Terminology Criteria for Adverse Events, version 4.0. Primary endpoints are PFS and OS. Secondary endpoints are ORR, duration of response, safety, and patient-reported outcomes. Approximately 430 patients will be enrolled.

Background:
Lurbinectedin (PM01183) is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. First signs of synergism with doxorubicin (DOX) and responses, especially in relapsed small cell lung cancer (SCLC) (overall response rate [ORR] ~67%, including about 10% of complete responses [CR]), were reported in a phase I expansion cohort in 21 second-line SCLC patients (ASCO 2015, abstract 7509). Main toxicity was hematological. A lower dose was used to improve safety, and activity was confirmed in an expansion cohort of 27 patients with relapsed SCLC (~37%, with 4% of CR)

Method:
Multinational (20 countries), multicenter (154 sites), open-label, randomized phase III study of PM01183/DOX vs. a control arm with investigator choice of either standard cyclophosphamide, DOX and vincristine (CAV) or topotecan (T). A total of 600 patients will be randomized (1:1) and stratified according to ECOG performance status (PS), central nervous system (CNS) involvement, previous treatment with antiPD1/antiPD-L1, chemotherapy-free interval and investigator´s choice of control arm. Patients with clinical benefit after 10 cycles of the combination could continue with single-agent PM01183 or CAV, until progressive disease or unacceptable toxicity. An interim safety analysis by an independent data monitoring committee (IDMC) is planned when the first 150 patients have been randomized. Most relevant inclusion criteria includes: age ≥18 years and confirmed diagnosis of SCLC (if primary site is unknown, the patient will be eligible if Ki-67 expression >50%), mandatory previous platinum-containing line (additional immunotherapy is allowed), ECOG PS 0-2, and adequate major organ function (including LVEF >50%). Patients are excluded if chemotherapy-free interval is <30 days, pre-treated with PM01183, DOX or T, symptomatic or steroids-requiring CNS involvement, or any medical condition that might preclude safe compliance with study treatment. Primary objective is to determine a difference in progression-free survival (RECIST v.1.1) by independent review committee. Secondary endpoints include overall survival, survival rates at 12/18/24 months, antitumor response (RECIST v.1.1), duration of response, quality of life, safety, subgroup analyses and pharmacokinetics of PM01183/DOX.

Result:
The first patient was included in August 2016. An interim safety analysis, requested by the IDMC, was conducted on the first 50 patients randomized and treated with 2 cycles, and resulted in a recommendation to continue the trial unmodified.

Conclusion:
The ATLANTIS randomized phase III study is currently ongoing. Trial recruitment is expected to be completed at Q1 2018.

Background:
ABP 215 is a proposed biosimilar that is similar to bevacizumab, a VEGF inhibitor, in analytical and functional comparisons. Pharmacokinetic (PK) similarity between ABP 215 and bevacizumab has been demonstrated in a separate phase 1 study. Here we present results from a phase 1 study demonstrating PK similarity between ABP 215 and bevacizumab in healthy adult Japanese men.

Method:
PK similarity was evaluated in a randomized, single-blind, single-dose, parallel-group study in healthy Japanese men comparing ABP 215 with EU-authorized bevacizumab. Primary endpoints were maximum observed serum concentration (C~max~) and area under the serum concentration-time curve from time 0 to infinity (AUC~inf~). Secondary endpoints included AUC from time 0 to the time of the last quantifiable concentration (AUC~last~), safety, tolerability, and immunogenicity.

Result:
Baseline characteristics were similar among the 48 subjects (n=24 in each group). PK similarity was demonstrated for the comparison of ABP 215 with bevacizumab. After 3 mg/kg intravenous infusion, the geometric means (GMs) of C~max,~ AUC~inf~, and AUC~last~ were 71.2 µg/mL, 25259 µg·h/mL, and 22499.3 µg·h/mL for ABP 215 and 70.16 µg/mL, 25801µg·h/mL, and 22604.6 µg·h/mL for bevacizumab respectively. The GM ratios for C~max,~ AUC~inf~, and AUC~last~ were 1.015 (90% confidence interval; CI, 0.946–1.088), 0.979 (90% CI, 0.914–1.049), and 0.995 (90% CI, 0.941–1.053) for ABP 215 vs bevacizumab respectively. All CIs fell within the prespecified bioequivalence criteria of 0.80–1.25. The incidence of treatment-emergent adverse events (TEAEs) was comparable between treatment groups. Adverse events (AEs) occurred in 2/24 subjects receiving ABP 215 and 1/24 subjects receiving bevacizumab. There were no deaths, no serious AEs or AEs leading to study discontinuation; no subject was positive for binding antidrug antibodies (ADAs) at any time point during the study.

Conclusion:
ABP 215 was shown to have similar pharmacokinetics compared with bevacizumab in this PK study in Japanese men; CIs were within the standard bioequivalence criteria of 0.80–1.25. Safety was comparable between the two groups; no subjects developed binding ADAs.

Background:
Afatinib has demonstrated progression-free survival (PFS) and overall survival (OS) improvements in patients with squamous cell carcinoma (SCC) of the lung; pembrolizumab also showed encouraging PFS/OS in lung SCC. Afatinib is a selective and irreversible ErbB family blocker that effectively inhibits signaling from all homo- and heterodimers formed by ErbB family members EGFR (ErbB1), HER2 (ErbB2), ErbB3, and ErbB4. Pembrolizumab is a humanized immunoglobulin G4 (IgG4) monoclonal antibody with high affinity and potent receptor-blocking activity for the programmed cell death 1 (PD-1) receptor. Concurrent inhibition of PD-1 and EGFR pathways represents a rational and promising approach for EGFR-driven tumors such as SCC of the lung, to increase the rate and duration of response, and delay the development of resistance, as single-agent efficacy can be moderate and more treatment options are needed. This trial assesses the efficacy and safety of afatinib in combination with pembrolizumab in patients with locally advanced or metastatic squamous non-small cell lung cancer (NSCLC) who progressed during or after first-line platinum-based treatment.

Method:
Trial design: Study 1200.283 (NCT03157089. LUX-Lung IO / Keynote 497) is a phase II, open-label, non-randomized single-arm study. Eligible patients have locally advanced or metastatic squamous NSCLC and have progressed during/after first-line platinum-based chemotherapy. Patients must have adequate organ function and ECOG PS 0/1. Prior treatment with immune checkpoint inhibitors or EGFR targeted therapy is prohibited. A safety run-in will be performed using afatinib once daily (starting dose 40 mg) in combination with pembrolizumab, (200 mg fixed dose once every 3 weeks, administered intravenously) to assess the safety profile and confirm the recommended Phase II dose (RP2D). In the main part of the trial, afatinib at the RP2D, in combination with pembrolizumab, may be continued for a maximum of 35 cycles (~2 years). After study completion, further therapy will be decided by the investigator and may include afatinib. Dose reduction of afatinib to 30 mg or 20 mg will be permitted in the case of adverse events. The primary endpoint is investigator assessed objective response (complete response [CR] or partial response [PR] according to RECIST v1.1). Secondary/further endpoints are disease control (CR, PR, or stable disease), duration of objective response, PFS, OS, tumor shrinkage, RP2D, and pharmacokinetics. Exploratory biomarker analysis will also be performed. This study will be conducted in the US, Spain, France, Korea, and Turkey, and will open for enrollment in September 2017; target enrollment is 50-60 patients.

Result:
Not applicable

Conclusion:
Not applicable

Background:
With the application of low dose computed tomography in screening lung cancer for high-risk population, more peripheral pulmonary lesions are found which need to be diagnosed or treated. Traditional methods include transthoracic needle aspiration (TTNA) or transbronchial lung biopsy (TBLB) are not recommended nowadays because of its low diagnostic rate, more complications and high radiation dose for patients. Moreover, they lack real-time navigation system for guiding bronchoscope to the distal lesion where traditional methods hardly reach and highly depends on operators with knowledge of CT scans. Electromagnetic navigated bronchoscopy (ENB) has proven to be a novel technology, including electromagnetic tracking, virtual bronchoscopic navigation and CT reconstruction technologies. Only two commercial ENB systems have been approved by FDA in the United States. And more than 1,000 medical institutions have been equipped with ENB in Europe and the United States. As of the end of June 2016, more than 10 imported ENB systems were installed in China.

Method:
This project has been supported by the ministry of science and technology of the People’s Republic of China in 2017(2017YFC0112700). This project will utilize the domestic LungCare ENB system and its improved version to carry out five innovative sub-projects. These projects will cover all the issues of ENB on the early peripheral lung cancers (Stage IA), including the diagnosis, localization and treatment.

Result:
First, the project will utilize the CFDA approved LungCare ENB system to perform a large, prospective, multicenter, randomized study, which aims to enroll up to total 1362 consecutive subjects presenting for evaluation (diagnosis, localization and treatment) of lung lesions utilizing the ENB procedure at up to 3 clinical sites. Second, LungCare ENB system will upgrade their products and develop two new navigation systems including the transthoracic electromagnetic navigation system(TTEN) and the video assisted thoracoscopic surgery electromagnetic navigation system (VATS-EN). Two clinical studies will be performed in 3 clinical sites individually.

Conclusion:
LungCare ENB total solution including ENB, TTEN and VATS-EN, will extend their electromagnetic navigation system of the single use from the bronchus to the thoracic wall, and even through the thoracoscope. The value of the project will form the whole-lung electromagnetic navigation system and focus on the accurate diagnose, localization and treatment of early peripheral lung cancer.

Background:
Ensartinib (X-396) is a novel, potent ALK TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Its phase 1/2 study (NCT01625234) demonstrated that ensartinib is well-tolerated and induces favorable responses in both crizotinib-naïve (ORR 80%) and crizotinib-resistant ALK+ NSCLC patients (ORR 71%), as well as those with CNS metastases.

Method:
In this global, phase 3, open-label, randomized study (eXalt3), approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized with stratification by prior chemotherapy (0/1), performance status (0-1/2), brain metastases at screening (absence/presence), and geographic region (Asia Pacific/other), to receive oral ensartinib (225 mg, once daily) or crizotinib (250mg, twice daily) until disease progression or intolerable toxicity. Eligibility also includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The primary endpoint was progression-free survival assessed by independent radiology review based on RECIST v. 1.1 criteria. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05.

Result:
Progress report Phase 3 recruitment began in June, 2016 and currently has 66 active sites in 21 countries. The duration of recruitment will be approximately 24 months. This study is registered with ClinicalTrials.Gov as NCT02767804.

Conclusion:
Section not applicable

Background:
PDR001 is a high-affinity, humanized antiprogramed cell death-1 (PD-1) antibody that blocks interaction with programmed cell death ligands, PD-L1 and PD-L2. Results from phase 1/2 study have shown that PDR001 has a manageable safety profile and preliminary antitumor activity in advanced solid tumors. ElevatION:NSCLC-101 is the first study to evaluate the safety and preliminary efficacy of PDR001 plus platinum-doublet chemotherapy in patients with PD-L1 unselected, advanced NSCLC.

Method:
ElevatION:NSCLC-101 is an open-label, multicenter, phase 1b study (NCT03064854) of PDR001 plus platinum-doublet chemotherapy in patients (≥18 years) with squamous or nonsquamous, stage IIIB (not a candidate for definitive multimodality therapy) or stage IV or relapsed locally advanced or metastatic NSCLC, lacking EGFR-sensitizing mutation and/or ALK- or ROS1-rearrangements. Other inclusion criteria: ECOG PS 0-1, ≥1 measurable lesion (per RECIST v1.1), relapse for >12 months from the end of neoadjuvant or adjuvant systemic therapy. PD-L1 expression will be assessed but will not be used to determine eligibility. This study comprises 2 parts (dose-confirmation and dose-expansion) and 4 treatment groups (A, B, C, and D). Groups A, B, and C (dose-confirmation and dose-expansion parts) will include treatment-naïve patients. Group D (dose-expansion part) will include second line patients – those who have received only 1 prior systemic therapy consisting of a PD-1 and/or PD-L1 inhibitor ± CTLA-4 inhibitor (last dose of prior immunotherapy, ≥6 weeks prior to start of study treatment). The treatment-naïve patients will receive gemcitabine/cisplatin (group A) or pemetrexed/cisplatin (group B) or paclitaxel/carboplatin (group C) plus PDR001 (initially 300 mg q3w; if intolerable, a provisional dose level (−1) of 300 mg q6w will be explored) for up to 4 cycles followed by maintenance with PDR001 ± pemetrexed (group B). The second-line patients (group D) will be randomized (1:1) to either platinum-doublet chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) alone/combined with PDR001. Primary endpoints: dose-confirmation part – MTD and/or recommended dose for expansion (DLTs during first 6 weeks of therapy; for groups A, B, and C); dose-expansion part – investigator-assessed ORR per RECIST v1.1 (for groups A, B, and C). Secondary endpoints: ORR (for group D); PFS, DCR, DOR, TTR (for groups A, B, C, and D); OS, PK, and safety. The study enrollment is still ongoing. Approximately 6 to 20 treatment-naïve patients will be assigned to each group (A, B, C) and once MTD/RDE is established, ~20 additional patients will be enrolled in each treatment group; ~60 pretreated patients will be enrolled in group D.

Result:
Not-applicable.

Conclusion:
Not-applicable.

Background:
Anti-PD-1 and anti-PD-L1 antibodies including pembrolizumab, nivolumab and atezolizumab have entered clinical practice in the management of metastatic NSCLC as monotherapy and immunotherapy-based combinations. We have established a real-world Advanced Non-Small Cell Lung Cancer Holistic Registry (ANCHoR) to understand how the emergence of immunotherapy impacts choice of treatment, clinical outcomes, and patient reported outcomes (PROs) in the different histo-molecular subtypes of metastatic NSCLC. The objectives of ANCHoR are to determine the treatment choice and treatment sequence by PD-L1 status in the various histo-molecular categories of NSCLC and to understand the impact of such treatment choice on response rates, progression-free survival (PFS), and overall survival (OS). Additionally we will measure the impact the treatment choices have on the PROs by utilizing the validated instruments, EuroQol-5D version 5L (EQ-5D-5L) and MD Anderson Symptom Inventory module specific to lung cancer (MDASI-LC).

Method:
The study will enroll patients with metastatic NSCLC diagnoses who are treated at MD Anderson Cancer Center (MDA) between January 1, 2017 and December 31, 2020. The study period will end on June 30, 2021 to allow a minimum of six months of follow-up. Trained abstractors will collect demographic, diagnostic, clinical, molecular (biomarker and PD-L1), treatment (regimens utilized in sequence and reason for discontinuation), response and survival (including PFS and OS), health care resource utilization and PRO (EQ-5D-5L and MDASI-LC) information that will be integrated in a comprehensive database. Information from the MDA electronic medical record will be extracted and populated in the GEnomic Marker-guided therapy INItiative (GEMINI) database and the PRO database which are linked. EQ-5D-5L followed by MDASI-LC will be completed directly by the patients and these will be automatically populated in the web-based PRO database at treatment initiation, at the time of response assessments and when switching lines of therapy.

Result:
Interim analysis will be conducted every six months to measure the impact of immunotherapy over time. Study results will be presented using descriptive statistics for continuous variables (mean, standard deviation, median, and interquartile range), categorical variables (frequency and proportions), and time-to-event variables (Kaplan-Meier). Regression models will be used for estimating the relationship between dependent variable and one or more predictors. Cox proportional hazards model will be used to estimate hazard ratios for time-to-event outcomes.

Conclusion:
The ANCHoR study is the first comprehensive registry of its kind that will enable the quantification of the changing impact of immunotherapy on the real-world NSCLC treatment landscape.

Background:
Overall survival ﴾OS﴿ for medically inoperable patients with localized non‐small cell lung cancer ﴾NSCLC﴿ treated with stereotactic body radiotherapy ﴾SBRT﴿ is poorer than for patients undergoing surgery. A possible explanation is contribution of comorbidities to the mortality. Klement et al. demonstrated that comorbidity did not predict the risk of early death for patients with localized NSCLC treated with SBRT. However, it was suggested that a comprehensive geriatric assessment (CGA) could improve OS. We have performed a randomized study to investigate whether CGA added to SBRT impact quality of life ﴾QoL﴿ and OS.

Method:
From January 2015 to June 2016 51 patients diagnosed T1‐2N0M0 NSCLC were enrolled. The patients were randomized 1:1 to receive SBRT +/‐CGA. EQ‐5D QoL health-index and VAS-scores were assessed at start of SBRT, at 5 weeks, and every third months for a year after SBRT. Repeated measures ANOVA compared EQ‐5D overall scores and changes from baseline. OS was analyzed by Kaplan‐Meier methods and compared with log‐rank test.

Result:
26 vs. 25 patients were randomized in the groups +/-CGA, respectively. 4 patients dropped out. There were no differences in patient characteristics between groups. In both groups QoL decreased from baseline but with no differences between groups. VAS scores decreased significantly in the no-CGA group (Table 1). The 1-year and potential 2-year OS was 92% vs. 73% and 72% vs. 57% for the groups +/-CGA, respectively (p=0.24). Figure 1



Conclusion:
In patients treated with SBRT for a localized NSCLC, a CGA did improve the subjective opinion (VAS-score) of QoL at 12 months follow up. A CGA did not statistically improve the health index of QoL and OS. However, more patients deceased within the first 12 months after SBRT in the group without a CGA performed. This study suggests that CGA may prevent early death and improve the patients’ subjective opinion of QoL after SBRT.

Background:
Stereotactic body radiation therapy (SBRT) is an important treatment option of solitary lung tumor. A total dose of 48Gy in 4 fractions (fr.) at the isocenter has been most widely used in Japan, however, local recurrences were observed in the long term follow-up study in 10% or more. To improve local control rates after SBRT, the most promising treatment strategy will be dose escalation. Then we started a pilot study to evaluate the safety and efficacy of dose escalation in SBRT for peripheral lung tumor.

Method:
We designed to enroll 35 patients treated with SBRT prospectively. The primary endpoint was the incidence of adverse effects within 1 year after SBRT. Adverse effects were evaluated by the CTCAE ver. 4.0. In this study, the prescription dose was 70 Gy in 4 fr. at the isocenter, covering the planning target volume (PTV) surface with 70%-isodose line.

Result:
A total of 35 patients were enrolled between October 2014 and January 2016. Patient and tumor characteristics are shown in the table. The median follow-up duration was 21.0 months (range, 4.2–31.2 months). Grade 2 radiation pneumonitis and Grade 2 rib fractures were observed in 5 patients (14.3%) and 5 (14.3%), respectively. There was no other Grade 3 or more adverse effect. Local recurrence was observed in one patient, and it was a recurrence of metastatic lung tumor. Out of 32 primary lung cancers, no local recurrence was observed.

Patient and tumor characteristics

Characteristics			Number	%
Patients			35	100
Age (y)
	Median (range)		77 (58-92)
Gender
	Male		23	66
	Female		12	34
ECOG performance status
	0		10	28
	1		22	63
	2		3	9
Disease
	Primary lung cancer		32	91
	Histology
		Adenocarcinoma	10	28
		Squamous cell carcinoma	3	9
		Clinically diagnosed	19	54
	T-stage
		T1a	15	43
		T1b	11	31
		T2a	6	17
	Lung metastasis		3	9
Target location
	Upper/middle		26	74
	Lower		9	26

Conclusion:
We confirmed that the treatment method is feasible in the acute and subacute phases. It was also suggested that this method can obtain excellent local control rate.

Background:
Curative intent therapy of stage I-III NSCLC may include surgical resection or definitive radiotherapy. Primary management with surgery or radiotherapy may be influenced by patient and disease characteristics. We sought to perform a stage by stage comparison of patients receiving surgery or radical radiation therapy as their curative treatment, and explore the impact of known prognostic factors on outcome.

Method:
A retrospective review was completed of all patients with stage I-III NSCLC referred to the BC Cancer Agency from 2005-2012. Cases were filtered to identify those receiving curative intent therapy including surgery, radiotherapy, and combined chemo-radiation. Information was collected on known prognostic and predictive factors. The primary outcome measure was overall survival.

Result:
A total of 3873 patients were referred. Of these, 1744 (45%) received curative therapy (713 surgery, 1031 radiotherapy); 592 (34%) presented with stage I disease, 386 (22%) with stage II, and 766 (44%) with stage III. At the time of analysis, 1199 (69%) patients had died. Median overall survival in stage-matched cohorts was significantly shorter in the radiotherapy group compared to the surgery group (stage I 34.9 mo vs 44.8 mo, p=0.003, stage II 27.6 mo vs 42.7 mo, p=0.014, stage III 26.5 mo vs 38.7 mo, p=0.001). However, in a multivariable analysis incorporating age, sex, weight loss, smoking history, and ECOG status, the survival difference between radiotherapy and surgery disappeared for stage I and II disease and persisted for stage III.

Univariate and multivariate analysis of prognostic factors and treatment group on survival

	Stage I				Stage II				Stage III
	UVA HR	p-value	MVA HR	p-value	UVA HR	p-value	MVA HR	p-value	UVA HR	p-value	MVA HR	p-value
Age at diagnosis	1.03	<0.001	1.03	<0.001	1.03	<0.001	1.03	<0.001	1.02	<0.001	1.02	0.002
Male vs female	1.31	0.01	1.24	0.04	1.30	0.04	1.12	0.39	1.14	0.11	1.00	0.99
Weight loss 5-10% vs <5% >10% vs <5%	2.01 1.40	<0.001 0.11	1.96 1.15	<0.001 0.51	0.96 1.44	0.81 0.06	0.87 1.18	0.46 0.39	1.33 1.56	0.02 0.001	1.35 1.28	0.02 0.08
Smoking status Former vs never Current vs never	1.78 1.65	0.01 0.04	1.58 1.72	0.06 0.03	2.39 2.73	0.02 0.006	1.85 2.62	0.10 0.01	1.64 1.60	0.003 0.004	1.44 1.32	0.03 0.10
ECOG >=2 vs 0-1	1.39	0.002	1.18	0.14	1.45	0.007	1.31	0.05	2.06	<0.001	1.98	<0.001
Radiotherapy vs surgery	1.36	0.003	1.09	0.44	1.37	0.02	1.27	0.07	1.41	0.001	1.36	0.004

Conclusion:
In stage I and II NSCLC, the performance of radical radiotherapy and surgery were comparable after controlling for known prognostic factors. Superior survival was observed with surgery in stage III disease however; this may be related to disease characteristics. Surgery and radiotherapy are both viable options for curative intent treatment and selection of the primary modality may relate to underlying patient and disease characteristics.

Background:
Radiotherapy is an alternative to surgery for patients with Stage I and II non-small cell lung cancer (NSCLC) who are medically inoperable or refuse surgery. However, the use of curative radiotherapy in these patients is variable. The aim of this study is to document radiotherapy patterns of care in Stage I and II NSCLC patients at three institutions in Sydney, Australia and evaluate reasons for palliative rather than curative treatment. Stereotactic ablative body radiotherapy (SABR) is a newer treatment technique. However, eligibility for this depends on tumour size and location. A secondary aim is to identify the proportion of patients who would be suitable for SABR treatment.

Method:
Electronic oncology databases at three institutions were queried to retrieve data on patients with Stage I or II NSCLC, who did not undergo surgery and were seen in a radiation oncology clinic between 1/1/2008 to 31/12/2014. Curative radiotherapy was defined as a minimum dose of 50Gy for conventional and 48Gy for SABR. Suitability for SABR was defined as peripheral tumours less than 5cm in size. Factors associated with curative treatment were determined using univariate and multivariate analyses and variables were compared using Chi-square and t-test.

Result:
There were 315 patients, with a median age of 77 years (30-93). Two-hundred-and-five (65%) had Stage I and 110 (35%) Stage II NSCLC. Eastern Cooperative Oncology Group performance status (ECOG PS) at first clinic visit was 0-2 in 252 (80%) patients. Two-hundred-and-six (65%) and 151 (48%) had pulmonary and cardiovascular comorbidities, respectively. Seventy-six (24%) patients received no radiotherapy, 58 (18%) palliative radiotherapy and 178 (56%) curative radiotherapy. Use of curative radiotherapy varied from 43% to 81% between the three institutions and increased from 51% during 2008-2011 to 64% during 2012-2014. The main reasons for receiving palliative or no radiotherapy were chronic obstructive pulmonary disease (COPD) or poor pulmonary function (26%) and comorbidities other than COPD or cardiovascular comorbidities (22%). Excluding patients with N1 disease, 25% who received palliative radiotherapy, 42% of patients who received no treatment and 37% of patients who received conventional radiotherapy were suitable for SABR treatment. ECOG PS (p=0.011), FEV1% (p=0.025) and institution (p=0.001) were significantly associated with use of curative radiotherapy in both univariate and multivariate analyses.

Conclusion:
Use of curative radiotherapy varied among cancer institutions. Patient factors were the predominant reason for palliative treatment. A significant proportion of patients who underwent palliative or no radiotherapy were potential candidates for SABR treatment.

Background:
The purpose of this study to evaluate the clinical outcome of proton beam therapy (PBT) for early stage lung cancer or small lung lesions clinically diagnosed as primary lung cancer in Japan.

Method:
Between April 2004 and December 2013, 669 patients with 682 tumors with histologically or clinically diagnosed Stage I non-small cell lung cancer (NSCLC) according to the 7th edition of UICC were treated with PBT. The medical record and imaging studies were retrospectively reviewed to analyze survivals, local control, and toxicities.

Result:
Four hundred eighty-six (72.6%) of 669 patients were men, with the median age of 76 years (range, 42 – 94 years). Tumors were distributed according to T-stage as follows: T1a (265 tumors, 38.9%), T1b (216 tumors, 31.7%), and T2a (201 tumors, 29.4%). Tumors were distributed according to histology as follows: squamous cell carcinoma (139 tumors, 20.4%), adenocarcinoma (277 tumors, 40.6%), others (32 tumors, 4.7%), and not proven (234 tumors, 34.3%). As for operability, 351 patients were found to be operable, 294 were inoperable, and 24 patients were unknown for operability. The median biological effective dose (BED) of PBT was 109.6 Gy RBE (range, 74.4 – 131.3 Gy RBE). The median follow-up time was 38.2 months (range, 0.6 – 154.5 months) for all patients. The 3-year overall survival (OS), progression-free survival (PFS), and local control were 79.5%, 64.1%, and 89.8%, respectively. Radiation pneumonitis ≥ Grade 3 according to CTCAE v3.0 was observed in 12 (1.8%) patients. The 3-year OS and PFS for 440 patients with histologically confirmed NSCLC were 78.0% (80.7% for IA, 73.0% for IB, p = 0.042) and 66.4% (71.9% for IA, 55.9% for IB, p = 0.0038), respectively. The 3-year OS and PFS for 229 patients with clinically diagnosed NSCLC were 82.4% (86.0% for IA, 60.4% for IB, p = 0.045) and 69.6% (74.0% for IA, 42.6% for IB, p = 0.0052), respectively. The 3-year OS and PFS for 351 operable patients were 86.7% (88.8% for IA, 80.3% for IB, p = 0.096) and 70.6% (76.4% for IA, 52.8% for IB, p = 0.0028), respectively. The 3-year OS and PFS for 294 inoperable patients were 70.5% (74.1% for IA, 62.8% for IB, p = 0.046) and 56.6% (62.6% for IA, 44.6% for IB, p = 0.0062), respectively.

Conclusion:
PBT for early stage lung cancer is an effective treatment option with low incidence of severe radiation pneumonitis.

Background:
A randomised phase III clinical trial comparing Stereotactic Ablative Body Radiotherapy (SABR) with conventional radiotherapy for early stage lung cancer in peripheral location has been conducted in Australia and New Zealand under the auspices of the Trans Tasman Radiation Oncology Group (TROG). As SABR technology at the commencement of the trial was new to most centres in our region and the techniques used are complex and technologically challenging a credentialing program was developed for centres wishing to join the trial.

Method:
The credentialing program used a prospective risk management approach with high risk elements considered to be (i) the ability to create a plan that meets all dosimetric constraints, (ii) the dose calculation in the presence of inhomogeneities and (iii) the management of motion. Participating centres were asked to develop treatment plans for two test cases made available in DICOM format, and inhomogeneity corrections and dose delivery was assessed during a site visit using a phantom with moving inserts (modified Modus Quasar).

Result:
Site visits were conducted in 17 Australian and 3 New Zealand radiotherapy facilities. All centres were able to produce acceptable plans for both test cases, in particular after the protocol was amended to allow delivery of 48Gy in 4 fractions for lesions close to the chest wall in addition to the original trial arm of 54Gy in 3 fractions. The tests conducted during site visit with lung and air inhomogenieties confirmed known shortcomings of the AAA algorithm for dose calculation behind the inhomogeneity. The dose was assessed using an ionisation chamber and radiochromic film in a stationary and moving cylinder (sinusoidal motion, 1cm amplitude, 4s period) in the phantom for a typical treatment delivery including at least one non-coplanar beam. The measurements confirmed in an end-to-end test that all participating centres were able to deliver SABR with the required accuracy. Overall, the site visit took 3 hours of time on the treatment unit and was well received by participating staff. For several facilities it proved to be a useful step in the process of developing a SABR program.

Conclusion:
The credentialing process including a site visit documented that participating centres were able to deliver dose to a phantom as required in the trial protocol. It also gave an opportunity to provide education about the trial and discuss technical issues such as 4D CT, small field dosimetry and patient immobilisation with staff in participating centres.

Background:
Follow-up recommendations after stereotactic body radiation therapy (SBRT) for early non–small cell lung cancer (NSCLC) patients are not well defined. We analyzed the prognostic value of early response evaluated by FDG-PET/TC scan.

Method:
Between April 2012 and September 2016, 63 primary lung lesions in unfit patients or who refused surgery were treated with SBRT. Three risk-adapted fractionation schemes that ensure DBE>100Gy were considered: 3x18Gy, 5x11Gy and 8x7.5Gy. In all patients two FDG-PET/TC scans were performed: one before the SBRT treatment and another one a month after the completion of the treatment. Changes in FDG-uptake were evaluated. We considered complete response (CR) when the FDG-uptake was normalized, partial response (PR) when there was a decrease and stable disease (SD) when no modification was observed. Local control (LC), cause-specific survival (CSS) and overall survival (OS) were analyzed according to response.

Result:
With a median follow-up of 16 months; LC, CSS, and OS at 2 years were 100%, 91% and 64%, respectively. We correlated the FDG-PET/TC response at one month with LC and OS at 2 years. The FDG-PET/CT response at one month was not related to LC at 2 years, which was above 95% for all patients. For patients who achieved CR at one moth, OS and CSS at 2 years was both 100% while patients with PR was 49% and 86% respectively and for those with SD were 63% and 92% respectively (Figure 1). Figure 1



Conclusion:
Our results suggest that an early complete response on FDG-PET/TC may be a good predictor factor of survival. Based on the grade of early PET-CT response, patients for stricter monitoring could be selected. Longer follow-up to confirm these findings is necessary.

Background:
Traditionally, patients with medically inoperable early stage non-small-cell lung cancer (NSCLC) were treated with conventional radiotherapy of 60 Gray (Gy) over 6 weeks. comparable results as surgery. Primary objective of this review was to evaluate the clinical outcomes of stage I NSCLC patients after SBRT, including 1-year, 3-year and 5-year local control, overall survival and cancer-specific survival rates. Secondary objectives were acute and late toxicities.

Method:
Patients with stage I NSCLC (tumor size ≤5cm), ECOG performance status ≤2, who were not surgical candidates (either inoperable or patient refusal) were treated by SBRT in our hospital since 2012. Tumor motions with respiratory cycles were accounted for by using four-dimensional computerized tomography. A margin of 5mm (1cm superior-inferior) was used to generate the planning target volume. A total dose of 50 or 60 Gy in 5 fractions over 2 weeks was given, depending on the location of tumors. Survival plots were produced by Kaplan-Meier estimate.

Result:
A total of 40 patients were included (male=23, 57.5%; female=17, 42.5%). Median age was 75 (range: 42-85). Half (n=20) of patients had stage Ia disease. Median gross tumor volume and planning target volume were 15.80cm3 (range:2.80-56.80cm3) and 47.6cm3 (range:12.50-117.70cm3) respectively. No concomitant systemic therapies were used. After a median follow-up of 23.6 months (range:3.5-68.6 months), twelve patients died (4 were non-cancer related). Median overall survival (OS) was 35.5 months (range:3.5-68.6 months). The 1-year, 3-year and 5-year OS was 92.4%, 48.2% and 37.2, while the cancer-specific survival was 94.7%, 53% and 40.9% respectively. Nine (22.5%) had local progressions, giving rise to the 1-year and 5-year local control rate of 87.2% and 75.3%. Acute and late toxicities occurred in 35% (n=14) and 17.5% (n=7) of patients but all are grade 1 only.

Conclusion:
SBRT in early stage I NSCLC achieves high local control rate and overall survival comparable to radical surgery. Comparing to conventional radiotherapy, SBRT is better tolerated and reduces the treatment period from 6 to 2 weeks. SBRT should be the preferred treatment for early stage NSCLC when radical surgery is not to be considered.

Background:
The standard care for Stage I non small cell lung cancer (NSCLC) is surgical resection, but stereotactic body radiotherapy (SBRT) can be an alternative treatment option, especially for patients with comorbidities. However, it is difficult to compare the outcomes of SBRT with surgical resection because their characteristics are so different, and the risk factors for recurrence after SBRT are not fully understood. In this study, we report pretreatment clinical characteristics and CT findings in patients treated with SBRT, and reviewed patients underwent surgery with similar tumors.

Method:
Between January 2012 and December 2015, patients treated with SBRT for cT1-2N0M0 NSCLC and 218 patients who underwent surgery for cT1b-2N0M0 NSCLC in our institution were analyzed.

Result:
During the study period, 88 patients were treated with SBRT. The 3-year disease free survival (3-year DFS) for all patients was 81.2%. There were 15 cases of recurrences (9 cases of lymph node recurrences, 8 cases of distant metastases and 2 cases of local recurrence. 4 cases were both lymph node and distant metastases). There was no recurrence among the patients with no more than 1cm of consolidation (cT1a or less according to the 8th edition of the Union for International Cancer Control TNM classification) and all recurrent cases were with solid pattern predominant tumors (maximum consolidation diameters were more than 50% of tumor diameters) based on CT findings. Then we evaluated outcomes and clinical characteristics of patients who were treated with SBRT or underwent surgery for cStage I, cT1b or more and solid predominant NSCLC during the same period. 61 patients were treated with SBRT and 218 underwent surgery (190 cases of lobectomy, 21 secmentectomy and 7 wedge resection). Among clinical characteristics, smaller tumor sizes tend to be treated with SBRT (average sizes were 2.25 and 2.57 cm respectively, p=0.055). The mean age was significantly higher in SBRT group (78.5 vs 68.0, p<0.001). Surgical resection was associated with improved DFS (3-year DFS 84.4% vs 73.4%, p=0.004) and lymph node metastasis was found in 34 cases (15.6%) pathologically in patients underwent surgery, suggesting they are incurable with SBRT.

Conclusion:
The main limitations of this study are the small number of cases and different patient characteristics. Taken together, our data suggesting SBRT is acceptable for patients with cT1a or less, cStage I NSCLC, and surgical resection is recommended for patients with more advanced NSCLC.

Background:
Plasma free amino acid (PFAA) levels are known to change in patients with malignant diseases. We have developed AminoIndex[TM] Cancer Screening (AICS[TM]) using “AminoIndex Technology”, which is a multivariate analysis of PFAA concentrations in various cancer patients and healthy controls. In Japan, AICS[TM] is now commercially available for simultaneous screening of seven cancer types, including lung cancer. The lung cancer specific AICS [AICS (lung)] are classified as rank A (AICS values: 0.0–4.9), rank B (5.0–7.9), or rank C (8.0–10.0); the closer to rank C, the higher risk of lung cancer. The aim of this study was to evaluate post-operative changes of AICS (lung) in patients who underwent curative surgical resection for lung cancer, as well as the associations of these changes with post-operative cancer recurrence.

Method:
The subjects were lung cancer patients with pre-operative AICS (lung) rank B-C, 44 patients (rank C; 29 cases, B; 15 cases) who underwent surgical curative resection. The pathological stage was 29 stage I, 8 stage II and 7 stage III. AICS (lung) was measured within 1 week prior to surgery and from 1.2 to 5.5 years after surgery, and the relationship between fluctuation before and after surgery and post-operative recurrence was analyzed.

Result:
Post-operative AICS (lung) ranks and values decreased in 52% (23/44) and 82% (36/44), respectively. For the pre-operative AICS (lung) rank C patients, post-operative AICS (lung) ranks and values decreased in 52% (15/29) and 86% (25/29), respectively. All 12 patients who had recurrence had a pre-operative AICS (lung) rank C. Among the 7 patients had recurred at the time of post-operative AICS (lung) measurement, 6 patients remained AICS (lung) rank C after surgery and 1 patient was rank B after surgery. On the other hand, among 5 patients in which recurrence was observed after post-operative AICS (lung) measurement, 4 patients remained post-operative AICS (lung) rank C and only 1 patient was rank B.

Conclusion:
Most patients had a decrease in the AICS (lung) rank and value after curative surgical resection. However, ten of 15 patients who had both pre- and post-operative AICS (lung) rank C had recurrence after surgery, suggesting the association between pre- and post-operative change in AICS (lung) and recurrence after lung cancer surgery. Pre- and Post-operative AICS (lung) measurement may be able to predict high-risk cases with post-operative cancer recurrent.

Background:
The purpose of this study is to compare the surgical outcomes after segmentectomy versus wedge resection in patients with clinical stage I non-small cell lung cancer (NSCLC) who were unfit for lobectomy.

Method:
Between April 2007 and December 2015, 99 patients with clinical stage I NSCLC who were considered unfit for lobectomy and underwent sublobar resection were identified. Propensity scores were estimated including variables such as age, sex, smoking history, solid tumor size, SUVmax of the tumor, preoperative pulmonary functions, and Charlson comorbidity index. Surgical outcomes were compared between patients who underwent segmentectomy and those who underwent wedge resection.

Result:
Thirty-nine patients underwent segmentectomy and sixty patients underwent wedge resection. Operation time (median, 169 min vs. 72.5 min, P <0.001) and blood loss (median, 84 g vs. 10 g, P = 0.001) were significantly different between the procedures. Severe postoperative complications (> Grade IIIa) was more frequently in segmentectomy (15.4%) than in wedge resection (3.3%, P = 0.054). Propensity score-adjusted multivariable analysis showed that operative procedure was an independent predictive factor for severe postoperative complication (segmentectomy, odds ratio = 8.18; P = 0.021). Overall survival (OS) and recurrence-free survival (RFS) were not significantly different between segmentectomy (3 y-OS, 79.1%, 3 y-RFS, 77.7%) and wedge resection (3 y-OS, 86.3%, 3 y-RFS, 68.5%; P = 0.81, P = 0.91, respectively). Propensity score-adjusted multivariable Cox analysis revealed that operative procedure was not an independent factor for OS (segmentectomy, hazard ratio = 1.7, P = 0.24) or RFS (segmentectomy, hazard ratio = 1.1, P = 0.82). In propensity score matching method, similar results were observed.

Conclusion:
Segmentectomy is more toxic, but provides similar prognosis compared with wedge resection. Wedge resection may be an optimal procedure in patients with clinical stage I NSCLC who were considered unfit for lobectomy.

Background:
Small pulmonary nodules have been detected frequently by computed tomography (CT). Lung cancers with cavity formation are also easily detected. There are a few reports focused on the cavity wall, although cancer cells exist along the cavity wall, not inside. We evaluated the impact of cavity wall thickness on prognosis and assessed the clinicopathological features in non-small cell lung cancer (NSCLC) with cavity formation.

Method:
Between 2005 and 2011, 1313 patients underwent complete resection for NSCLC. Of these cases, we reviewed 65 patients (5.0%) diagnosed with NSCLC with cavity formation by chest CT. We classified the patients into three groups based on the maximum cavity wall thickness, namely, ≤ 4 mm (Group 1, 8 patients), > 4 mm and ≤ 15 mm (Group 2, 33 patients), and > 15 mm (Group 3, 24 patients).

Result:
The number of patients with pathological whole tumor size > 3 cm was 2 (25%) in Group 1, 17 (52%) in Group 2, and 23 (96%) in Group 3 (p < 0.001). Cases with lymph node metastasis were 0 (0%) in Group 1, 5 (15%) in Group 2, and 10 (42%) in Group 3 (p = 0.016). The 5-year overall survival (OS) rates were 100% in Group 1, 84.0% in Group 2, and 52.0% in Group 3, with significant differences between Group 1 and Group 3 (p = 0.044) and between Group 2 and Group 3 (p = 0.034). In univariate analysis, neither whole tumor size nor lymph node metastasis was a prognostic factor for OS (p = 0.505, p = 0.274). Only cavity wall thickness was a significant prognostic factor by multivariate analysis (p = 0.009).Figure 1



Conclusion:
Maximum cavity wall thickness was an important prognostic factor in NSCLCs with cavity formation, comparable with other established prognostic factors.

Background:
Some pulmonary nodules are so small that we surgeons can’t perceive by touch nor visually recognize during operation. For resection of such small nodules we have been undergoing preoperative lipiodol markings for 7 years. The appearance of the marking-spots on computed tomography (CT) is classified into 3 types in a previous research [H Miura, et al: CT findings after lipiodol marking performed before video-assisted thoracoscopic surgery for small pulmonary nodules. Acta Radiologica, 2016, Vol. 57(3) 303-310] .

Method:
CT-guided lipiodol marking for 121 nodules were performed in 115 patients before surgery. Lipiodol was injected using a 23-guage needle near the nodules. During surgery, the location of nodules could be detected using C-arm-shaped fluoroscopic unit as radiopaque spots and we resected them. We classified the CT appearance of the lipiodol marking retrospectively into 3 types; Dense, Punctate and Unclear as the previous research.

Result:
All nodules were successfully resected on the same day as marking performed. The results of pathological examination were 68 lung cancers (56%), 38 metastatic lung tumors (31%) and 15 others (12%). The classification of lipiodol spots resulted as following. 75 spots (62%) were Dense, 45 spots (37%) were Punctate, and 1 spot (0.8%) was Unclear. There was no significant difference in the average operative duration between the group of Dense and Punctate. Patients with smoking history occupied 67% of the Punctate group, on the other hand only 37% of the Dense group had smoking history (P<0.0001).

Conclusion:
Lipiodol marking for small pulmonary nodules are helpful and effective, especially for diagnosis and treatment of early stage lung cancer. Smoking history of patients has something to do with the CT appearance of lipiodol spots. Regardless of how marking shape is, difficulty of surgery doesn’t change in the point of operative duration.

Background:
Long term pulmonary function after lung resection is related with quality of life in patients with lung cancer. Previous studies found that impaired pulmonary function persisted for at least 3 months after lung resection followed by gradual restoration, time-dependent improvement. This study aimed to identify factors associated with delayed recovery to predicted FEV1 calculated with perfusion scan or segment counting method in non-small-cell lung cancer patients after lobectomy.

Method:
Medical records of seventy-four patients with non-small-cell lung cancer who underwent lobectomy and preoperative perfusion scan was retrospectively reviewed. Achieving 100% of predicted FEV1 calculated with perfusion scan was defined as event, and time to event was analyzed with parametric survival model with Weibull distribution handling interval censored data. Another survival model was elucidated with definition of the event as achieving 100% of predicted FEV1 calculated with segment counting method.

Result:
In a multivariable survival model (Perfusion scan), LUL lobectomy had shorter accelerated failure time value compared with RUL lobectomy (p=0.0328), and ‘Adjuvant chemotherapy before event’ had longer accelerated failure time value (p=0.0202) after adjusting the variable ‘CTD indwelling duration after operation more than 10 days’. In another multivariable survival model (segment counting method), LUL lobectomy had shorter accelerated failure time value compared with RUL lobectomy (p<0.001), and ‘Adjuvant chemotherapy before event’ had longer accelerated failure time value (p=0.034) after adjusting the variable ‘CTD indwelling duration after operation more than 10 days’ and ‘pneumonia within 1 month after operation’.

Conclusion:
LUL lobectomy showed faster recovery to predicted FEV1 than RUL or RML lobectomy. Adjuvant chemotherapy had delayed recovery to predicted FEV1.

Background:
More and more pulmonary ground-glass opacity (GGO) were detected and surgically resected, but the resection extent remains unconcluded, especially for those micro- small lung cancer (≤1cm) (mi-SLC), some are adenocarcinoma in situ (AIS), some minimally invasive adenocarcinoma (MIA), both belonging to early stage lung cancer. Wedge resection may be enough for curing lung MIA.

Method:
Case 1: Woman, aged 59 in Nov 2013, right middle lobe pure GGO 1.0cm, peripheral; sickly weak for years; anti-inflammatory strategy used, GGO size no change. Case 2: man, aged 64 in Oct 2013, right upper lobe mixed GGO 1.0cm, peripheral; with hypertension and chronic bronchitis for years; anti-inflammatory strategy used, the GGO showed a little increased one month later. Both patients were referral to China Medical University Lung Cancer Center for surgical resection, “miMRST”, minimally invasive small incision, muscle- and rib-sparing thoracotomy, minimally invasive lung cancer radical surgery, was scheduled.

Result:
About 10cm lateral chest incision, with the latissimus dorsi and serratus anterior muscles protected, no rib cut needed, was enough for most lung cancer resection and mediastinal lymph node dissection, no need for the surgeon’s hands entering into the thoracic cavity, not as large-incision standard posterolateral thoracotomy (SPLT) and modified muscle and rib sparing thoracotomy (MRST) usually do. For Case 1, right middle lobe wedge resection was undergone first, frozen pathological diagnosis was atypical adenomatous hyperplasia (AAH), carcinoma should be excluded by following wax slide pathology. For Case 2, right upper lobe wedge resection was performed, frozen diagnosis was AAH, carcinoma should be excluded by following wax slide pathology. Both patients recovered much better and quickly than other patients who underwent SPLT. Postoperative pathology was MIA for both cases. Considering both in a status of sickly and weak health condition, no further tratment was used. Follow-up: both patients are living healthilly, in their 4th year postoperatively, obviously more healthy and stronger than before; no sign of recurrence and metastasis.

Conclusion:
Even though lobectomy and systematic mediastinal lympph node dissection still remains the standard surgical procedure for non-small cell lung cancer, more and more limited (wedege) resection for early stage lung cancer, including SLC and mi-SLC, especially MIA, showed a better outcome. Wedge resection is of first choice for these aged, sickly and weak patients, further, wedge resection might be enough for curing mi-SLC, eapecially those GGO MIA. Prospective observation is needed. (This study was partly supported by Science Foundation of Shenyang City, China, No. F16-206-9-05)

Background:
In the new TNM classification (8th), significant revision was made for pathological (p) T descriptors. Tumors, 3 cm or less in size, measuring invasive size, were subclassified into five categories, Tis, T1mi, T1a, T1b and T1c, termed T0-1 tumors here. Purpose of this study was to examine clinical importance of new pT descriptors and apply to indication criteria of limited surgery for pT0-1 lung adenocarcinoma.

Method:
We retrospectively reviewed pathological data of lung adenocarcinomas surgically resected between 2011 and 2016 at our institute, and reclassified them according to the new TNM classification. We found 874 tumors classified as pT0-1. We compared invasion-related factors such as lymph node (LN) metastasis, lymphatic and /or vascular invasion (LVI) and existence of lepidic component among the five T categories.

Result:
There were 154, 196, 195, 255 and 74 cases in the pTis, T1mi, T1a, T1b and T1c category, respectively. LN metastasis was found in 50 of 874 (6%) cases. LN metastasis rates were 0%, 2%, 10% and 27% in T1mi, T1a, T1b and T1c, respectively. In 108 of 874 cases, invasive size was equal to whole tumor size, meaning that they contain less of lepidic component. LN metastasis rates of the 108 cases were 13%, 13% and 27% in T1a, T1b and T1c, respectively, implying that LN metastasis of T1a diseases were much often with less lepidic component. In the 824 cases without LN metastases, LVI was observed in 156 (19%) cases. LVI rates were 1%, 21%, 39 and 46% in T1mi, T1a, T1b and T1c, respectively. In 89 of 824 cases, invasive size was equal to whole tumor size. LVI rates of the 89 cases were 31%, 54% and 54% in T1a, T1b and T1c, respectively, meaning that LVI rates were more frequent in T1a-c diseases with less lepidic component.

Conclusion:
LN metastasis was rare (2%) in T1a diseases, and they may be good candidates for limited surgery such as segmentectomy. However, T1a diseases with less lepidic component, showing 13% of LN metastasis, may be difficult to cure by limited surgery. On the other hand, in T1b and T1c diseases, LN metastasis rates did not significantly differ between cases with and without lepidic component. T1mi diseases, rarely showing LVI, can be managed same as Tis and cured by partial resection. Taken together, it is the most important to predict pathological T descriptors preoperatively accurately by imaging analysis for T0-1 lung adenocarcinoma.

Background:
The diameter of the solid part of the tumor in a computed tomography (CT) image determines the clinical T descriptor of the new TNM staging system in non-small cell lung cancer (NSCLC). The purpose of this study was to investigate the appropriateness of the clinical T descriptor (cT) in respect to postoperative prognosis.

Method:
This retrospective study included consecutive patients who underwent complete resection in Oita University Hospital between 2006 and 2014 and those who underwent complete resection in Kyushu University hospital between 2003 and 2012. The complete clinical data of 1061 NSCLC patients were available for prognostic analyses. The whole tumor size (TS) in diameter and solid-part size (SPS) in diameter were measured by the thin-section CT image before surgery. The tumors with SPS/TS ratio (STR) = 0, those with 0 < STR < 100, and those with STR = 100 were defined as pure ground glass tumors (GGT), part-solid tumors (PST), and solid tumors (ST), respectively. The survival curves were estimated according to the Kaplan-Meier method and were assessed by the log-rank test.

Result:
The tumors included 809 adenocarcinomas (Ad), 197 squamous cell carcinomas, 31 large cell carcinomas, 18 adeno-squamous cell carcinomas, and 6 other types of tumor. The 5-year survival rate of patients according to the new cT descriptor (version 8) were cTis, 97.6%; cT1mi, 90.7%; cT1a, 87.8%; cT1b, 81.5%; cT1c, 72.8%; cT2a, 69.6%; cT2b, 55.6%; cT3, 55.0%; and cT4, 23.4%. In analyses of Ad patients, the 5-year survival rate of patients according to the whole tumor size were >0 -10 mm, 89.9%; >10 -20 mm, 89.1%; and >20 -30 mm, 84.1%, and that according to the solid part size were 0mm, 97.6%; >0 -10 mm, 91.9%; >10 -20 mm, 84.8%; and >20 -30 mm, 80.8%. The new cT descriptor predicted patient prognosis more effectively than the old cT descriptor of whole tumor size. Postoperative 5-year survivals of the GGT, PST and ST of Ad patients were 97.6%, 89.0%, and 76.3%, respectively (P<.0001). In analyses of the small-size PST (≤ 3 cm), the new cT descriptor did not adequately predict patient prognosis (P=.458).

Conclusion:
The new cT descriptor is a better prognostic indicator than the old cT descriptor in NSCLC. However, patients with small-size PST had a significantly better prognosis than those with ST Ad. Additionally, the new cT descriptor failed to adequately predict the prognoses of the patients with small size PST adenocarcinoma.

Background:
Video-assisted thoracoscopic surgery (VATS) has been rapidly gaining popularity worldwide in the treatment of early stage non–small cell lung cancer (NSCLC) because it is potentially less invasive. However, there has not been a large randomized controlled trial (RCT) to prove its superiority over thoracotomy. Therefore, a large multicenter RCT in China was designed and initialed in order to verify the role of VATS.

Method:
A non-inferiority phase 3 randomized controlled trial was undertaken at five tertiary centers in China. Patients aged 18-75 years who were diagnosed of clinically early-stage NSCLCs were randomized in a 1:1 ratio into VATS and thoracotomy groups. Radical lobectomy plus mediastinal lymph node dissection was the standard surgery as per protocol. The short-term outcomes including acute phase inflammatory reaction, performance status, postoperative pain, respiratory function and quality of life would be analyzed and reported in this article. Patients continue to be followed up for the primary endpoints (5-year overall and disease-free survival). This study is registered with the ClinicalTrials.gov, number NCT01102517.

Result:
Between January 2008 and March 2014, 508 patients were recruited and 481 were eligible for randomization. 236 patients were randomly assigned to the VATS group, while 245 to the thoracotomy group. Finally, 425 were eligible for analyses (215 and 210, respectively). For acute phase inflammatory reaction assessment, cytokines including IL-2、IL-4、IL-6、IL-10、TNF-α and IFN-γ were tested in different time points within 48 hours postoperatively. No significant difference was found between the 2 groups except IL-6 (P=0.0411). Patients who received VATS procedures had better daily Karnofsky performance status in the first week (P=0.0029). Visual analogue scale (VAS) was applied for pain assessment at the time points of postoperative day 1 to 7 and every 3 months within the first year. Our study showed VATS was superior to open procedures in pain control within the first week after surgery (P=0.0274). However, this benefit diminished within the year. Spirometry was tested at the time points of day 7, 1 and 3 months postoperatively. Both FEV1 and FVC were better preserved in VATS group throughout the time (P=0.0005). Finally, lung cancer symptom scale (LCSS) was used to evaluate the quality of life, and there was no significant difference demonstrated between the 2 groups within the first year after surgery.

Conclusion:
The short-term outcome of our trial has demonstrated that VATS may be superior to thoracotomy in the surgical treatment for NSCLC in terms of short-term performance status, pain control and respiratory function preservation.

Background:
Complete surgical resection is the standard treatment of stage I NSCLC. The aim of the current study was to evaluate overall survival of T1N0 NSCLC after complete resection.

Method:
The Institut de Cardiologie et Pneumologie de Quebec Biobank was queried for all patients with pathological T1N0M0 NSCLC who underwent complete (R0) surgical resection between November 1999 and February 2017. Survival was examined using the Kaplan-Meier method with log rank analysis. Significance was set at p≤0.05.

Result:
We identified 1071 eligible patients, 624 (58%) were female with mean age of 64±9y, 763 (71%) were adenocarcinoma and 183 (17%) were squamous cell carcinoma. Regarding surgical modality, 285 (27%) patients underwent sublobar resection, 772 (72%) lobectomy or bilobectomy and 14 (1%) pneumonectomy. The 30-day mortality of the cohort was 0.3% (3 patients). During 17 years of follow-up, a total of 253 (24%) patients died; of these events, 160 (63%) were cancer-related. Median OS of the cohort was 12.8y (CI 11.2 – 14.2). When comparing lobar versus sublobar resection, median OS was 12.8y and 8.7y respectively (HR 1.92; CI 1.45-2.55, p=<0.0001) (Figure 1). Figure 1: Overall survival according to type of resection Figure 1



Conclusion:
In our institutional database study, median OS after complete resection of T1N0 NSCLC was 12.8y. Patient undergoing lobectomy had a survival advantage over patients who had sublobar resection. Until more definitive data confirms our findings, patients with T1N0M0 disease should be treated with lobectomy.

Background:
The operative method in ground glass pulmonary nodules is controversial. The prognostic value of histological subtypes in resected node-negative small-sized lung adenocarcinoma has not been widely investigated. This study aim to investigate the prognostic factors in patients with resected small ground glass nodules with consolidation/tumor (C/T) ratio of 0.5 or less determined by chest computed tomography.

Method:
A total of 377 patients with completely resected node-negative lung adenocarcinoma of 3cm or smaller and C/T ratio of 0.5 or less were included in the study. Prognostic factors for overall survival (OS) or probability of freedom from recurrence (FFR) were investigated.

Result:
The 5-year OS and probability of FFR were 93.7% and 91.5%, respectively. During follow-up, 15 (4.0%) patients developed recurrence. Univariate analysis showed that order age (P = 0.008) and greater tumor size (P = 0.008) had significantly worse OS. Patient underwent sublobar resection had significantly worse OS than those with lobectomy (P = 0.003). Greater tumor size (P = 0.006) and sublobar resection (P = 0.002) were still significant prognostic factors for worse OS in multivariate analysis. Univariate analysis showed that order age (P = 0.007), greater tumor size (P = 0.001), and micropapillary/solid predominant group (P = 0.002) had significantly lower probability of FFR. Operative method (sublobar resection vs. lobectomy) was not a significant prognostic factor for FFR (P = 0.726). Older age (P = 0.016), greater tumor size (P = 0.026), and micropapillary/solid predominant group (P = 0.043) still had significantly lower probability of FFR in multivariate analysis.

Conclusion:
For patients with completely resected node-negative lung adenocarcinoma of 3cm or smaller and C/T ratio of 0.5 or less, greater tumor size was a poor prognostic factor for both OS and probability of FFR. Sublobar resection was a significant prognostic factor for worse OS, but not probability of FFR. The new adenocarcinoma histopatholofgical classification has significant impact on recurrence in these patients.

Background:
We investigated the incidence and location of occult nodal metastasis (ONM) in patients who had undergone lobectomy and lymph node dissection for clinical stage I lung adenocarcinoma (ADC). We performed a risk regression analysis to identify any associated radiologic and pathologic factors.

Method:
Clinical stage I lung ADC patients (stage II and III were excluded by CT and FDG-PET/CT scans) who underwent lobectomy and systematic lymph node dissection (N=715, 2005-2011) were included in the analysis. ONM were defined as pathologically diagnosed metastatic lymph nodes that are not suspected to be involved by cancer on both CT and PET scans.

Result:
Among 715 patients, 75 (10.5%) ONM were identified: 64 (85%) hilar or peribronchial and 32 (43%) mediastinal. Multivariable risk regression analysis identified tumor diameter, SUVmax, and lymphovascular invasion as risk factors (P<0.01). The incidence of subcarinal lymph node (LN) metastasis was very low among patients whose primary tumors were in the right upper lobe or left upper division (N=1/439, 0.2%). Lower mediastinal LN metastasis was rarely identified only when the primary tumor was located in the right lower or left lower lobe (N=2/210, 1.0%).

Conclusion:
One in ten patients with clinical stage I lung adenocarcinoma showed occult nodal metastases, with the highest incidence in hilar lymph nodes; this observation may be relevant for clinicians when considering sublobar resection for these patients. Figure 1

Background:
Tobacco exposure is the main determinant of lung cancer. Data on tobacco exposure is often collected via self-reported smoking which is prone to misclassification. In the current study we sought to evaluate the extent to which cotinine, an objective measure of recent tobacco exposure, can inform on lung cancer risk.

Method:
We used data from 20 international cohorts and designed a nested case-control study including 5364 incident lung cancer cases and 5364 controls. Cases and controls were individually matched by age, sex, cohort, and smoking status (never, former, current). Cases from never and former smokers were intentionally oversampled. Centralised biochemical analysis was performed to measure circulating cotinine concentrations as an objective indicator of recent tobacco exposure. The association between cotinine and lung cancer risk was evaluated using conditional logistic regression. Discrimination between future lung cancer cases and controls was evaluated using receiver operating characteristic (ROC) curves.

Result:
Higher circulating cotinine concentrations were strongly associated with lung cancer risk among current smokers (OR~ per doubling in cotinine concentrations ~[~log2~]: 1.22, 95% confidence interval [CI]: 1.17-1.28, especially women (OR ~log2~: 1.35, 95% CI: 1.22-1.50). Among former smokers, positive associations between higher cotinine concentrations and lung cancer risk were driven by those participants with cotinine levels consistent with active smoking (OR ~log2~: 1.08, 95% CI: 1.05-1.11). We saw no association between cotinine concentrations and risk in never smokers, with the exception of men from the United States whose cotinine levels may be indicative of active smoking (OR: 1.17, 95% confidence interval [CI]: 1.02-1.34). Having cotinine levels consistent with active smoking (>115 nmol/L) was more common among self-reported former smokers (cases: 14.6%, controls: 9.2%) and less common among self-reported never smokers (cases: 2.7%, controls: 0.8%). A risk prediction analysis in current smokers indicated that circulating cotinine combined with self-reported smoking can provide a small improvement in discrimination between future lung cancer cases and controls in comparison to self-reported smoking alone (improved area under the curve for men: 2%, women: 4%).

Conclusion:
Cotinine as an objective measure of tobacco exposure was consistently associated with lung cancer risk among current smokers, especially women. Former and never smokers with cotinine levels consistent with active smoking also showed increased risk. For lung cancer risk prediction modelling among current smokers, cotinine combined with self-reported smoking performed slightly better than cotinine or self-reported smoking alone.

Background:
India has the second largest tribal population of the world next to the African countries. Despite remarkable world-wide progress in the field of diagnostic, curative and preventive medicine, still there are large populations of people living in isolation in natural and unpolluted surroundings far away from civilisation, maintaining their traditional values, customs, beliefs and myths. Hence the present study was conducted to assess the oral health status, treatment needs among the Malayali tribes in the Yelagiri hills, Tamil nadu. AIM: To assess the prevalence of head and neck cancers among the Malayali tribes, Yelagiri Hills, Tamil Nadu, India. To assess the association of tobacco use with head and neck cancers among the Malayali tribes, Yelagiri Hills, Tamil Nadu, India.

Method:
A cross-sectional descriptive study was conducted to assess the tobacco use and head and neck cancer prevalenceamong 660 Malayali tribes in the Yelagiri Hills. Inhabitants of the villages aged 18 to 75 years who were residing for more than 15years were included. Data was collected using a survey proforma which comprised of a questionnaire and WHO Oral Health Surveys – Basic Methods Proforma(1997). The collected data was subjected to statistical analysis.

Result:
.Results showed that among 660 study population, 57.7% had no formal education, 64.5% had indigenous brushing habits. 58% had the habit of tobacco, of which 37% were males and 21% were females. The percentage of oral mucosal lesions observed were as follows: 19.09% leukoplakia, 29% ulceration and 6% malignant tumor. 37% of the study populations had other abnormal conditions like candidiasis and OSMF. Prevalence of oral mucosal lesions in the study population was due to tobacco usage and alcohol consumption and lack of awareness regarding the deleterious effects of the products used.

Conclusion:
The oral health status of Malayali tribes was poor with high prevalence of periodontal disease and dental caries. Oral cancer and cancerous lesions were at a very high percentage. Regular oral examination by dental professionals, dental health education and motivation to maintain oral hygiene should be insisted to improve the oral health status of this community.

Background:
Armand Trousseau reported the concept of blood coagulation disorders accompanying malignancies in 1865. Currently, Trousseau syndrome is also defined as cerebral infarction due to malignant tumors. Among cerebral infarction patients with cancer, lung cancer (LC) and prostatic cancer are reported to be relatively likely to develop Trousseau syndrome. When it occurs, treatment for cancer is difficult, and prognosis is poor. We conducted a retrospective study of LC patients before and after the onset of cerebral infarction, respectively.

Method:
Among 1,185 cases of patients with LC from 2006 to 2016, we registered 15 cases with complications of cerebral infarction before or after LC detected. Fifteen patients were divided into two groups. One was a group of cerebral infarction before the detection of LC (A group) and the other was a group of infarction complication after LC detection (B group).

Result:
Patient characteristics of A group consisting of 8 cases and B group consisting of 7 cases were as follows, respectively: male/female, 5/3 and 3/4 cases; median age, 67.4 and 72.0 years; small cell lung cancer/squamous cell carcinoma/adenocarcinoma/large cell neuroendocrine carcinoma, 2/1/4/1 and 1/1/4/1 cases; stage I/II/III/IV, 2/1/1/4 and 0/0/2/5 cases; treatment intervention for LC, 8 and 3 cases. Median survival time was respectively 13.7 months for A group and 5.5 months for B group, although there was not significant in Kaplan-Meier survival curve.

Conclusion:
Lung cancer detected after or at the same time of cerebral infarction is considered to have better prognosis since early diagnosis and treatment against LC is possible.

Background:
DNA repair system uphold individuals’ genomic content from consistence impertinence implicated by continuous exposure to DNA damaging agents present in tobacco smoke, ionizing radiations,air pollution etc. BER (Base excision repair) and DSBR (Double strand break repair) are the two important pathways in this respect. However, polymorphic DNA repair genes might modulate the repair capacity and ultimately the survival.

Method:
Genotyping for the SNPs for genes OGG1, MUTYH, XRCC1, XRCC3, XRCC4, XRCC6, XRCC7.was done. Statistical analysis was done using MEDCALC. Logistic regression was used to evaluate the odds ratio. We even did use data mining tools MDR (Multi-dimensionality Reduction) and CART (Classification and regression tree analysis) to analyze the high interacting groups posing high risk. Survival analysis was done using Kaplan meier, and Cox regression analysis.

Result:
Statistical analysis revealed some interesting facts in relation to susceptibility. It was revealed that OGG1 Ser[326]Cys possessed a potent risk (OR=2.4, p= 0.0003) towards lung cancer whereas mutant genotype (GG) was protective towards lung cancer (OR=0.4, p=0.0185). Further analysis revealed XRCC1 Gln[632]Gln (OR=2.67, p=<0.001) depicted an overall high risk towards lung cancer. Histological analysis suggested mutant genotype in case of XRCC1 Pro[206]Pro implied a protective effect for SCLC subtype (OR=0.29, p=0.0017) on the contrary XRCC1 Gln[632]Gln showed a high risk in SQCC diseased group (OR=4.16, p=<0.0001). A high risk was observed on combining XRCC1 Gln[632]Gln with XRCC1 Pro[206]Pro (OR=5.6, p<0.0004) and Arg[194]Trp (OR=2.10, p=0.03). MDR analysis showed three factor model including XRCC1 206, 632, 280 was the best model (CVC=10, prediction error=0.34). Further Classification and Regression tree (CART) analysis revealed terminal node 1 carrying mutant of XRCC1 632 and wild type of XRCC1 280 represented the highest risk group. Further, survival analysis revealed a minor involvement of XRCC1 SNPs in survival. It was observed mutant genotype for XRCC1 Arg[399]Gln showed an insignificant better survival (MST=9.6). XRCC1 Gln[632]Gln showed a high hazards rate for SCLC subtype (H.R=0.26, p=0.05). An interesting finding of the study was related to chemotherapy regimen where Cisplatin/Carboplatin+ Docetaxel was observed to increase survival for XRCC1 399 mutant genotype (AA) (H.R=0.26, p=0.05). Cisplatin/Carboplatin+ Irinotecan increased survival in both heterozygotes (GA) and combined variants (GA+AA) (HR=0.22, p=0.014; H.R=0.23, p=0.012).

Conclusion:
To conclude the polymorphic DNA repair genes affect the susceptibility in lung cancer patients of North Indian population. However, the prognosis is not much altered. The analysis of individualized chemotherapy would help us to develop prognostic biomarkers for individualized therapy.

Background:
Lung cancer screening targets a high risk subgroup of the population, comprising current and ex-smokers. There are data to suggest that smokers view screening in a nihilistic way and perceive early detection to be of limited use and, as such, are less likely to consider screening participation. Other screening programmes have also shown markedly reduced uptake in those from the most deprived groups. Smoking rates and lung cancer incidence are highest in more socially deprived areas and lung cancer survival is worst in this group. An understanding of the key barriers to engagement with lung cancer screening is therefore vital prior to implementation of a national screening programme.

Method:
Focus groups were established in socially deprived communities within the East Midlands, United Kingdom, using community contacts. The Framework approach was used to analyse data into themes and sub-themes. To supplement these focus groups, questionnaires were developed and purposive sampling used to try to obtain a maximum number of views from a cross-section of the deprived communities. Participants were smokers or ex-smokers aged 40 years or older.

Result:
Recruitment to focus groups was very challenging, despite remuneration being offered. In total there were 13 participants and a further 56 people responded to questionnaires. Key barriers to screening participation identified were accessibility, with many participants preferring community-based drop-in sessions, perceived stigma and blame surrounding smoking and fear and nihilism regarding a lung cancer diagnosis. Although many were supportive in principle around the idea of screening, they felt that the way it was presented to them was crucial. Participants emphasised the importance of community engagement and the use of community leaders to talk to those who were eligible for screening in a way that they could understand and thus promote it rather than it coming from a medically qualified individual.

Conclusion:
This work gives an insight into some of the ideas and opinions around lung cancer screening and highlights some barriers that need to be addressed prior to implementation of a national screening programme. A combination of practical and emotional barriers, alongside the role of community engagement and education were identified as important. As lung cancer screening will focus on a high-risk group of smokers and ex-smokers, their perception of smoking stigma and blame will need to be addressed in a non-judgemental way and novel education and invitation material may need to be developed, delivered through community approaches, to promote screening in a positive light.

Background:
Lung cancer screening with low-dose CT (LDCT) decreased lung cancer mortality. However, its major limitation for high false positive rate was concerned. Tumor markers in combination with LDCT may increase its screening value for lung cancer.

Method:
In this prospective LDCT screening study, we enrolled subjects who were former or current heavy smokers (>30 pack-years) aged 50-70 years. The LDCT screening results were classified as negative, indeterminate, or positive (suspicious for primary lung cancer) based on the probability for lung cancer, mainly focused on nodule size and opacity at baseline LDCT and new or nodule growth at the follow-up LDCT. Serum CEA and Cyfra 21-1 were taken only from subjects with indeterminate and positive LDCT result with a cut-off level of 5 ng/ml and 4 ng/ml, respectively. These markers were followed with LDCT at least once a year. Positive tumor marker was defined as an abnormal level of either CEA or Cyfra 21-1.

Result:
Among 634 high risk subjects investigated, there were 70 subjects who had indeterminate LDCT and 22 subjects who had positive LDCT at initial screening cycle. A total of 17 lung cancer cases were diagnosed in 2 years, 9 from initial screening and 8 from follow-up cycles. The likelihood ratio of positive (LHR+) for lung cancer diagnosed in 12 months with positive tumor marker was 6.61 (p=0.003) among subject with indeterminate baseline LDCT, and 1.51 (p=0.670) among those with negative. LHR+ for lung cancer diagnosed after 24-month follow up was 6.31 (p<0.001) and 0.86 (p=0.881) respectively. The LHR+ for lung cancer diagnosed in 12 months among subjects with positive baseline LDCT, with positive and negative tumor marker was 69.44 (p<0.001) and 11.57 (p=0.015), respectively. The corresponding LHR+ for 24-month cancer was 13.61 (p<0.001) and 18.15 (p<0.001), respectively.The crude AuROC of parallel CEA/Cyfra 21-1 & LDCT and of CEA & LDCT for lung cancer screening in combination with LDCT were significantly higher than LDCT alone (0.76 VS 0.68, p=0.033 and 0.75 VS 0.68, p=0.038, respectively). The AuROC was also significantly higher after adjusted for age & smoking status (0.84 VS 0.80, p=0.019, and 0.84 VS 0.80, p=0.029, respectively)

Conclusion:
CEA in combination with LDCT significantly increased values for lung cancer screening in high-risk populations than using LDCT alone particularly in participants in patients with indeterminate baseline LDCT.

Background:
Retrospective, longitudinal, unicentric and cohort study that analyzes the demographic characteristics of the Mexican population with lung cancer and its association with wood smoke exposure.

Method:
The study had 123 patients pathologically diagnosed with lung cancer between January 2013 to January 2014 at the National Institute of Respiratory Diseases. The primary endpoint was the histological type of lung cancer and the secondary the rate of exposure to wood smoke. Two cohorts were analyzed, the first with patients without exposure to wood smoke and the second with no exposure.

Result:
The sample was formed by 68 men (55.3%) and 55 women (44.7%). They were smokers in 47.2% of the patients, with an average of 12.7 packs/year. The 47.15% had exposure to smoke from wood, with an average of 77.5 hours/year. The 88.6% had non-small-cell lung cancer (69.9% adenocarcinoma, 11.4% squamous and 7.3% other types), and 11.4% small cell lung cancer. The EGFR mutation was positive in 21% of adenocarcinomas. Patients with diagnosis of adenocarcinoma had the highest exposure to wood smoke (p<0.003). The cohort for exposure to wood smoke was significant for the development of lung cancer was 61 hours/year (p <0.001).

Conclusion:
The histological type of lung cancer most prevalent was adenocarcinoma, present in women with high exposure of wood smoke. The cohort of 61 hours/year was determined as a risk factor, the latter is not a predictor of EGFR mutation.

Background:
The National Lung Screening Trial (NLST) reported reduced all-cause and lung cancer- specific mortality among patients screened for lung cancer with low-dose computed tomography (LDCT). NLST subgroup analyses have shown even greater mortality reductions among socioeconomically disadvantaged racial minorities due to abnormalities other than pulmonary nodules discovered on LDCT. These incidental findings (IFs) often represent clinically significant undiagnosed disease in socioeconomically disadvantaged individuals. In early 2015, the Center for Medicare/Medicaid Services (CMS) added lung cancer screening as a preventive service benefit, which led to the widespread implementation of lung cancer screening programs across the country. Our study aims to quantify the association between insurance type, and the discovery of clinically significant undiagnosed disease on LDCT in high-risk smokers.

Method:
This retrospective cohort study provides a preliminary analysis of electronic health record data from The Ohio State University Lung Cancer Screening Program from September 2016 (when Medicaid coverage for lung cancer screening took effect) to March 2017. Eligible participants met CMS criteria for annual lung cancer screening with LDCT. The outcome of interest was major IFs discovered on LDCT (e.g. coronary artery disease, vascular disease, emphysema) not previously identified in the patient’s medical history. Logistic regression analysis was conducted to estimate odds ratios (ORs) to quantify the association between insurance type (Medicaid, Medicare/VA and private) and new incidental diagnosis (yes/no) adjusting for age, gender, race, and smoking history.

Result:
Data from130 patients who had a first-time lung cancer screening were analyzed. Two-thirds of participants were male, 39% were non-white and 57% were current smokers, with mean age of 63 years (SD=5.4). Almost 20% of participants (n=25) received Medicaid, 42% received Medicare/VA (n=54) and 38% had private insurance (n=49). Multivariable logistic regression analysis revealed that the odds of new incidental diagnoses were 8 times higher for patients with Medicaid versus private insurance (OR=8.0; 95%CI=2.6,24.9; p<0.001). The odds for IF were 3.5 times higher when comparing Medicaid versus Medicare/VA (OR=3.5; 95%CI=1.0,11.9; p=0.0430). Covariates age and race were significantly associated with a new IF (OR=2.9; 95%CI=1.03,8.4; p=0.0432 for age and OR=2.5; 95%CI=1.1,5.8; p=0.0328 for race), but gender and smoking history were not statistically significant.

Conclusion:
These results demonstrate increased clinically significant previously unidentified IFs among Medicaid-insured high-risk smokers, and suggest that LDCT lung cancer screening could provide an opportunity for secondary prevention by diagnosing occult disease in socioeconomically disadvantaged individuals. We will continue to monitor these data as more patients are screened and sample size is increased.

Background:
The cause and mechanism of lung cancer in “never smokers” are still unclear. Additionally, the onset of driver mutations (e.g., EGFR, ALK, KRAS, and RET) and the mechanism of their ethnic difference are unclear. Several studies have suggested that some trace elements may affect the onset of lung cancer. However, the effect of trace elements on lung cancer carcinogenesis is poorly understood. The aim of this study was to assess if trace elements may be the cause of carcinogenesis in lung cancer tissues of patients with lung cancer with a non-smoking history, driver mutations, or histology.

Method:
The study included patients with non-small cell lung cancer who had undergone surgical resection. For the measurement of trace elements, surgically resected formalin-fixed paraffin-embedded lung cancer samples were studied using particle induced X-ray emission analysis. In total, 54 elements were investigated in each sample. EGFR mutation, KRAS mutation, and ALK rearrangement were assessed using commercially available CLIA testing. Based on the pathology and driver mutation status, samples were classified into the following groups: lung adenocarcinoma (LADC) with EGFR mutation (LADC EGFRm+); LADC with KRAS mutation (LADC KRASm+); LADC without EGFR mutation, KRAS mutation, and ALK rearrangement (LADC wt); and lung squamous cell carcinoma (SCC). Tissues from 20 patients with a non-malignant disease (e.g., pneumothorax) were also analyzed for trace elements as controls.

Result:
In total, 80 patients with non-small cell lung cancer were included. The median patient age was 70years. Of the 80 patients, 30 (37.5%) were males and 72 (90%) had stage I/II disease. The levels of 6 trace elements were increased in the LADC wt group. Copper was increased in the LADC EGFRm+ group. Cobalt and zinc were increased in the LADC KRASm+ group. There were no differences in trace element levels between the SCC group and the control group.

Conclusion:
Trace elements may play a role in the pathology and molecular signature of lung cancer.

Background:
Several studies have reported an association between the BsmI polymorphism of vitamin D receptor(VDR) and lung ancer risk; however, the results are inconsistent. In this study, a meta-analysis was performed to assess the association between the BsmI polymorphism of VDR and susceptibility to lung cancer.

Method:
Published case-control and cohort-based studies from PubMed ,Embase, Wanfang, and CNKI were retrieved, and data were manually extracted. The odds ratios (ORs) and 95% confidence intervals (CIs) of the included studies were pooled. Begg’s and Egger’s test were used to evaluate publication bias.

Result:
Nine articles with 2343 cases and 1578 controls were included. The pooled effect size showed an association between the BsmI polymorphism and the risk of lung cancer (dominant model, OR: 0.58, 95% CI: 0.41–0.82; allele model, OR: 0.67, 95% CI: 0.52–0.86). In a subgroup analysis, a significant association between the BsmI polymorphism and low lung cancer susceptibility was detected among Asians (dominant model, OR: 0.47, 95% CI: 0.35–0.62; allele model, OR: 0.54, 95% CI: 0.41–0.71).

Conclusion:
The BsmI polymorphism was found to be significantly associated with a decreased risk of lung cancer, particularly in Asians.

Background:
In 2011, the National Lung Screening Trial showed that annual screening with low-dose computed tomography (LDCT) in high-risk patients reduced lung cancer mortality by 20%. The United States Preventative Services Task Force (USPSTF) now recommends lung cancer screening (LCS) for high-risk individuals (Grade B). Evidence from the National Health Interview Survey suggests that only 2-4% of eligible individuals are referred for LDCT, likely in part due to a lack of familiarity among primary care physicians with LCS guidelines. In this analysis, we sought to obtain a baseline acumen of providers’ knowledge and awareness about LCS and develop a series of interventions including embedding USPSTF criteria into electronic medical record (EMR) ordering to educate providers and facilitate more effective use of LCS for high-risk patients.

Method:
We surveyed internal medicine residents at the University of Illinois – Chicago (UIC) General Medicine Clinic (GMC) using paper surveys. The survey included six questions on USPSTF LCS guidelines. Next, educational efforts were addressed through a lecture, email reminders, and informational clinic flyers. The EMR order set was updated to include USPSTF criteria directed ordering. The number of appropriately ordered screens through GMC was tracked monthly. A post-intervention survey was distributed to evaluate if providers’ knowledge was improved by educational interventions.

Result:
Fifty-three IM residents were surveyed regarding LCS guidelines and appropriateness for LDCT screening. Of the respondents, 87% knew the correct test for screening was LDCT, 66% knew only smokers with >30 pack year history were eligible, 45% knew the minimum age criteria (55 years-old), 28% knew the maximum age (80 years-old), 42% knew interval to re-order screening for a negative test (1 year), and 38% knew the maximum time since quitting (15 years). Following the initial interventions, there was an increase in the volume of appropriately ordered LDCT screening tests ordered through GMC clinic (from 6.8 per month [May 2016 to September 2016] to 10.8 per month [October 2016 to April 2017]). Post-intervention knowledge assessment is underway and will be presented.

Conclusion:
Although LCS is recommended by USPSTF, there are gaps in knowledge about eligibility criteria among internal medicine residents. We present data that suggests using educational interventions and changes in EMR to increase awareness and knowledge is associated with an increase in appropriate usage of LDCTs for LCS. Ultimately, we plan to broaden these interventions to additional primary care clinics (eg., Family Medicine, Pulmonary) to improve proper use of LCS at our institution.

Background:
Nivolumab, an immune checkpoint inhibitor, exerts anti-tumor effects against various types of malignant tumor, whereas all usual care should be taken to its related adverse events including immune-related adverse events (irAEs). Of these events, nivolumab-induced pneumonitis, which infrequently develops but sometimes results in a fatal outcome, requires an early detection and prompt response. The purpose of this study was to understand the pathogenesis of nivolumab-induced pneumonitis, leading to avoiding its onset and increase in severity.

Method:
We retrospectively compared the clinicopathological characteristics between patients with malignant melanoma (M; n = 2) and those with non-small cell lung cancer (NSCLC) (L; n = 2), all of whom developed nivolumab-induced pneumonitis in Tokyo Medical University Hachioji Medical Center.

Result:
The patients with a median age of 64.5 years (L; 52 years: M, 73 years) were all males, and all NSCLCs consisted of adenocarcinoma histology. The median time from diagnosis to initiation of nivolumab treatment was 34.5 months (L; 33 months: M; 43 months), and that from the initiation of nivolumab treatment to the onset of pneumonitis was 15 days (L; 12.5 days: M; 139.5 days). Image findings showed a non-specific interstitial pneumonia (NSIP) pattern ameliorated by only treatment cessation in one patient with malignant melanoma and organizing pneumonia (OP) patterns that improved with corticosteroids and oxygen inhalation in other three patients. The median survival time from the initiation of nivolumab treatment was 165 days (L; 140.5 days: M; 489 days), and one patient with malignant melanoma who developed the pneumonitis 262 days after nivolumab treatment was successfully retreated with nivolumab.

Conclusion:
Nivolumab had a high incidence of drug-induced pneumonitis, which consisted mostly of OP patterns highly responsive to corticosteroids. Particular attention should be paid to an early onset after the initiation of treatment.

Background:
PD-1 inhibitor-related pneumonitis is recognized as a serious immune-related adverse event especially among NSCLC patients. The study investigated the radiographic patterns, clinical course, and risk factors of pneumonitis in advanced NSCLC patients treated with commercial PD-1 inhibitors.

Method:
The study included 210 patients (93 men, 117 women; median age: 65) with advanced NSCLC treated with commercially prescribed single-agent nivolumab or pembrolizumab. Chest CT scans during therapy were reviewed for abnormalities suspicious for pneumonitis by an independent review of two radiologists. Radiographic patterns of pneumonitis were classified using the ATS/ERS classification of interstitial pneumonia.

Result:
Pneumonitis was radiographically detected in 20 patients (20/210; 9.5%). Median time from the initiation of therapy to pneumonitis was 7.8 weeks. The radiographic pattern of pneumonitis was a cryptogenic organizing pneumonia (COP) pattern in 18, a non-specific interstitial pneumonia (NSIP) pattern in one, and a hypersensitivity pneumonitis (HP) pattern in one patient. Fifteen patients (75%) were symptomatic and 5 patients (25%) were asymptomatic with radiographic abnormalities alone. PD-1 inhibitors were held in 17 patients (85%), and corticosteroids were given in 12 patients (60%). Seven patients were hospitalized for treatment of pneumonitis. Three patients were re-treated with PD-1 inhibitors and two developed recurrent pneumonitis. There were no significant differences in clinical characteristics between patients with and without pneumonitis (p>0.34). Figure 1



Conclusion:
PD-1 inhibitor-related pneumonitis was noted in 9.5% of the advanced NSCLC patients treated with commercially prescribed PD-1 inhibitors. Radiographic pattern of pneumonitis was most commonly a COP pattern. Recurrent pneumonitis was common among those who were re-treated with PD-1 inhibitors. Further studies are necessary to identify risk factors for pneumonitis.

Background:
Programmed death-1 (PD-1) inhibitor, nivolumab, is one of the standard second-line treatments for advanced non-small cell lung cancer (NSCLC); however, its efficacy for patients with epidermal growth factor receptor (EGFR) mutation is still debatable.

Method:
We retrospectively reviewed the medical records of 82 patients with advanced NSCLC who were treated with nivolumab at Kyoto University Hospital between December 2015 and December 2016, and identified 24 patients harboring EGFR mutation. In this analysis, 1) treatment effect was compared between patients with and without EGFR mutation, and 2) clinical characteristics affecting the efficacy of nivolumab were examined in patients with EGFR mutation.

Result:
Overall response rate (ORR) was 13% and disease control rate (DCR) was 44% in the entire population. ORR (8% versus 15%, p=0.37) and DCR (25% versus 51%, p=0.024) were lower in patients with EGFR mutation compared with those in patients without EGFR mutation. Median progression-free survival (PFS) was 2.0 months for the entire population (95% confidence interval [CI], 1.73-2.57), and 1.8 and 2.2 months for EGFR mutation-positive and EGFR mutation-negative patients, respectively (hazard ratio [HR]=0.68 (95% CI, 0.4-1.19), p=0.17). In the EGFR mutation-positive population, higher Brinkman index and shorter response duration with precedent EGFR-TKI were correlated with longer PFS with nivolumab. Three patients with EGFR mutation achieved durable disease control lasting more than 1 year, two of whom harbored uncommon EGFR mutation (G719X).

Conclusion:
Nivolumab had limited efficacy in EGFR mutation-positive NSCLC patients; however, some patients derived meaningful clinical benefit from nivolumab. Further studies are warranted to elucidate the clinical characteristics predicting the efficacy of nivolumab in this population.

Background:
Immune checkpoint inhibition (ICI) has now become the new standard treatment for non-small-cell lung cancer (NSCLC). However, immune-related adverse events (irAEs) are frequently observed. In melanoma, those patients who had irAEs were shown to be associated with prolonged overall survival. Little is known about the correlation between the development of irAEs and clinical efficacy in NSCLC patients.

Method:
Patients with advanced NSCLC treated with nivolumab monotherapy at Sendai Kousei Hospital (n=70) between January 2016 to March 2017 were included in our study. Subjects were categorized into either the irAEs-incident group (IrAEs group) or non-irAEs-incident group (Non-irAEs group) and were evaluated with respect to objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall-survival (OS), and treatment continuation rate. They were also further divided into either responder group or non-responder group, and we analyzed predictive factors of treatment responses.

Result:
The median onset of irAEs incidence was 42 days, and categorization of irAEs identified 5 cases of interstitial pneumonia (7%), 5 cases of infusion reactions (7%), 22 cases of skin reactions (31%), 4 cases of neuromuscular disorders (6%), 7 cases of thyroid dysfunction (10%), and 1 case of hepatitis (1%). The following were observed: patient background (IrAEs / Non-irAEs group) number of cases 29/41 cases, median age both 68 years old, male 93% / 83%, treatment response CR/PR/SD/PD (0/17/10/2)/ (1/2/12/26), ORR 59% (17 cases) / 7% (3 cases) [Odds ratio: 0.06, p <.001], DCR 93% (27 cases) /37%(15 cases) [Odds ratio: 0.04, p＜.001], Median PFS (months) NR/3.0 [HR (95% CI) 0.15 (0.06–0.39), p =0.001], Median OS (months) NR/10.8 [HR (95% CI) 0.31 (0.10–0.93), p=0.0275], treatment continuation rate 69% (20 cases)/34% (14 cases) [Odds ratio: 0.24, p = 0.014]. The number of subjects in the responder group was 20 and that in the non-responder group is 50. Univariate analysis identified a significantly higher occurrence of irAEs in the responder group than in the non-responder group as well as the number of patients with higher positivity of anti-thyroid-antibody. Upon multivariate analysis, the development of irAEs [Odds ratio: 0.05, p <.001] and the positivity of anti-thyroid antibody [Odds ratio: 0.16, 0.022] were identified as independent predictors of treatment response.

Conclusion:
The development of irAEs during nivolumab monotherapy for NSCLC may be strongly correlated with improved outcomes. The development of irAEs and the positivity of anti-thyroid antibody were independent predictors of treatment efficacy.

Background:
Central nervous system (CNS) involvement is frequent in NSCLC patients and associated with poor prognosis. However, its impact on immune checkpoints inhibitors’ (ICI) outcomes remains unknown.

Method:
We retrospectively collected the clinical and imaging data of a cohort of 271 patients treated with ICI in our institute from Nov. 2012 to April 2017. We analyzed overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR), and CNS outcomes using brain CT scan and/or MRI. Both body and CNS outcomes were assessed prospectively by investigators.

Result:
With a median follow up of 17 months (95% IC 15-21), 259 patients were evaluated, 48 (19%) had CNS involvement before immunotherapy; 225 were (87%) smokers, 78% had PS ≤1, with median age of 63.1; 166 (64%) had adenocarcinoma; 67 (26%) were KRASmut, 14 (5%) EGFRmut and 3 (1%) ALK positive. PDL1 was ≥1% by immunohistochemistry in 68 (28%), negative in 28 (11%) and unknown in 163 patients. Median number of prior lines was 1 (0-11). The global ORR was 20%. The median OS was 8 months (95% IC 6-11). No difference was observed in OS between CNS+ vs. CNS- population (p= 0.09). The global ORR was 18% vs. 20%, in CNS+ and CNS- patients, respectively (p=1). To date, CNS–relative data are available for 36 patients: n= 32 brain metastasis, n=7 meningeal carcinomatosis, including 4 cytological positivity, n=2 leptomeningeal and n=1 medullar metastasis. Thirty-one patients (86%) had brain target lesions and 15 were evaluable for CNS outcome (CNS progressive disease (PD) before starting ICI and/or no brain radiation therapy (RT) in the previous 6 months. Median interval between consecutive CNS assessments was 2 months. Twenty-two had CNS PD before immunotherapy: 41% (9/22) received radiation therapy (RT) the month before immunotherapy (4 whole brain RT, 5 stereotactic). No differences were observed according to prior RT, with a median OS of 10 months (95%IC 2-NR) vs. 8 months. (95%IC 5-NR) for prior vs. no prior RT (p=0.79). The median OS for the 7 patients with meningeal carcinomatosis was 2 months (0 to 20). The CNS ORR was 27% (4/15, 3 partial, 1 complete response) and CNS DCR was 60% (9/15). One CNS pseudo progression (7%) and one dissociated brain response (7%) were observed.

Conclusion:
CNS involvement did not seem to be associated with a negative impact on immunotherapy outcomes in advanced NSCLC patients. Final analysis of the entire cohort will be presented.

Background:
PD-L1 binds PD-1 and B7.1 on effector T cells to induce anergy and blockade of this interaction unleashes antitumor T-cell activity. Irinotecan, a topoisomerase 1 inhibitor, has been widely used for cancer treatment. Although there are numerous clinical studies evaluating combination of standard chemotherapeutic agents and PD-L1/PD-1 inhibitors, irinotecan has not yet been investigated so that there is little information about its compatibility. In this study, we investigated the efficacy of an anti-PD-L1 antibody in combination with irinotecan using mouse models and analyzed the mode of action.

Method:
Mice were inoculated with the syngeneic breast cancer cell line FM3A and anti-mouse PD-L1 antibody (10 mg/kg, anti-PD-L1) was intraperitoneally (i.p.) administered three times a week, and irinotecan (250 mg/kg) was i.p. administered once on the day of treatment initiation (day 1). The number and activation status of immune cells were analyzed by flow cytometry; the CD8+ cell localization in tumor tissue was assessed by immunohistochemistry. Tumor draining lymph nodes were assessed for tumor-specific immunity by an IFN-gamma release assay.

Result:
Despite a transient decrease of lymphocytes in peripheral blood on day 8, irinotecan augmented antitumor activity of anti-PD-L1 on day 19 (Tumor volume [mean ± SD]: Control = 2226 ± 829 mm[3]; anti-PD-L1 = 1265 ± 878 mm[3]; irinotecan = 1514 ± 775 mm[3] and Combination = 593 ± 558 mm[3]). On day 19, in the combination group tumors, a pathologically confirmed significant increase of CD8+ cells was observed vs each monotherapy group. Tumor cell-stimulated IFN-gamma release by lymph node cells was increased in the combination group and anti-PD-L1 group vs control group. Frequency of Ki67+ CD8+ cells in the combination group significantly increased vs each monotherapy group in both tumors and lymph nodes on day 8. Irinotecan was found to increase MHC I and PD-L1 expression on tumor cells and decrease Treg in both tumors and lymph nodes on day 4.

Conclusion:
The anti-tumor activity of anti-PD-L1 plus irinotecan was significantly higher than each agent alone regardless of initial hematotoxicity. Enhanced proliferation of CD8+ cells in both tumors and lymph nodes was considered to be one of the mechanisms of increased tumor specific CD8+ cells. In addition to direct cytotoxic effects on tumor cells, irinotecan increased MHC I and PD-L1 expression and decreased Tregs, which may contribute to combination effects with anti-PD-L1. The present study may provide a rationale to conduct clinical studies of anti-PD-L1 in combination with chemotherapy, especially irinotecan.

Background:
Randomized phase III trials demonstrated that nivolumab was significantly more efficacious than docetaxel in previously treated NSCLC patients; however, subgroup analysis indicated that nivolumab had no superior antitumor effects in patients with EGFR mutations. Recent studies have shown that predictive biomarkers, such as PD-L1 expression on tumor cells and infiltration of CD8[+] T cells into tumor tissues, were associated with response to nivolumab. The present study was conducted to evaluate the antitumor effects and biomarkers of nivolumab in NSCLC patients with EGFR mutations.

Method:
We retrospectively assessed 8 EGFR-mutated NSCLC patients treated with nivolumab.

Result:
All patients had adenocarcinoma histology. Six patients had 19 deletion, 1 had L858R and 1 had S768I point mutations. During nivolumab treatment, no patients achieved partial response and stable disease. Seven patients had progressive disease and 1 was not evaluable. The median number of cycles was only 2. The median progression free survival and median overall survival from the beginning of nivolumab was 32 days (95% C.I. 7 to 51) and 370 days (95% C.I. 230 to 480). PD-L1 expression (28-8 pharmDx) was observed in 3/2/1 patients before the start of nivolumab using cutoffs of >1%, >5% and >50% tumor cell staining. Immunohistochemistry revealed that CD4[+] and CD8[+] tumor infiltrating lymphocytes were observed in all patients before nivolumab.

Conclusion:
The current study indicated that nivolumab was not effective in patients with EGFR mutations regardless of predictive biomarkers of nivolumab.

Background:
Nivolumab is an immune checkpoint inhibitor targeting human IgG4 programmed death 1 for advanced or recurrent non-small lung cancer (NSCLC), and programmed death ligand 1 (PD-L1) expression of tumor tissue is expected to be a biomarker of the sensitivity to Nivolumab. More recent biopsy is likely to be more suitable since PD-L1 expression of tumor cells is influenced by time or by anti-tumor therapies such as chemotherapy or radiotherapy, and most clinical studies have referred to the PD-L1 expression using the latest biopsy samples before administration of Nivolumab. Therefore, it remains controversial whether PD-L1 expression of the archive specimen obtained at the time of initial surgery for primary disease is correlated with the sensitivity of recurrent diseases to Nivolumab.

Method:
We retrospectively reviewed 10 NSCLC patients who had undergone radical surgery for primary tumor and received Nivolumab for their recurrent diseases. The median interval between the initial surgery and Nivolumab administration was 28.1 months (2-75), and median number of anti-tumor regimens prior to Nivolumab was 2.2 (1-5). Archive specimens of primary tumors and second biopsy samples of recurrent diseases from the 10 patients were stained to measure PD-L1 expression both with the PD-L1 IHC 28-8 pharmDx Daco (assay 28-8), and with the PD-L1 IHC 22C3 pharmDx Daco (assay 22C3).

Result:
Among the 10 patients, complete response (CR)/partial response (PR)/ stable disease (SD)/progressive disease (PD) for Nivolumab were 1/2/3/4 patients, respectively. All patients had PD-L1 expressions as tumor proportion score (TPS)≧1%, of which 7 showed TPS≧10% in the assay 28-8. All 3 patients (30%) with CR/PR showed TPS≧10%. The TPS obtained by assays 28-8 and 22C3 were similar in 9 of 10 patients. Two patients underwent biopsies for their recurrent sites, which showed decreased PD-L1 expression compared with primary tumor, resulted in PD for Nivolumab.

Conclusion:
The PD-L1 expressions of surgical archive specimen might be almost associated with the sensitivity to Nivolumab, however, time and antitumor therapies may modulate the PD-L1 expressions and might be able to affect the sensitivity to Nivolumab. Further pre-clinical and clinical studies are warranted to evaluate the availability of surgical archive specimen in the treatment of postoperative recurrence by the immunocheckpoint inhibition.

Background:
Although the biological durability of Nivolumab, the PD-1 blocking antibody, was reported to continue longer than 12 weeks, the maximum duration of its efficacy, along with toxicity, after discontinuation and the correlation between residual binding and clinical events in cases of sequential therapeutic regimens remain unclear.

Method:
Peripheral blood, pleural effusion and bronchoalveolar lavage fluid were obtained from non-small cell lung cancer patients previously treated with Nivolumab. To evaluate the efficacy of the treatment, we developed a simple technique to identify Nivolumab binding status — complete binding, partial binding and no binding — in T cells from patient samples using flowcytometry, which can also be used to obtain T cell differentiation markers and transcriptome profiles, particularly in the Nivolumab bound T cell population. Based on this method, we tracked the binding status in T cells primarily from peripheral blood in patients who received a sequential therapeutic regimen after Nivolumab treatment.

Result:
While the decrease in frequency of Nivolumab binding after discontinuation was observed in all cases where long term monitoring was possible, Nivolumab binding in T cells from peripheral blood was detected until more than 20 weeks, though effective binding could have ceased before that time point. We found that the direct effects on Nivolumab binding via sequential treatment were limited. Finally, we observed in clinical cases that our monitoring technique was also helpful in understanding the cause of clinical events and its residual efficacy in patients who previously received Nivolumab.

Conclusion:
Monitoring of Nivolumab binding to T cells after discontinuation can be valuable when planning sequential therapeutic regimens in the following ways: estimating the potential residual efficacy, predicting the risk of immune-related adverse events and the time of relapse due to complete loss of efficacy, and investigating the changes in the immune profile in Nivolumab bound T cells.

Background:
The current study aimed to comprehensively investigate the impact of various clinicopathological features on the efficacy of programmed cell death 1 (PD-1) and ligand (PD-L1) inhibitors in patients with previously treated non-small cell lung cancer (NSCLC).

Method:
Randomized controlled trials that compared PD-1/PD-L1 inhibitors monotherapy with chemotherapy or placebo in patients with previously treated NSCLC were included.

Result:
Five trials were included (n = 3025). For all studies, PD-1/PD-L1 inhibitors significantly prolonged overall survival (OS) [hazard ratio (HR) = 0.70; P < 0.001] and progression-free survival (PFS) than chemotherapy (HR = 0.86; P = 0.020). Subgroup analysis showed that anti-PD-1/PD-L1 monotherapy could markedly improve OS in elderly (HR = 0.69; P < 0.001), female (HR = 0.70; P < 0.001), never-smoking (HR = 0.73; P = 0.001) and histology of squamous cell carcinoma (HR = 0.67; P < 0.001) patients but not PFS. Notably, PD-1/PD-L1 inhibitors can not prolong both the OS (HR = 0.76; P = 0.390) and PFS (HR = 0.74; P = 0.210) of patients with central nervous system (CNS) metastasis whereas patients without CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy on OS (HR = 0.71; P < 0.001).

Conclusion:
PD-1/PD-L1 inhibitors monotherapy could significantly prolong both OS and PFS in patients with previously treated NSCLC. Elderly, female, never-smoking and histology of squamous cell carcinoma patients could also benefit from PD-1/PD-L1 inhibitors monotherapy on OS. However, whether patients with CNS metastasis could benefit from anti-PD-1/PD-L1 monotherapy remains further validation.

Background:
This phase I study investigated the tolerability, safety and pharmacokinetics of nivolumab in combination with chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC).

Method:
Patients who have stage IIIB without indication for definitive radiotherapy, stage IV，or recurrent NSCLC were eligible. nivolumab (10 mg/kg，day 1) and chemotherapy [arm A: cisplatin (80 mg/m[2], day 1) / gemcitabine (1250 mg/m[2], day 1 and 8), arm B: cisplatin (75 mg/m[2], day 1) / pemetrexed (500 mg/m[2], day 1), arm C: carboplatin (AUC 6, day 1) / paclitaxel (200 mg/m[2], day 1) / bevacizumab (15 mg/kg, day 1), arm D: docetaxel (75 mg/m[2], day 1)] were administered every three weeks. Arm A and B were administrated for four cycles and arm C was for four to six cycles as first-line chemotherapy. After that, nivolumab in arm A, nivolumab / pemetrexed in arm B, and nivolumab / bevacizumab in arm C were continued every three weeks as maintenance therapy until disease progression. Arm D were administrated until disease progression as second-line chemotherapy.

Result:
Six patients each in four arms, total 24 patients were enrolled. Median follow-up time was 20.4 months. Progression free survival [median (range)] were 6.3 (0.7-42.2+) months in arm A, 11.8 (1.4-47.4+) months in arm B, 40.7 (5.3-43.5+) months in arm C, and 3.2 (1.9-10.9) months in arm D. Three-year progression-free survival rates were 20% in arm A, 16,7% in arm B, 62.5% in arm C, and 0% in arm D.

Conclusion:
nivolumab 10 mg/kg showed acceptable toxicity profile and encouraging antitumor activity in combination with chemotherapies in Japanese patients with advanced NSCLC. Especially, arm C showed favorable response rate and long progression free survival in this study.

Background:
Response Evaluation in Solid Tumors (RECIST) criteria were developed to assess response to cytotoxic therapy. Response to immune checkpoint inhibitors depends on tumor and host factors including the presence of immune cells (IC) in the tumor environment. Organs differ in IC content. We hypothesized that nivolumab was more active in tumor lesions in IC rich than IC poor organs.

Method:
We retrospectively analysed serial computed tomography (CT) scans of patients treated with nivolumab applying RECIST 1.1 criteria to assess overall response (ORR) and response in different organ sites. ­ CT examinations were performed on a 3[rd] generation dual-source CT system and read by two experienced radiologists. We classified metastatic sites from NSCLC into three groups: 1) IC rich: lymph nodes, 2) IC intermediate: liver, lungs, 3) IC poor: bone, soft tissue. Standard descriptive statistics were used; time-to-event endpoints were analyzed using Kaplan-Meier methods.

Result:
52 patients with advanced NSCLC were analyzed. Median age was 66 years, 44% were female, 58% had adenocarcinoma, 92% were former or current smokers. Prior to nivolumab treatment start patients had lesions in the lung (42%), liver (25%), lymph node (56%), soft tissue (13%) and bone (23%). In 62% of the patients the primary tumor was still in situ. ORR and disease-control-rate (DCR) were 20% and 45%, respectively. Median overall survival was 11.9 months, median progression-free survival was 2.3 months and median duration of response (DOR) 10.3 months. Response (RR) to nivolumab differed depending on organ site: RR and DCR according to organ sites were 28% and 90% in lymph nodes, classified as IC rich. RR was 8%, 9% and 16% and DCR was 58%, 55% and 81% in liver, lung metastases and primary tumor, respectively, classified as IC intermediate. In IC poor organs RR was 0% in soft tissue metastases and nine out of 12 patients with bone metastases, which included non-measurable non-target lesions only, had progressive lesions at time of overall tumor progression.

Conclusion:
Immunotherapy has differential effects at different organ sites of metastases. Nivolumab treatment appears to be more active in IC rich organs than at IC intermediate and IC poor sites. Our results suggest that the combination of immune checkpoint inhibitors with local treatment strategies to IC intermediate or poor organs should be explored.

Background:
Patients with interstitial lung disease (ILD) have a higher incidence of non-small cell lung cancer (NSCLC) and have few treatment options for NSCLC. While immune checkpoint inhibitors (ICI) are used for NSCLC treatment, the incidence of ICI-related ILD in patients with preexisting ILD is still unknown. Therefore, we retrospectively evaluated the efficacy and safety of nivolumab in patients with NSCLC with preexisting ILD.

Method:
We reviewed patients who were administered nivolumab at National Hospital Organization Kyoto Medical Center, Kyoto University Hospital, and Japan Red Cross Fukui Hospital. All patients were initiated on nivolumab therapy between December 24, 2015 and December 31, 2016 and were reviewed until May 31, 2017 or the date of death. We compared the response rate (RR), disease control rate (DCR), overall survival time (OS), incidence of nivolumab-related ILD, and severity of nivolumab-related ILD between patients with and without preexisting ILD.

Result:
Of 173 NSCLC patients administered nivolumab, 14 (8%) had preexisting ILD. The major radiographic pattern of preexisting ILD was a non-specific interstitial pneumonia pattern (10 patients), followed by the usual interstitial pneumonia pattern (4 patients). The RR and DCR were 21% and 57% versus 12% and 40% in patients with and without preexisting ILD (p = .393 and p = .263), respectively. The median OS from the initiation of nivolumab was not reached (95% confidence interval [CI], 4.1 months to not analyzed [NA]) with preexisting ILD and was 11.7 months (95% CI, 7.5 months to NA) without ILD (hazard ratio, 0.71; 95% CI, 0.29 to 1.77). The incidence of nivolumab-related ILD was significantly higher with preexisting ILD than without ILD (50% vs 15%, p = .004); however, the incidence of grade 3 or 4 nivolumab-related ILD was not significantly different in those with and without preexisting ILD (14% versus 6.3%, p = .251). The median time to the onset of nivolumab-related ILD was 2.3 months (range, 0.5 to 4.0 months) with preexisting ILD versus 2.4 months (range, 0.03 to 12.4 months) without ILD. No ILD-related death occurred.

Conclusion:
Treatment with nivolumab in NSCLC patients with preexisting ILD might offer comparable efficacy to that in those without ILD. Although a higher incidence of nivolumab-related ILD was observed in patients with preexisting ILD, incidence of severe nivolumab-related ILD was not significantly different between those with and without preexisting ILD. Additional studies should be conducted to determine the efficacy and safety of nivolumab in patients with NSCLC with preexisting ILD.

Background:
Immune checkpoint inhibitors have shown clinical efficacy in non-small-cell lung cancer (NSCLC). However, data for efficacy in brain metastasis is limited because patients with untreated brain metastases were excluded in clinical trials.

Method:
We retrospectively evaluated NSCLC patients with brain metastases who had received immune checkpoint inhibitors at Chiba Cancer Center between January 2016 and May 2017.

Result:
Eighteen patients were eligible for this study. Of these, ten were men, and eight were women; median age was 56 years (range, 32–75 years). Fourteen patients had adenocarcinoma, three had squamous cell carcinoma, and one had a transformation from adenocarcinoma to squamous cell carcinoma. Surgery and whole brain radiation was previously performed in four patients each, while stereotactic radiosurgery was performed in nine patients. Four patients were not treated with local brain therapy. Sixteen patients were treated with nivolumab, while two patients were treated with pembrolizumab. Among 16 patients who had assessable brain metastases, one (6%) had a complete response (CR), ten (63%) had a stable disease (SD), and five (31%) had a progressive disease (PD). Among four patients with locally untreated brain metastases, there was one (25%) each with CR and SD, while two (50%) had PD. Seven (44%) patients had worsening of cerebral edema, including one who was treated with glucocorticoids. Immune checkpoint inhibitors had to be stopped in four patients due to worsening of brain metastases; two of them were treated again with immune checkpoint inhibitors after stereotactic radiosurgery.

Conclusion:
Immune checkpoint inhibitors have the potential to improve brain metastases of NSCLC; however, caution needs to be exercised for worsening of cerebral edema in some cases.

Background:
Patients with advanced lung cancer have poor survival, although they have received multidisciplinary therapy. Therefore, the novel effective therapy is needed. In various malignancies, tumor cells escape the host immune defenses, in which regulatory T cells (Tregs) play an important role. Tregs, maintaining self-tolerance and homeostasis in the immune system, suppress antitumor immune responses in cancer patients. Thus, Tregs are crucial in controlling antitumor immune responses. Several clinical studies show that a number of Tregs at tumor site was correlated with poor prognosis and Tregs suppress the antigen-specific T-cell induction in immunotherapy. Therefore, controlling Treg functions is probably promising immunotherapy. The study of adult T-cell leukemia-lymphoma (ATL) revealed that Tregs strongly express CCR4 molecule of a CC chemokine receptor on their surface. The humanized anti-human-CCR4 monoclonal antibody (mogamulizumab) recognizes CCR4 molecule and shows a robust ADCC activity against CCR4-positive cells such as Tregs. Thus, Tregs depletion by mogamulizumab probably enhances the host immune response against the tumor. We recently finished the clinical trial of mogamulizumab treatment in advanced solid cancer, and the monitoring of Tregs in the peripheral blood mononuclear cells during treatment indicated efficient depletion of those cells, even at the lowest dose of 0.1 mg/kg used.

Method:
In this study, we analyzed the response against chemotherapy before and after mogamulizumab treatment in 6 advanced lung cancer patients who were enrolled in the clinical trial. In 3 of those patients, we analyzed the number of immune cells (CD3 T cells and CCR4[+/-] FoxP3[+]Tregs) and expression of PD-L1 (SP142) on tumor cells in lung cancer tissues by immunohistochemistry at diagnosis and after mogamulizumab treatment.

Result:
Although the patients finished standard chemotherapy and therefore were to be refractory, 4 of 6 patients showed the partial response (PR) in chemotherapy after mogamulizumab treatment. While 2 of 6 patients showed PR in chemotherapy before mogamulizumab. In 3 of those patients, we observed efficient depletion of CCR4[+]FoxP3[+]Tregs after mogamulizumab treatment in all patients, while CCR4[-]FoxP3[+]Tregs were detected in lung cancer tissues. In 2 PR patients in chemotherapy after mogamulizumab treatment, we observed increased number of CD3 and PD-1[+]cells. In one patient, increased PD-L1 expression on tumor cells was observed. On the other hand, in one SD patient in chemotherapy after mogamulizumab, the number of CD3, PD-1[+] cells, and expression of PD-L1 on tumor cells were decreased.

Conclusion:
Treg depletion by mogamulizumab may induce inflamed tumor microenvironment in some lung cancer patients, and result in reviving chemotherapy sensitivity.

Background:
Nivolumab has been approved in a second line, of non-small cell lung cancer (NSCLC) after the failure of the first line of platinum-based chemotherapy. The use of immunotherapy is assuming a new challenge in the clinical practice of the oncologist, who has to familiarize himself with a different toxicity profile than chemotherapy.The objective of this study is to describe the clinical characteristics of our patients, focusing on the toxicity profile found and trying to find something that will help us to identify patients who are going to have poor early evolution.

Method:
We have reviewed 49 patients treated with nivolumab, from their use in expanded access, until April 2017. Retrospective information was collected on the clinical, pathological, hematological and treatment characteristics of these patients. Statistical analysis was performed using the SPSS software version 21.0.

Result:
The characteristics of the patients are summarized in Table 1. More than half of the patients presented toxicity, in any of their grades, being approximately 56,5 % grades 1-2, and 8% grade 3. Only one patient was presented grade 4 toxicity. The different toxicities are described in Table 1. Attention is drawn to a large number of patients (23) who receive 4 or fewer cycles, who died quickly, most often in the context of rapid progression, and at other times unable to reevaluate the disease. Regardless of these patients, the time of progression was 7.6 months, and the overall survival was 12.6 months, data that can be superimposed on those seen in EECC. Figure 1



Conclusion:
Immunotherapy in NSCLC has become a basic pillar of treatment, presenting a different toxicity profile to that of chemotherapy, which we are learning to manage. We thought that it would be important, something that discard those patients who were presumed to have a rapid bad evolution.

Background:
Nivolumab is one of immune-checkpoint inhibitors and has the first agent approved by the U.S. Food and Drug Administration for advanced non-small cell lung cancer (NSCLC). However, the rate of objective responses remains at approximately 20%.Additionally, immune-checkpoint inhibitors often have developed immune-related adverse events. We have previously reported that PD-L1 single nucleotide polymorphisms (SNPs) were possible biomarker for efficacy of nivolumab. We investigated the association between genetic polymorphisms in the PD-1/PD-L1 gene and clinical outcome for nivolumab including response and adverse events.

Method:
A total of 68 consecutive patients with NSCLC were treated with nivolumab from December 2015 to October 2016 at Kyoto University. Of these patients, 59 participated in the present study. The remaining 9 patients were excluded from this study because 3 patients declined informed consent, 2 patients had no follow up blood examination, one patient had a history of double cancer and 4 patients had determined as progression disease within 15days from the first administration of nivolumab. Seven SNPs (PD-L1; rs822339, rs1411262, rs2890658, rs4143815, rs2282055, PD-1; rs2227981, rs2227982) were genotyped using TaqMan genotyping assay. Response was assessed as per the Response Evaluation Criteria in Solid Tumors (version 1.1) by investigators respectively. Adverse events were assessed as per the Common Terminology Criteria for Adverse Events (version 4.0) by an investigator. We defined hyperthyroidism as elevated FT4 or FT3 and hypothyroidism as low FT4.We explored the association of adverse events and the PD-1/PD-L1 SNPs subtypes using the Cochrane-Armitage test and Fisher’s exact test as appropriate. Difference of progression free survival (PFS) between each group was assessed using the log-rank test.

Result:
Median PFS in this group was 67days (95% confidence interval, 54 to 107 days). Median PFS was significantly longer in patients with thyroid dysfunction than in those without thyroid dysfunction (152 vs 58 days; P = 0.0349). GG and GT genotype of rs2282055 were related to better PFS (82 vs 65 days; P = 0.0311). There were no significant association between thyroid dysfunction and SNPs. However, absence of thyroid dysfunction in patients with TT genotype of rs22282055 suggests that rs2282055 might be related thyroid dysfunction (P=0.1863 Fisher’s exact test).

Conclusion:
In the patients treated with nivolumab, GG and GT genotype of rs2282055 might be a predictive biomarker for response and might contribute the occurrence of thyroid dysfunction.

Background:
Cancer/testis (CT) antigen is a class of antigens that express predominantly in the testes and various tumor types. Some CT antigens have been shown to be highly immunogenic and are considered to be attractive targets for cancer immunotherapy.　We identified XAGE1 as a dominant CT antigen in lung adenocarcinoma (LAD). In this study, we investigated the correlation of clinical response and XAGE1 immunity in LAD.

Method:
XAGE1 antigen expression and immune checkpoint molecules were determined with tumor tissues by immunohistochemistry. The XAGE1 antibody and T-cell immune responses, as well as immune cell phenotypes, were analyzed with blood samples.　The overall survival (OS) of the XAGE1 antigen-positive and -negative, and XAGE1antibody-positive and -negative patients were investigated.

Result:
The XAGE1 antigen is expressed in 30 to 40% of LAD. In pStage I-IIIA LAD, expression of the XAGE1 antigen was correlated with shortened OS in both Hokkaido (n=77) and Kawasaki (n=120) cohort, suggesting its relation to malignancy. Based on the expression profiles of XAGE1, and immune checkpoint molecules of PD-L1 and Galectin-9 on tumor cells, we developed a discriminant function capable of efficiently predicting OS in pStage I-IIIA LAD. The XAGE1 antibody response was observed 6% (9/155) in pStage I-IIIA, and 20% (34/167) in cStage IIIB-IV LAD, respectively, suggesting a higher antibody response rate in more advanced stage patients. In the antibody-positive patients, CD4 and CD8 T-cell responses were frequently elicited, and phenotypic and functional analyses of T cells indicated immune activation. Furthermore, we revealed that the OS of antibody-positive patients was prolonged significantly compared with that of antibody-negative patients with either XAGE1 antigen-positive EGFRwt (31.5 vs. 15.6 months, P = 0.05) or EGFRmt (34.7 vs. 11.1 months, P = 0.001) LAD. Multivariate analysis showed that XAGE1 antigen expression was a worse predictor in patients with EGFRmt tumors (HR: 5.23). On the other hand, the presence of the XAGE1 antibody was a strong predictor for prolonged OS in patients with XAGE1 antigen positive tumors (HR: 0.18) and in patients with either EGFRwt or EGFRmt tumors.

Conclusion:
Frequent antibody and T cell responses indicate the strong immunogenicity of the XAGE1 antigen. The findings suggest that production of XAGE1 antibody predicts good prognosis of lung adenocarcinoma patients as an immune biomarker and sheds light on the role of the protective effect of this naturally occurring immune response supporting the concept of immunotherapy.　

Background:
Recent development of cancer immunotherapy such as anti-PD-1 inhibitors improved outcome and changed therapeutic landscape in advanced non-small cell lung cancer (NSCLC). However, systemic treatment prior to immunotherapy might influence host T-cell function and therapeutic outcome. Previous anti-angiogenesis treatment may positively or negatively affect outcome of subsequent immunotherapy.

Method:
We conducted a retrospective review of advanced NSCLC patients who were treated with anti-PD-1/PD-L1 inhibitor at University of Kansas Medical Center. Patient characteristics including prior systemic therapy were investigated for association with therapeutic outcome, which included disease control rate (DCR: CR+PR+SD/CR+PR+SD+PD), progression-free survival (PFS), overall survival (OS), and reason for discontinuation of immunotherapy. Kaplan–Meier curves were fitted and the differences were assessed using Log-rank test. In addition, Cox proportional hazard model was used in order to assess the effects of variables on survival of the patients. Association between anti-angiogenesis treatment and other clinical features was assessed using chi-squared or Fisher’s exact test.

Result:
Among 141 patients who were treated with anti-PD-1/PD-L1 inhibitor, we analyzed only those who were treated with nivolumab (n=134). Majority of patients had age<70 (76%), stage IV at diagnosis (66%), nonsquamous histology (58%), male sex (58%), performance status 0-1 (77%), EGFR negative or unknown (94%), one prior systemic treatment regimen (81%), and no prior anti-angiogenesis agent (88%). There was significant correlation between prior anti-angiogenesis and stage IV at diagnosis/nonsquamous histology/higher number of systemic treatment lines. With a median follow up of 22.8 weeks, prior use of anti-angiogenesis agent was significantly associated with shorter PFS (Table). There was also a trend of inferior DCR and OS (Table). Multivariate analysis demonstrated that prior anti-angiogenesis agent use had shorter PFS (p=0.0444) and OS (p=0.0741). Frequency of adverse event for reason of discontinuation was not statistically significant.

Table: Influence of prior anti-angiogenesis treatment

Prior anti-angiogenesis	N	DCR%	median PFS (weeks)	median OS (weeks)
Yes	16	30.0	8.29	13.1
No	118	60.7	11.3	27.5
P-value		0.0912	0.0060	0.1697
Statistical method		Fisher’s exact	Log-rank	Log-rank

Conclusion:
This retrospective analysis suggests prior exposure to anti-angiogenesis agent negatively impact on therapeutic outcome of cancer immunotherapy.

Background:
Lung cancer is the leading cause of cancer mortality worldwide therefore understanding the role of immune system in antitumor immunity is of a great interest. Here we compared immune cell infiltration and responses in tumors and non-tumoral lung tissue from 43 adenocarcinomas (AC) and 39 squamous cell carcinomas (SCC) of non-small cell lung cancer patients.

Method:
In this study we compared immune cell populations, T cell responses and secreted cytokines in primary tumors and non-tumoral lung tissue as well as in blood of non-small cell lung cancer (NSCLC) patients undergoing neoadjuvant surgery. Moreover, we compared immune suppressive populations such as CD4[+]CD25[+]Foxp3[+ ]T regulatory cells and myeloid-derived suppressor cells (MDSC).

Result:
Whereas T, B and NK cells infiltration was comparable in AC and SCC, the number of dendritic cells was lower in SCC tumors. CD8[+] T cell and NK cell proliferation, IFN-γ-production from T cells and secretion of proinflammatory cytokines after stimulation in vitro was lower in SCC compared to AC tumors. A higher number of Tregs was detected in tumors and blood of AC patients, whereas a higher number of MDSC was found in SCC patients. The suppressive function of Tregs was comparable between AC and SCC patients, but MDSC in SCC patients displayed a higher suppressive function as shown by inhibition of CD3z expression and IL-2 and IFN-γ production in T cells, Lox-1 plasma concentrations compared to AC patients and age-matched controls.

Conclusion:
Our results suggest that immune system of SCC patients might be subjected to higher immunosuppression than AC patients. Our observations also give rationale to target specifically MDSC in SCC patients and Tregs in AC patients for designing combinatorial immunotherapeutic approaches.

Background:
Anti-PD-1 immune therapy improved survival in NSCLC, whereas some patients were not responding to this treatment, indicating the requirement of alternative strategies for these patients. B7-H3, an immune checkpoint molecule, has known to be expressed in some cancer cells including NSCLC. In this study, we examined the therapeutic potential of targeting B7-H3 using a mouse model, also elucidated the expression levels of B7-H3 on NSCLC tumor cells.

Method:
Pan02 murine cancer cells were inoculated in syngeneic mice, and anti-tumor efficacy of anti-B7-H3, anti-PD-L1 antibodies were evaluated. T-cell expression of IFN gamma was evaluated in the spleen and tumor infiltrating lymphocytes using flow-cytometer. B7-H3 expression on tumor cells in patients with NSCLC (n=69) was evaluated by immunohistochemistry.

Result:
In the mouse model study, the treatment with anti-B7-H3 antibody significantly prevented the tumor-growth as compared to isotype antibody. The numbers of CD4+ and CD8+ T-cells infiltrated in the tumor significantly increased following treatment with anti-B7-H3 antibody. Importantly, depletion of CD8+ T-cells cancelled the anti-tumor effect of anti-B7-H3 antibody treatment, indicating that the blockade of B7-H3 potentiates anti-tumor CD8+ T-cell responses. In fact, CD8+ T-cell expressions of IFN gamma in response to tumor cells were improved when mice were treated with anti-B7-H3 antibody. Furthermore, combination with anti-B7-H3 and anti-PD-L1 antibody treatment showed synergic effect in inhibiting tumor-growth. The expressions of B7-H3 were evident on NSCLC tumors, which consists 62% of NSCLC patients.

Conclusion:
Anti-B7-H3 antibody exhibited CD8+ T-cell-mediated anti-tumor effects in the mouse model study. B7-H3 was aberrantly expressed in NSCLC tumor cells. Anti-B7-H3 antibody or its combination with anti-PD-1 antibody is suggested to be effective for patients with NSCLC. Figure 1

Background:
PD-1/PD-L1 interaction affects various immune cells, including macrophage and dendritic cells, which play crucial roles in anti-cancer immunity. Early alteration of inflammatory cytokines, such as IL-6, TNF-α, or CRP, which is a surrogate marker for IL-6, following anti-PD-1 antibody administration may represent activation of those cells and be related to the efficacy and safety of anti-PD-1 antibody treatment; however, these remain unexplored thus far.

Method:
Serum IL-6 and TNF-α were measured with CLEIA/ELISA method in 10 non-small cell lung cancer patients having evaluable serums before and after anti-PD-1 antibody (nivolumab or pembrolizumab) administration. For CRP, medical records were reviewed and serum CRP was measured in 34 non-small cell lung cancer patients before and after anti-PD-1 antibody administration. The relationship of IL-6, TNF-α, and CRP alterations within 7 days with the response rate and frequency of severe adverse events (≥ Grade 3) (SAEs) was analyzed.

Result:
In 10 patients analyzed for IL-6/TNF-α, age was 68 (45 – 74) (median [range]) years, PS 0/1: 7/3, Sqc/Non-Sqc: 4/6, and the days before/after anti-PD-1 antibody administration were 0 (0 – 7)/ 3.5 (2 – 7). IL-6/TNF-α was 20.3 (2.6 – 49.9) pg/mL /1.6 (0.7 – 6.3) pg/mL at pre-treatment, and 22.9 (3.6 – 96.1)/3.3 (0.7 – 9.6) at post-treatment, respectively. Partial or complete responses were seen at 4/7 (57%) and 0/3 (0%) in IL-6 elevated and non-elevated cases, respectively (p=0.048), while 2/6 (33%) and 2/4 (50%) of TNF-α elevated and non-elevated cases showed response (p=0.589). SAEs were significantly frequent in TNF-α elevated cases (3/6 [50%] vs. 0/4 [0%] in non-elevated cases, p=0.048). In 34 patients analyzed for CRP, age was 67 (45 – 89); PS 0/1/2/3: 18/12/2/2; Sqc/Non-Sqc: 14/20; the days before/after anti-PD-1 antibody administration: 1 (0 – 7)/ 3 (2 – 7). CRP was significantly increased after anti-PD-1 antibody administration (1.8 [0.1 – 17.8] mg/dL at pre- and 2.4 [0.0 – 27.8] at post-treatment; p=0.001), and in 31 efficacy-evaluable cases, more responses were recognized in CRP-elevated cases (10/22 [45%]) compared to non-elevated cases (1/9 [11%]), although not statistically significant (p=0.054). SAEs were seen in 5/25 (20%) of CRP-elevated cases vs. 4/9 (44%) of CRP-non-elevated cases (p=0.17).

Conclusion:
Anti-PD-1 antibody affected inflammatory cytokine production and significantly increased CRP within a week in patients with non-small cell lung cancer. The early induction of inflammatory cytokines after PD-1 antibody administration may have a key role on the induction of anti-cancer immunity and adverse effects.

Background:
Immune checkpoint inhibitors (ICIs), by inhibiting immunosuppressive molecules overexpressed in the tumoral environment like CTLA-4 or PD1, increase the anti-tumor immune response and have been approved for an increasing number of cancers. However, they are responsible for immune related adverse effects (IRAEs), and patients with preexisting autoimmune diseases (PAD) have been excluded from clinical trials evaluating those molecules. The aim of this study was to evaluate their safety in routine practice in patients with PAD and the anti-tumoral response in this population.

Method:
Three national expert networks, focusing respectively on skin cancers, thoracic cancers, and inflammatory diseases, participated in the study. All patients who received an ICI despite a PAD were retrospectively included in this nationwide retrospective study.

Result:
31 patients were included in the study (19 men (61%), median age of 66). Most frequent PADs were rheumatoid arthritis (n=9; 29%), psoriasis (n=6; 19%), lupus (n=4; 13%), ulcerative colitis (n=3; 10%), and spondyloarthritis (n=3; 10%). Eleven patients were receiving an immunosuppressive therapy when the ICI was initiated, and 10 had an active disease at that time. Neoplasm types were melanoma (n=16; 52%), non-small-cell lung carcinoma (n=12; 39%), and urologic neoplasms (n=3; 9%), with a median disease duration of 19 months. The majority of the patients (30/31) received an anti-PD1 drug, for a median duration of 4 months. PAD flares were frequent (n=18; 58%) but mostly mild: CTCAE grade 1-2 (n=12; 67%), grade 3-4 (n=3; 17%). 14 patients (78%) received corticosteroids or NSAIDs, and 3 (17%) methotrexate or acitretine for the treatment of these flares. IRAEs not associated with PAD appeared in 10 patients (32%): arthralgia (n=5), colitis (n=2), thyroiditis (n=2), vitiligo (n=2) with mild severity. None of the patients received TNF blockers, neither for a flare nor for an IRAE. 5 patients discontinued the immunotherapy because of an adverse effect. Regarding the cancer response rate, 4 patients over 11 who were taking an immunosuppressive treatment were responders (36%), versus 12 over the 20 other patients (60%).

Conclusion:
PAD flares are frequent during ICI therapy and other IRAEs are also possible, usually easily managed with corticosteroids only. Anti-tumor response could be reduced when an immunosuppressor is ongoing at the beginning of the ICI, within the limit of the number of patients already so far. Overall, the tolerance of ICIs in patients with PAD seems acceptable, but a multidisciplinary follow-up with the PAD referral physician is appropriate to manage frequent PAD flares and/or IRAEs.

Background:
Real-world data in non-small cell lung cancer (NSCLC) patients treated with nivolumab are currently lacking. This study aimed to obtain a detailed understanding of the characteristics and outcomes of these patients.

Method:
We retrospectively analyzed data for stage IIIB-IV (7th edition) NSCLC patients treated with nivolumab between January 2016 and January 2017.

Result:
A total of 394 patients were included in the study. Most patients had a PS of 0 or 1 (76%) and non-squamous histology (80%). Epidermal growth factor receptor (EGFR) gene mutations were detected in 16% of all patients. Two hundred and seventy-two patients (69%) had received ≥ 2 prior systemic therapies. Response rate was 20.8 %, and median progression-free survival (PFS) was 2.2 months. Estimated PFS and overall survival (OS) at 1-year were 17 % and 55 %, respectively. Multivariate analysis using Cox proportional hazards models identified poor performance status (PS 2-4) and EGFR mutation as independent predictors of PFS (hazard ratio [HR] 2.17; 95% confidence interval [CI], 1.68 to 2.80, P<0.001; HR 1.44; 95% CI, 1.02 to 2.02, P=0.04, respectively). In 255 patients without these negative predictive factors for PFS, response rate was 27.3 %. In these patients, estimated PFS and OS at 1 year were 23 % and 64 %. Severe immune related adverse events (≥Grade 3) were identified in 11.2 % of all patients, and 8.3 % of the patients developed pneumonitis (any grade). Overall incidence of pseudoprogression was approximately 2 %.

Conclusion:
Nivolumab has demonstrated a favorable efficacy and safety profile in real-world patients. Poor PS and EGFR mutation positivity were independent negative predictive factors for PFS. Importantly, pseudoprogression was rare in real-world patients.

Background:
The role of anti-PD-1/PD-L1 inhibitor monotheapy has been demonstrated for advanced non-small cell lung cancer (NSCLC). However, its benefits in terms of response and progression-free survival are limited to small proportion of patients. The successful treatment of advanced NSCLC requires a combination of various treatment modalities. Therefore, this study evaluated whether subsequent chemotherapy administered after immunotherapy (PD-1/PD-L1 inhibitors) (SCAI) would have enhanced antitumor response in patients with NSCLC.

Method:
This study included patients with available response data for their SCAI. We compared the objective response rates of SCIA with those of the last chemotherapy administered before immunotherapy (LCBI).

Result:
In total, 73 patients met the inclusion criteria and were included into the analyses. Among them, 10 patients received PD-1/PD-L1 inhibitors as first-line therapy, and therefore 63 had available response data for LCBI. The ORR of SCAI and LCBI were 53.4% and 34.9%, respectively (P = 0.03). Out of 73 SCAI, 24 were platinum-doublet chemotherapy and 49 were non-platinum monotherapy, and among 63 LCBI, 43 and 20 were platinum-doublet and non-platinum monotherapy, respectively. The ORR for platinum-doublet of SCAI and LCBI were 66.7% (16/24) and 39.5% (17/43), respectively (p = 0.03). The ORR for non-platinum of SCAI and LCBI were 46.9% (23/49) and 25.0% (5/20), respectively (p = 0.09). Figure 1



Conclusion:
The ORR for SCAI was significantly higher than that of LCBI. This data indicate anti-PD-1/PD-L1 inhibitors could make tumors more vulnerable to subsequent chemotherapy.

Background:
Nivolumab, a human IgG4 programmed death (PD)-1 immune checkpoint inhibitor antibody, is approved in Israel and other parts of the world, for the treatment of patients with advanced non-small cell lung cancer (NSCLC) and disease progression during or after platinum-based chemotherapy, without a need to determine the level of PD-L1 expression in the tumor. In this series, we retrospectively analyzed the results of treating patients with NSCLC by nivolumab. This series represents real life results, out of a clinical trial, with broad inclusion criteria.

Method:
A retrospective analysis was carried out in a thoracic oncology service in a tertiary medical center (Tel-Aviv Medical Center), on patients with NSCLC, any subtype. All the patients were treated by nivolumab as part of a generous compassionate program supported by BMS.

Result:
The patients were allocated to one single arm of nivolumab 3mg/kg administered intravenously once every 2 weeks. Response assessment was performed in 63/77 patients who got at least four cycles of nivolumab. There was a complete response in 1 patient, partial response in 11, stable disease in 25, progressive disease (PD) in 25. The observed response rate of nivolumab as a service treatment in unselected patients with unknown PD-L1 status adenocarcinoma of the lung was 19 %. The disease control rate was 58.7%. Median progression free survival (PFS) from the first dose of nivolumab to treatment interruption is 4 months. Survival data were analyzed after 22 months. The overall survival was 34.9%, while PFS was 19.3%. All failures of nivolumab occurred within the first 12 months of administration. Median overall survival (OS) from the first dose of nivolumab till death or last follow up when alive, is 8 months.

Conclusion:
Anti PD1 agents are active and well tolerated in patients with NSCLC. This is based on selected population in clinical trials and on non-selected cohorts reflecting daily service in thoracic oncology units.

Background:
Nivolumab is current standard of care for patients with pretreated advanced non-small cell lung cancer (NSCLC). The patients’ and physicians’ experience of using nivolumab in real-world clinical practice in Taiwan is unknown. We aimed to evaluate the efficacy and safety of nivolumab therapy in Taiwan.

Method:
We retrospectively reviewed the medical records of the patients with age > 20 years who were diagnosed to have advanced NSCLC and received nivolumab therapy through the Expanded Access Named Patient Program in 2016. Nivolumab 3 mg/kg was administered intravenously every 2 weeks.

Result:
A total of 94 patients were included in this analysis. The median age was 60 years (range, 31-76), and 63.8% of these patients were non-smoker. Most of the patients (75.5%) had adenocarcinoma histology, and 34.0% of the patients harbored an EGFR mutation. The median cycle number of nivolumab therapy was 9 (range, 1-28). The median treatment duration was 4.6 months (95% CI, 3.0-6.6). Nivolumab monotherapy is still ongoing in 16 patients (17.0%) on the date of data cutoff. The objective response rate was 13.8%. The median overall survival was 12.0 months (95% CI, 9.2 to not reached). In univariate analysis, sex, age, smoking history, EGFR mutation, squamous histology, and previous extracranial irradiation therapy were not predictors of prolonged survival. Only ECOG performance status (PS) < 2 before starting nivolumab therapy was a predictor of prolonged survival (HR: 0.32; 95% CI, 0.17-0.59). The most common treatment related adverse events (AEs) included fatigue (34.0%), nausea (17.0%), rash (12.8%), asthenia (8.5%), and pyrexia (5.3%). Grade ≧ 3 AEs developed in 7.4% of the patients. All grades interstitial lung disease developed in 4.3% of the patients. One patient died of grade 5 diarrhea after one dose of nivolumab therapy.

Conclusion:
The efficacy and safety data in Taiwan were in line with previous clinical trial reports. Patients with PS < 2 may have better survival outcome after receiving nivolumab therapy.

Background:
In patients undergoing thoracic radiotherapy (TRT), anti-programmed cell death-1 (PD-1) antibodies including nivolumab and pembrolizumab may enhance cytotoxic effects. However, the risk of pneumonitis may be increased and this issue is truly worthy of consideration.

Method:
We retrospectively evaluated a total of 42 patients with non-small cell lung cancer who relapsed after TRT with or without concurrent chemotherapy and have undergone nivolumab at two institutions between December 2012 and May 2017.

Result:
The median age of all patients was 67.5 years (range 39–76 years), and 5 patients (12%) were female. Five patients (12%) had postoperative recurrent disease, 7 patients (17%) had stage IV disease and the remaining 30 patients (71%) had stage III disease. Thirty patients (71%) received thoracic radiotherapy concurrent with cytotoxic chemotherapy. Eleven patients received nivolumab within 6 months after completion of TRT (Group A) and 31 patients received nivolumab more than 6 months after completion of TRT (Group B). For the patients in this study, response rate (RR) was 19% and median progression-free survival was 3.2 months. Group A had significantly shorter PFS than Group B (Group A; 1.4 months vs Group B; 5.5 months, p=0.018, log-rank test). Nine patients (21%) experienced possible treatment-related pneumonitis, two patients were in Group A and 7 patients were in Group B. All three patients who experienced grade 5 pneumonitis were in Group B; received nivolumab after 9 months, 11 months and 46 months after completion of TRT, respectively.

Conclusion:
Patients who were resistant to TRT had significantly shorter PFS. Regarding pulmonary toxicity, the risk of pneumonitis may be higher in the patients who received nivolumab after TRT and more attention should be paid to the patients who received it more than 6 months of completing TRT.

Background:
Nivolumab demonstrated efficacy and safety in patients with previously treated advanced/metastatic NSCLC in the two phase 3 trials CheckMate 017 and 057 (median OS, 9.2–12.2 months; 1-year OS rate, 42–51%; 2-year OS rate, 23–29%; any-grade treatment-related AEs [TRAEs], 68%; grade 3–4 TRAEs, 10%). As patients with ECOG PS 2 were excluded from these phase 3 trials, there is limited evidence for nivolumab efficacy in this patient subgroup. CheckMate 169 (NCT02475382) is an expanded access program (EAP) of nivolumab in patients with advanced NSCLC and disease progression after ≥1 prior systemic therapy; efficacy/safety results from the Canadian cohort are presented here.

Method:
Eligible patients were aged ≥18 years with relapsed stage IIIb/IV NSCLC and an ECOG PS of 0–2 who had received ≥1 prior platinum-containing therapy. Patients with carcinomatous meningitis or untreated brain metastases were excluded. Nivolumab (3 mg/kg IV Q2W) was administered until disease progression or unacceptable toxicity for a maximum of 2 years. In addition to providing nivolumab to patients, the primary objective was to assess safety and OS. Outcomes in specific patient subgroups, including elderly patients (aged ≥70 years) and those with poor performance status (PS 2), were assessed in post hoc analyses.

Result:
Of 161 patients treated in Canada, 53% were male, 94% were current/former smokers, 32% had squamous NSCLC, and 43% had received ≥2 prior therapies. 30% were aged ≥70 years and 19% had an ECOG PS of 2. At the time of analysis, 76% of patients had discontinued treatment. Nivolumab was well tolerated. In the overall population, TRAEs of any grade were reported in 69% of patients, with grade 3 or 4 events in 14%; no TR deaths occurred. 9% of patients discontinued due to TRAEs. The safety profile of nivolumab in patient subgroups (age ≥70 years and PS 2) was similar to the overall population. The median OS (95% CI) in the overall population was 9.1 months (7.5, 14.4), with a 1-year OS rate of 44%. The median OS was 8.0 months (5.3, 12.9) for elderly patients and 5.9 months (3.6, 7.9) for those with PS 2. The presentation will include patient case studies from the subgroups.

Conclusion:
In this EAP of nivolumab in Canadian patients with previously treated NSCLC, safety and OS were consistent with observations from prior controlled trials. Safety in elderly patients and those with PS 2 was consistent with the overall population.

Background:
Survival data with nivolumab are based on selected populations and might not reflect outcomes in clinical practice. Overall Survival (OS) and Progression Free Survival (PFS) with anti-PD1 therapy in a large population of unselected patients with advanced Non-Small-Cell-Lung Cancer (NSCLC) are not well documented. We aimed to assess survival data with nivolumab in a large cohort of unselected patients and association of OS with clinical and biological factors.

Method:
Clinical and survival data were collected in a cohort of NSCLC patients treated with nivolumab who experienced confirmed progressive disease (PD) after ≥ 1 line of chemotherapy (CT). Patients received nivolumab at a dose of 3 mg/kg every 2 weeks until PD or unacceptable toxicity. Nivolumab benefit was analyzed according to PFS and OS. The overall response rate (ORR) was analyzed by RECIST 1.1. Age, response to prior CT, eosinophil counts (Ec), prior radiotherapy (RT), lymphocyte counts (Lc), neutrophil counts (Nc), LDH rate were assessed. Kaplan-Meier and Cox regression were performed.

Result:
257 patients treated with nivolumab were enrolled from 9 centers between Sept. 2015 and Oct. 2016. Median age was 62 years [29-85]; 186 patients were males (72%), 93% PS≤1 at the time of the diagnostic; 220 (86%) smokers; 219 (85%) stage IV ; 130 patients (51%) received prior RT. 163 patients (63%) had adenocarcinoma, 70 (27%) squamous cells carcinoma ; 54 (21%) were KRASmut, 11 (4%) EGFRmut, 3 (1%) ALKpositive. PD-L1 expression was unknown (test not required in current practice for nivolumab). The median of prior lines was 1 [1-6]. Median PFS with nivolumab was 3 months [1,9-4]. Median OS was 15 months [1-; NR]. The ORR was 23% (58 patients), the disease control rate was 42% (109 patients). The median duration of response was 6 months [1- ;16]. Age (> or < 70) (p=0.202), response to prior CT (p=0.05) and Ec ≥ 0.5 G/l (p=0.606) were not significantly associated with improved OS. Prior RT was significantly associated with poor OS (p=0.004). Lc < 1 G/l (p=0.019), Nc ≥ 7 G/l (p=0.018), LDH ≥ 500 U/l (p=0.008), were significantly associated with poor OS.

Conclusion:
1) Efficacy of nivolumab in real life is the same as reported in published studies with a median OS of 15 months in clinical practice. 2) In our study neutrophil, lymphocyte and LDH rates predict a poor OS.

Background:
Immune checkpoint inhibitors have progressed a new treatment option in non-small cell lung cancer. The tumor proportion score (TPS) of programmed death ligand 1 (PD-L1) is a predictive biomarker for determining the efficacy of treatment by immune checkpoint inhibitors. However, the relationship between clinical factors and the TPS is not well understood.

Method:
We retrospectively investigated patients whose samples were submitted for TPS evaluation from January 2017 to May 2017 and compared a TPS of 0% with a TPS of over 1% to identify the correlation between clinical factors and the TPS.

Result:
A total of 86 patients had samples evaluated for the TPS within study period. PD-L1 IHC testing was performed using a PD-L1 IHC 22C3 pharmDx kit for all samples. Two samples were determined to be unsuitable. Age, sex, tissue type, smoking history, performance status, stage, and gene mutation status were investigated as clinical factors. The diagnostic procedure, biopsied organ, tissue, or stored samples were investigated for their association with the TPS. The chi-square test was performed for the univariate analysis of all these factors. There was a significant difference in a TPS of 0% and a TPS of more than 1% in patients with ADC (P = 0.0339, odds ratio: 0.352, 95% CI: 0.0427–0.959) and an EGFR mutation (P = 0.0417, odds ratio: 0.427, 95% CI: 0.250–0.729). In addition, female sex tended to be associated with a TPS of 0% (P = 0.0526, odds ratio: 0.575, 95% CI: 0.335–0.986). However, SCC (P = 0.0113, odds ratio: 0.288, 95% CI: 0.0745–0.802), TBLB (p = 0.0278, odds ratio: 0.288, 95% CI: 0.0873–0.0951), and EBUS-TBNA (P = 0.0161, odds ratio and 95% CI: not applicable) were identified as factors associated with a TPS of over 1% in the same statistical analysis. Lymph node biopsy tended to be associated with a TPS of over 1% (P = 0.0643, odds ratio: 0.263, 95% CI: 0.0543–1.28).

Conclusion:
Adenocarcinoma and EGFR mutations are associated with a TPS of 0%, and squamous cell carcinoma is associated with a TPS of over 1%.

Background:
Immune checkpoint inhibitors are the standard of care for non-small cell lung cancer (NSCLC) patients following first line therapy. There is limited information available on the outcomes of patients receiving these therapies for NSCLC outside of a clinical trial.

Method:
We retrospectively collected data from patients who received Nivolumab for advanced NSCLC on the Bristol-Myers Squibb (BMS) Access Program across four tertiary oncology institutions in Brisbane, Australia, to analyse their outcomes in a real-world setting, and compare these outcomes to those in Phase III randomised clinical trials.

Result:
85 patients were enrolled to this Ethics Committee approved audit - 32 females (37.6%); 53 males (62.4%); 54, PS 0-1 (63.5%); 30, PS 2-3 (35.3%); median age 67 yrs (range 42-84). 84 patients were evaluable for progression. 20% (17/84) of patients had a radiological partial response (PR) during the course of their treatment, and an additional 22.4% (19/84) patients had stable disease (SD) as their best response. In PS 0-1, 24% (13/54) had a PR, compared with only 10% (3/30) in PS 2-3 patients. The overall median progression-free survival (PFS) was 1.8 months, being 2.7 months in PS 0-1 versus 1.2 months in PS 2-3 patients. Median overall survival (OS) was 5.9 months; 6.5 months in PS 0-1 versus 2.3 months in PS 2-3 patients. Median OS for adenocarcinoma was 6.2 months, versus 4.7 months for squamous cell carcinoma. At 12 months after initiation of nivolumab 34% of patients were alive; 44% PS 0-1 versus 16% PS 2-3 patients. Grade 3 or 4 treatment related adverse events were observed in 10% of patients. Analysis of the prognostic relevance of routine haematological and biochemical parameters is ongoing.

Conclusion:
Nivolumab has clinically significant long term benefits in the treatment of relapsed NSCLC with 12 month survival rates in keeping with clinical trials in PS 0-1 patients. The development of predictive biomarkers remains central to identifying those patients, particularly with poor performance, most likely to benefit from immune checkpoint inhibitors.

Background:
Immunotherapy is now part of the standard of care for the treatment of metastatic non-small cell lung cancer (NSCLC). Immune checkpoint blockers, including anti-PD1 and anti-PDL1 therapies are generally well tolerated, but pose a risk of immune-related toxicities. With 40-50% of patients surviving at 12 months post second-line nivolumab treatment, survivorship concerns such as quality of life need to start being considered in these patients. Immune-related musculoskeletal symptoms are often overlooked, but can result in significant morbidity for a patient.

Method:
We present a case series of four patients who developed significant anti-PD1-induced rotator cuff injury during treatment for either metastatic NSCLC or metastatic mesothelioma.

Result:
Three patients were given nivolumab for advanced NSCLC, and one patient was given pembrolizumab for metastatic epithelioid mesothelioma. The severity of rotator cuff injuries ranged from tendonitis and bursitis, to a full thickness rotator cuff tear. One patient had bilateral rotator cuff injuries. The symptoms began 6-12 weeks after commencing immune checkpoint anti-PD1 therapy and resulted in significant morbidity for the patients in terms of daily activities. All injuries were managed conservatively with a combination of steroid injections, anti-inflammatories and physiotherapy. Pembrolizumab was ceased in the mesothelioma patient after 6 cycles, and the musculoskeletal symptoms rapidly resolved. Two of the NSCLC patients ceased nivolumab due to progressive disease, at 5 months and 9 months respectively. The third NSCLC patient continues on nivolumab, with stable disease at 17 months. In the NSCLC patients who had continued on nivolumab despite musculoskeletal symptoms, the rotator cuff injuries settled over time with conservative management.

Conclusion:
Immune-related musculoskeletal symptoms are inadequately reported in clinical trials, but can result in significant morbidity for patients, and therefore may impact on their compliance with immune checkpoint blockade therapy. Increased vigilance and prompt management of this condition within the context of multi-disciplinary care may assist with symptom-control.

Background:
CheckMate 032 (NCT01928394) is an open-label, phase 1/2 trial evaluating the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab in patients with advanced or metastatic solid tumors. In this study, nivolumab ± ipilimumab showed durable responses, encouraging survival, and manageable safety in patients with small-cell lung cancer (SCLC) that progressed after ≥1 previous platinum-containing regimens. An exploratory objective is to describe changes in patient-reported health status using the EuroQoL-5 Dimensions (EQ-5D) instrument.

Method:
The EQ-5D visual analog scale (VAS; scale: 0–100 [worst–best health]; minimally important difference [MID]=7) was assessed in the treatment period at baseline (week 1 prior to study drug administration) and then every 2 weeks in the nivolumab (3 mg/kg) arm and at baseline and then every 3 weeks in the nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) arm through week 13, and in both arms at subsequent tumor assessments (every 6 weeks until week 24 and every 12 weeks thereafter). After treatment discontinuation, the EQ-5D was assessed at follow-up visits 1 and 2, and at survival visits. EQ-5D VAS mean and mean within-patient change from baseline were estimated at each assessment. Time to first deterioration (TTD) in health status was also evaluated.

Result:
In the nivolumab (n=245) and nivolumab plus ipilimumab (n=156) arms, EQ-5D VAS completion rates were 90% and 85%, respectively, at baseline and remained ≥60% at the last assessment (≥5 patients/arm; weeks 97 and 121, respectively). Baseline mean EQ-5D VAS scores for the nivolumab and nivolumab plus ipilimumab arms were 67.1 and 65.2, respectively, scores similar to a lung cancer population norm (68). With monotherapy, EQ-5D VAS mean within-patient changes from baseline suggested health status stability while on treatment (estimated changes
Conclusion:
Preliminary EQ-5D VAS results from CheckMate 032 showed that on-treatment health status in patients with recurrent SCLC remained stable with nivolumab and improved (ie, increases in scores exceeded the MID) with nivolumab plus ipilimumab. For patients remaining on treatment for ≥6 months, mean EQ-VAS scores in both arms trended towards the population norm.

Background:
Nivolumab has been established as a novel standard of care in patients with pre-treated non-small-cell lung cancer (NSCLC). Patients treated with nivolumab sometimes experience its unique adverse events, called immune-related Adverse Events (irAEs). Given the mechanisms of action of immune-checkpoint inhibitors (ICIs), occurrence of irAEs may potentially reflect antitumor response. Here, we report the clinical correlation between irAE and efficacy in NSCLC patients treated with nivolumab.

Method:
Between Dec 2015 and Feb 2017, 38 advanced NSCLC patients were treated with nivolumab at our institution. All patients were enrolled in our single-institutional observational cohort study (UMIN000024414). We divided the patients into two groups: irAEs group and no-irAEs group and evaluated the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Efficacy was assessed by RECIST version 1.1, and toxicity was graded based on CTCAE version 4.0.

Result:
Of thirty-eight, median age was 68.5 (range, 49 to 86), 74% was male, 68% was non-squamous cell carcinoma, and 82% was performance status of 0-1. Among overall population, ORR was 23.7%, and median PFS was 91 days. Eleven patients (29%) experienced irAEs and median time to onset irAEs was 53 days (range, 14 to 213 days). There was no significant correlation observed between PD-L1 expression on tumor and occurrence of irAEs. Most common irAE was pneumonitis (n = 5) and others were hypothyroidism (n = 4), hyperthyroidism, hypopituitarism, hepatitis, rash and elevated thyroid stimulating hormone (one, each). Patients with irAEs had significantly higher efficacy compared with those without (ORR: 63.6% versus 7.4%, p < 0.01 (Fisher’s exact test), mPFS: not reached (NR) versus 49 days, p < 0.01 (log-rank test). Landmark analysis in patients who achieved progression free ≥ 12 weeks showed a similar trend (p = 0.07). Next, we performed additional analyses on correlation with specific irAEs. Patients with pneumonitis and those without demonstrated similar outcome (p = 0.95 (log-rank test)). With regard to endocrine irAEs, the similar result was also observed (p = 0.95 (log-rank test)).

Conclusion:
In our study, there was a correlation between irAEs and efficacy in NSCLC patients treated with nivolumab. Occurrence of specific irAE was not necessarily associated the efficacy.

Background:
The past several years have witnessed unparalleled changes in treatment for patients with advanced NSCLC. Although these changes present significant hope, it remains unclear if oncologists have been able to stay current on the breadth of practice changes, and effectively incorporate evidence-base into practice. The objective of this study was to evaluate oncologists’ competence regarding the use of immune checkpoint inhibitors (ICI) in the management of advanced NSCLC and the impact of education on narrowing gaps in clinical practices.

Method:
An online education environment that employed video vignettes to simulate practice, presented 3 CME-certified case activities, each illustrating a clinical challenge. Questions regarding point-of-care decisions were posed as a means of testing the oncologist’s ability to make treatment decisions and to communicate effectively with patients who have NSCLC. These case activities included patients with non-squamous and squamous NSCLC and who exhibited adverse events. For each activity, an assessment instrument using case-based, multiple-choice questions was administered to compare each oncologist’a responses to questions posed before and after the education was presented. Confidentiality of respondents was maintained, responses were de-identified, and aggregated prior to analyses. McNemar's χ[2] test compared learners' responses from pre- to post-assessment. The activities were launched between October 21, 2016, and December 6, 2016, and data were collected through April 26, 2017.

Result:
2,399 oncologists participated in at least one of the 3 activities. Responses of 325 participants who answered all questions during the study period were included. Upon completion of the activities, an improvement was observed in oncologists’ ability to: Identify the correct evidence-based regimen including when to use ICIs for a patient that has progressed on first line therapy (76% vs 98%, P <0.001) Counsel patients on the expected effectiveness of ICI in patients (69% vs 89%, P <0.001) Select the most appropriate monitoring strategy to detect immune-related adverse events in patients receiving an ICI (52% vs 78%, P <0.001) Order appropriate tests to identify the etiology of symptoms that appear during treatment (60% vs 92%, P <0.001) Properly manage immune-related adverse events due to treatment with ICI (67% at baseline to 88% post education, P =0.001) In addition, comfort with prescribing ICIs also increased.

Conclusion:
Use of online, case-based CME utilizing video vignettes to simulate practice improved competence among participating oncologists, demonstrating that online CME can be an effective tool to improve clinical decision-making in the rapidly changing environment of advanced NSCLC disease management.

Background:
Despite significant improvement of clinical outcomes of the patients with advanced non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors, our knowledge of optimal predictive and prognostic biomarkers are still evolving.

Method:
We retrospectively evaluated 159 advanced NSCLC patients who received nivolumab after platinum-based chemotherapy. We correlated several variables with progression free survival (PFS) to develop the iSEND model (Sex, ECOG [Performance status], NLR [Neutrophil-to-Lymphocyte Ratio] & DNLR [Delta NLR = NLR after treatment - pretreatment NLR]). We categorized the patients into good, intermediate, and poor iSEND groups and evaluated clinical outcomes of each group. Performance of iSEND model was evaluated at 3, 6, 9, and 12 months by receiver operating characteristic (ROC) curves. We performed bootstrap internal validation to evaluate the predictive performance of the iSEND model by using the split-sample validation technique. We used logistic regression to correlate different iSEND groups and clinical benefit.

Result:
The median follow-up was 11.5 months (95% C.I.: 9.4-13.1). There were 50 deaths and 43 other progressions without death. The 3-, 6-, 9-, and 12-months PFS rates were 78.4%, 63.7%, 55.3%, and 52.2% in the good group, 79.4%, 44.3%, 25.9% and 19.2% in the intermediate group, and 65%, 25.9%, 22.8%, and 17.8% in the poor group, respectively. (Figure 1) Time-dependent area under curves (AUC) of the iSEND model for PFS at 3-, 6-, 9-, and 12-months were 0.718, 0.74, 0.746, and 0.774. The poor iSEND group had significant correlation with progressive disease compared to the good group at 12+/-2 weeks. Figure 1. Kaplan-Meier curves for Progression Free Survival of different iSEND model groups Figure 1



Conclusion:
The iSEND model is an algorithmic model that can categorize clinical outcomes of advanced NSCLC patients receiving nivolumab into good, intermediate, or poor groups and may be useful as a predictive model.

Background:
PD-1/PD-L1 blockade has rapidly been adopted for treatment of NSCLC. However, much remains to be learned about the implications of the side-effect profile of PD-1/PD-L1 blockade. We previously showed that the 38 patients who experienced a treatment related AE (trAE) on the KEYNOTE-001 trial at UCLA had superior clinical outcomes compared to the 59 that did not. Treatment related hypothyroidism was the most predictive trAE for response to therapy [objective response rate (ORR): 83.3% (5/6 patients with response)]. The highly predictive nature of treatment related hypothyroidism led us to further evaluate the implications of thyroid dysfunction in our patient cohort by analyzing the association between therapeutic efficacy and thyroid specific laboratory values obtained on trial.

Method:
We performed a retrospective analysis of the 97 NSCLC patients treated on KEYNOTE-001 at UCLA with either 2 mg/kg Q3W or 10 mg/kg Q2/3W of pembrolizumab (data cut-off 12/2016). Patients had Thyroid Stimulating Hormone (TSH), free Thyroxine 4 (fT4), and Triiodothyronine (T3) assessed at baseline (prior to therapy), cycle 2, and every other cycle thereafter. In some instances, labs were obtained at safety follow-up and unscheduled visits. Tumor response was evaluated using investigator assessed immune related response criteria (irRC), with imaging q9wks.

Result:
97.9% (95/97) of the patients treated at UCLA on KEYNOTE-001 had a baseline set of thyroid indices, while 74.7% (68/97) had >3 sets of values. Patients with an abnormal TSH during study participation had a higher ORR, 35.5% (11/31), than those that did not, 14.1% (9/64) (p=0.0296), with an acquired TSH abnormality (first observed after C1D1) more predictive of response than a baseline abnormality [acquired TSH abnormality: ORR 42.9% (9/21) vs baseline abnormality: ORR 20% (2/10)]. An abnormal fT4 or abnormal T3 on trial were also both independently associated with improved response to therapy [fT4 abnormality+: ORR: 50% (5/10) vs fT4 abnormality-: 17.7% (15/85) (p=0.0317) and T3 abnormality+: ORR 47.4% (9/19) vs T3 abnormality-: ORR 14.5% (11/76) (p=0.0037)]. As with TSH, acquired fT4 and T3 abnormalities were associated with higher ORR than baseline abnormalities.

Conclusion:
Thyroid dysfunction, assessed by abnormalities in TSH, fT4, or T3, was associated with improved efficacy of pembrolizumab on the KEYNOTE-001 trial at UCLA and an acquired thyroid abnormality, defined as first occurrence after C1D1, was more predictive of improved efficacy than a baseline abnormality. Future work is ongoing to evaluate this association in a larger patient population and molecular mechanisms that may be underlying this observation.

Background:
Nivolumab is a fully human IgG4 programmed death-1 (PD-1), an immune checkpoint inhibitor antibody and it has demonstrated durable responses and tolerability in heavily pretreated patients with advanced NSCLC. This is an observational study to describe our experience with Nivolumab in previously treated patients with advanced NSCLC .

Method:
The aim of the study was to report the efficacy and safety profile of Nivolumab in pretreated patients with advanced NSCLC of our everyday clinical practice. The exploratory assessments include the progression-free survival (PFS) and overall survival (OS) and the rates of treatment related adverse events (AEs). Elegibility criteria included, histologically or citologically confirmed NSCLC clinical stage IIIB vs IV, evaluable disease, at least one prior therapy from January of 2016 to current date.

Result:
From January of 2016 to May of 2017 , a total of 46 patients were enrolled in the study from our Hospital. The patients demographics were: median age 64 years (47-77), 6 (14%) female and 38 (86%) male. El 61% (n=27) non squamous-cell and 39% (n=17) squamous-cell carcinoma. The stage was IV in 71%(n=53) and III in 29% (n=13) .All the stage III patients have been treated with concurrent chemoradiotherapy. 41 patients ( 93%) have received platinum-based therapy previously to Nivolumab : 22 ( 50%) combined with Premetrexed and 19 (43%) with other drugs. 72% (n=20) have been treated with 2 or more prior therapy lines. Among 48 patients evaluated the best response to Nivolumab was: 4% (n=2) complete response, 36%(n=34)partial response and 25%(n=11) disease stabilization At the time of database lock, the median of PFS with Nivolumab was 2.3 IC 95% (1.2-2.7) and OS was not reached. Grade 1-2 treatment related adverse events (AEs) occurred in 32% patients and the most common ones were endocrine 16% (n=7) and neumonitis 4% ( n=2) but there were one case isolated of grade 3-4 encephalitis, nephritis and hypophysitis. The 4% ( n=29) patients need to be admitted to the hospital due Nivolumab toxicity versus 16% due to chemotherapy toxicity.

Conclusion:
Early data from this study suggest that Nivolumab is effective and well tolerated in patients with pretreated advanced NSCLC but in our serie the toxicity was relevant with some patients

Background:
PD-1 inhibitors are new anti-cancer treatments that aimed to re-instate the natural anti-cancer immune-mediated cytotoxicity. Although this new class of therapy offers hope for many advanced stage cancer patients (pts), little is known on the characteristics of pts who are likely to respond. We hypothesized that response rate (RR) and overall survival (OS) would be inversely associated with pre-treatment tumor volume (PTV), independent of other variables such as age, lymph node (LN) metastasis and liver metastasis.

Method:
Data from NSCLC pts who received at least one dose of PD-1 inhibitors before August 31, 2016 were captured from our institution’s pharmacy database. The primary objective was to determine the correlation of PTV to best response, evaluated using RECIST v1.1 criteria. PTV was measured using the Philips Intellispace Multi-Modality Tumor Tracking (MMTT) application. Secondary objectives were estimation of progression free survival (PFS) and overall survival (OS).

Result:
Data on 113 NSCLC pts with at least one site of measurable disease were captured. They received at least one dose of PD-1 inhibitors prior to data cut-off. Median age was 64 (IQR: 57-70). 64 (56.6%) were male. 69 (61.1%) were treated on a clinical trial. There were 75 (66.4%) adenocarcinoma, 32 (28.3%) squamous cell carcinoma (SCC) and 6 (5.3%) poorly differentiated NSCLC. Median PTV was 60.2 cm[3] (IQR: 15.1-115.8). 89 (78.8%) pts had LN metastasis and 25 (22.1%) had liver metastasis at baseline prior to treatment. 2 (1.8%) had complete response, 25 (22.1%) had partial response, 42 (37.2%) had stable disease and 34 (30.1%) had progression of disease documented as their best response. The association between PTV and best response, considered as an ordered 4-category variable was not strong (Kendall’s tau-b=0.11, p=0.14). PTV, age and LN metastasis were not associated with OS with hazard ratio and p value of hazard ratio (HR) 1.1 [95%CI 0.9-1.46] p=0.26, HR 1 [95%CI 0.96-1.01] p=0.29 and HR 0.8 [95% CI 0.39-1.52] p=0.45, respectively. However, having liver metastasis prior to treatment was associated with significantly shorter survival with HR 2.6 [95%CI 1.35-4.81] p=0.004.

Conclusion:
Contrary to our hypothesis, pre-treatment tumor volume in NSCLC did not prove to be a predictor of response to PD1 inhibitors but having liver metastasis prior to treatment was associated with significantly shorter survival.

Background:
Despite the impressive benefits of the immune checkpoint blockade in NSCLC, its use can be hampered by the occurrence of serious adverse events. IRcutAEs are underestimated and poorly described according to data from the clinical trials.

Method:
Before starting immunotherapy, all NSCLC p were prospectively referred to the Dermatology Department. Periodic monitoring visits were also scheduled for each p, in order to describe the IRcutAEs and their treatments. The study included data from all consecutive NSCLC p treated with immunotherapy in our institution.

Result:
Since May 2016, 50 p were recruited for the present study. According to clinical characteristics; 18 p had squamous histology, 43 p received treatment as second line or further, and 36 p were treated with nivolumab. During the follow-up period, 15 p (30%) developed IRcutAEs. Lichenoid reactions were the most common AE (9 p, 60%), but some specific conditions were also observed, such as a cutaneous lupus (1 p, 6.6%) or an eruptive pseudoangiomatosis (1 p, 6.6%).

Conclusion:
IRcutAEs are common during antiPD1-PDL1 therapy. By offering a dermatological follow-up, the diagnosis and management of this type of toxicity can be provided to NSCLC p initiating immunotherapy.

Background:
Nivolumab (NIV) is a standard second-line treatment for previously treated patients with advanced non-small cell lung cancer (NSCLC). Although there is a possibility that a higher effect can be expected by combination NIV and cytotoxic agents, verification in a clinical trial is required. Because there was only one report of phase Ib trial (N=6) of NIV + docetaxel (DTX) combination (Kanda et al, Ann Oncol 2016), we planned a feasibility study to examine the safety of this combination prior to large scale clinical trials.

Method:
Eligibility criteria included a history of platinum-based chemotherapy, PS 0-1, and adequate organ functions. Patients received NIV 3 mg/kg (days 1, 15) and DTX 60mg/m[2 ](day 1) every 4 weeks for a maximum of 2 courses. The primary endpoint was safety of 1st course and evaluated dose-limiting toxicities (DLT). This study used a 3 + 3 design and was considered to be feasible if DLT occurred in one-thirds or less of the patients. The secondary endpoints were the adverse events and the response rate. DLT was defined in accordance with the phase Ib study of Kanda et al .

Result:
Between Aug 2016 and Sep 2016, three patients were enrolled into this trial in 2 centers in Japan. First case was 57 years old female / adenocarcinoma, 2nd case was 44 years old male / squamous cell carcinoma, 3rd case was 58 years old male / adenocarcinoma. Grade 3 or more adverse events occurred only in one case of Grade 4 neutropenia, and no DLTs were observed in any cases. All patients completed 2 courses and objective tumor responses were PD, SD, PR, respectively. Two of three patients still survive more than 10 months from start of this therapy.

Conclusion:
NIV+ DTX combination therapy was acceptable for safety and further evaluation is warranted. Because the use of combination NIV plus cytotoxic agents is not approved in Japan, we are planning to conduct a phase II / III trial (CONDUCT study) comparing NIV + DTX with NIV alone in previously treated patients with advanced NSCLC in the Thoracic Oncology Research Group (TORG), using an Advanced Medical Healthcare in Japan.

Background:
To evaluate the efficacy and safety of PD-1 antibody in first-line treatment of advanced lung squamous cell carcinoma

Method:
To analyze the short-term efficacy and related adverse effects of PD-1 antibody in one elderly patient with advanced squamous cell carcinoma of the lung.

Result:
An eighty-year-old male was hospitalized due to "cough with blood-stained sputum for two months", who was physically healthy in the past years and had a long-term history of smoking. Two months ago, he began to cough with blood-stained sputum occasionally. He had no chest pain, dyspnea, fever and night sweat. He went to local hospital for diagnosis and chest CT showed right upper lobe mass and atelectasis. The up-mentioned symptoms got worse one month ago and percutaneous aspiration lung biopsy was performed in local hospital. The pathological study showed squamous cell carcinoma of lung and the result of EGFR mutation testing was wild type. After transferring to our hospital, bronchoscopy revealed lumen in upper right was completely obstructed by neoplasm and trachea and right middle bronchus presented with compressive stricture. Biopsy was performed and immunohistochemistry study confirmed the diagnosis of lung squamous cell carcinoma. PD-L1 immunohistochemistry staining found high expression of PD-L1 in nucleus. No abnormal result was found in baseline assessment of routine blood count, biochemistry analysis of blood, thyroid and adrenal cortex function. PD-1 antibody 200mg, d1, Q3w was used according to the instructions. In routine assessment before the second cycle of treatment, he was found hyperthyroidism and adrenal insufficiency, but the patient had not any related symptoms. Thus, the adverse effects were designated as grade 1, unnecessary for intervention. The serum tumor marker related to squamous cell carcinoma was significantly reduced, so he continued to receive the treatment according to previous schedule. During the assessment before the third cycle of treatment, the routine blood test and all serum tumor markers were found normal. Chest CT showed partial remission of the neoplasm according to RECIST criteria. There was no further deterioration in thyroid and adrenal cortex function, etc.

Conclusion:
Significant objective response to PD-1 antibody could be expected in first-line treatment of advanced squamous cell carcinoma of lung with high PD-L1 expression. but early-onset abnormal function of multi-organ may occur simultaneously which warrants intensive focus and follow-up.

Background:
Immune-related adverse events occur in a subset of patients (pts) treated with immune checkpoint inhibitors blocking PD1/PD-L1 interaction. It has been reported that NSCLC pts treated with pembrolizumab who developed thyroid dysfunction (TD) had better clinical outcome. In this retrospective study, we examined the prognostic value of TD in advanced NSCLC pts treated with nivolumab.

Method:
Ninety-seven pts with advanced NSCLC treated with nivolumab in second and latter lines out of clinical trial at the Institut Català d’Oncologia (Barcelona, Spain) between November 2015 and March 2017 were included in this analysis. Thyroid tests were assessed at baseline and at the clinician’s discretion during treatment. TD was defined as abnormal levels of TSH value during nivolumab treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method.

Result:
Of 97 pts, most patients received nivolumab in second line (73%). The median age was 63 years (38-82), most were men (76%), former or active smokers (87%), with adenocarcinoma (59%) or squamous cell carcinoma (31%), and had good performance status (88% ECOG PS 0-1). With a median follow-up of 8 months, 42 (43%) patients had died and 60 (62%) presented progressive disease. Sixteen pts (16.5%) developed TD that was G1 (9, 56%) or G2 (7, 44%). Two pts who developed G2 hyperthyroidism required steroid treatment and 5 pts who developed G2 hypothyroidism received substitutive hormone therapy. Median time until TD was 41 days (95% CI 37-45) and pts with TD received more cycles of nivolumab compared with euthyroid pts (11.5 versus 4, respectively). Pts with TD were more likely to achieve a tumor response compared to euthyroid pts (44% versus 14%, p=0.13). Median PFS and OS were significantly longer in pts who developed thyroid dysfunction compared with euthyroid pts. Median PFS was 3.7 months in euthyroid pts vs NR in pts with TD (p=0.001; odds ratio, 0.14; 95% CI 0.04-0.48) and median OS was 8.1 months vs NR, respectively (p=0.005; odds ratio, 0.15; 95% CI 0.03-0.69).

Conclusion:
This real-world data analysis showed that treatment-related TD predicts favorable clinical outcome from nivolumab in advanced NSCLC pts. A comprehensive analysis of thyroid stimulating hormone (TSH) kinetics will be presented at the meeting.

Background:
Nivolumab is a human IgG4 monoclonal antibody that targets programmed cell death-1 (PD-1). In advanced non-small-cell lung cancer patients, nivolumab has been well tolerated. However, some patients develop nivolumab-related pneumonitis.

Method:
We retrospectively analyzed the clinical features and prognosis of nivolumab-related pneumonitis in non-small cell lung cancer patients in the institutions of the Nagasaki Thoracic Oncology Group.

Result:
From January 1, 2016 to May 31, 2017, 101 non-small cell lung cancer patients were treated with nivolumab monotherapy and 8 patients (7.9%) developed nivolumab-related pneumonitis. 7 were male, and 1 was female, with a median age of 70 years. The histological subtype was squamous cell carcinoma in 3 patients, non-squamous cell carcinoma in 5 patients. 6 patients were stage III or IV. 2 patients were postoperative recurrence. Radiographic pattern was cryptogenic organizing pneumonia (COP) in 6 patients and acute interstitial pneumonia (AIP)/acute respiratory distress syndrome (ARDS) in 2 patients. The median time from nivolumab treatment initiation to development of pneumonitis was 8.5 weeks (range, 1-16). 2 patients of AIP/ARDS pattern developed pneumonitis within 2 weeks. Bronchoalveolar lavage conducted in 4 patients and bronchoalveolar lavage fluid revealed elevation of lymphocyte in all patients. All patients received corticosteroids. 6 patients of COP pattern had clinical and radiographic improvement. 2 patients of AIP/ARDS pattern worsened clinically and died during the course of pneumonitis treatment. One of patient experienced recurrent pneumonitis in the course of corticosteroid taper.

Conclusion:
We retrospectively analyzed the clinical features and prognosis of nivolumab-related pneumonitis in non-small cell lung cancer patients. Nivolumab-related pneumonitis showed variable onset and radiographic patterns. COP pattern was most common. Most patients were successfully treated with corticosteroids, but AIP/ARDS pattern was risk of poor prognosis.

Background:
Dose-dense cisplatin and daily oral etoposide +/- bevacizumab, mAb to the vascular endothelial-growth factor is a safe and active treatment for un-resectable NSCLC patients. It elicited remarkable Immunological effects, including rise in central-memory-T-cells and activated-dendritic cells and decline in regulatory-T-cells, potentially additive to anti-PD-1/PDL-1 immune-checkpoint inhibition. We therefore, performed a retrospective analysis aimed to evaluate both overall survival (OS) and progression free survival (PFS) in patients receiving treatment with Nivolumab, a mAb to PD-1, after they had received different first line chemotherapy regimens.

Method:
Statistical analysis (Log-rank test) was performed on forty-nine consecutive NSCLC pts engaged to receive Nivolumab (3mg/kg every 15 days) between October 2015 and December 2016. All of them had received frontline platinum-based doublets for advanced disease and 15 of them had received the mPEBev regimen.

Result:
A prolonged PFS was found in patients who received frontline mPEBev compared to the other treatments (mPEBev vs. standard doublets: 14.30 vs. 7.9 months; p=0.038). In this group, we also detected a trend to longer survival (mPEBev vs. standard doublets: 15.6 vs. 11.34 months; p=0.107 with a 12-month-OS-rate of 79% and 32.6%, respectively). We finally recorded that baseline neutrophil and LDH values were correlated with both PFS (neutrophil counts < vs. ≥ median value: 6.28 vs. 14.4 months; P=0.095. LDH < vs. ≥ median value: 14.25 vs. 8.53 months; p= 0.036) and OS (neutrophil counts < vs. ≥ median value: 9.6 vs. 16.8 months; p= 0.101, with a 12-month OS-rate of 42% vs 63%, respectively; LDH < vs. ≥ median value: 16.66 vs. 11.51 months; p=0.039).

Conclusion:
Frontline chemotherapy may affect the efficacy of Nivolumab treatment; the mPEBev regimen, in particular, may induces immunological patterns able to improve the effectiveness of PD-1/PDL-1 blockade. Perspective studies and immunological correlations are presently ongoing.

Background:
Anti-PD1/PDL1 immunotherapy has been regarding as standard second line therapy in patients with advanced NSCLC, also as the 1[st] line setting in subpopulation with PDL1 expression of more than 50%. Anti-PD1/PDL1 drugs such as nivolumab, pembrolizumab and atezolizumab showed a durable response in those benefit population, while immune-related adverse events(irAEs) were also frequently happened. This study aimed to describe the high-risk factors for irAEs in patients with advanced NSCLC after the treatment of anti-PD1/PDL1 monoclonal antibody.

Method:
We retrospectively reviewed 72 patients with advanced non small cell lung cancers treated with PD-1/PD-L1 inhibitors (nivolumab =27, pembrolizumab =44, atezolizumab =1) in Shanghai Pulmonary Hospital from Jun 2015 to May 2017. All adverse events were assessed and classified by grades according to NCI CTCAE (version 4.0).

Result:
AEs occurred in 34 patients (47.22%). Grade 1 or 2 events included increased amylase (5), increased lipase (5), transaminitis (4), rash/ pruritus (4), xerostomia (3), nausea (3), fatigue(3), anemia (3), decreased WBC (2), hypokalemia (2) and fever, arthralgia, sense of neck stiffness, cardiac arrhythmia, decreased PLT and hypocalcemia in 1 patient each.Twelve (16.67%) patients experienced grades 3-5 events including 6 cases with ILD(grade 5=1), 3 with pleural effusions/pericardial effusions, 2 with hypothyroidism, and 1 with grade 3 fatigue. Subgroup analysis showed that patients with BRAF mutations(2 with adenocarcinomas,1 with squamous carcinomas and 1 with NSCLC) experienced significantly higher rate of serious AEs (2 ILD and 2 pleural effusions) after receiving pembrolizumab (100%vs 11.76%,p＜0.001), while it was similar according to the other driver genes mutation status (EGFR, KRAS, HER2, ALK). Patients with poor ECOG PS experienced a marginally statistically significant higher grade 3-5 AEs (p=0.063), while it was similar according to different subgroup of age (p=0.538), gender (p=0.189), histological type (p = 0.999), smoking status (0.122), lines of previous therapy (p=0.172), baseline serum LDH level(p=0.290) and CD8+ of peripheral blood (p=0.814). In addition, prior thoracic radiation has a numerical higher prone to develop ILD (23.07%vs 5.08%, p = 0.116).

Conclusion:
Poor performance status and BRAF mutation might predict irAEs in patients with advanced NSCLC receiving PD-1/PD-L1 inhibitors, further large cohort study is warranted to investigate the high-risk factors for irAEs in patients with advanced NSCLC.

Background:
Data are mounting regarding rare mutations such as MET (exon 14 skipping mutation and MET amplification), ROS1 translocation and rare EGFR mutations and response to targeted therapy, simultaneously data are increasing concerning treatment of Non-Small Cell Lung Carcinoma (NSCLC) patients with immune check point inhibitors. As yet, the role of immunotherapy in patients with rare genomic alterations has not been determined. We describe a case series of patients who can benefit from both therapies and summarizes their response for each treatment.

Method:
We present a retrospective case series of four patients with NSCLC and genomic alterations, diagnosed and treated from November 2015 to June 2017 in a single tertiary center with targeted therapy and immunotherapy. Hybrid capture-based next generation sequencing was performed.

Result:
Two males and two females (mean age 58) were included. Three of them were diagnosed with Adenocarcinoma and the remaining one was diagnosed with squamous cell carcinoma. Each patient was diagnosed with a specific gene alteration (C-met exon 14 skipping mutation, EGFR Q861L, MET amplification and ROS1 translocation). Patients underwent targeted therapy as well as immunotherapy. Two patients had PD-L1 staining >50%. One patient demonstrated an early and durable complete response with immune check point inhibitors, one patient had progressed on immunotherapy quickly but respond well to targeted therapy, two patients responded as expected to targeted therapy and got immune check point inhibitors as a second line and still being treated with good response.

Conclusion:
The role of immunotherapy for patients with uncommon EGFR mutations, ROS1 and C-MET who express PD-L1 is still unclear. Further studies in this unique population are needed.

Background:
Treatment with PD-1/PD-L1 inhibitors are now the standard of care for patients with advanced non-small cell lung cancer. PD-L1 expression, in addition to interferon score and tumour mutational burden, are predictive biomarkers, however early clinical predictive biomarkers are lacking.

Method:
Patients with NSCLC who received treatment with PD-1/PD-L1 inhibitors between 1 Jan 2014 – 31 Dec 2016 were retrospectively identified from electronic health records. Data was collected on patient, treatment and tumour characteristics. Discrete variables were compared using Fisher’s exact test. Odds ratios (OR) were calculated with 95% confidence intervals (CI) for significant associations, using contingency tables.

Result:
We identified 91 patients, with a mean age of 65 years, of whom 52% were male. The majority were ex-smokers (69.2%), followed by never smokers (23.1%). Non-squamous histology was seen in 59.3% of patients and 86.8% of the patients had ECOG performance status 0-1. The lactate dehydrogenase (LDH) at baseline, cycle 2, and the change-in LDH≥10% at cycle 2 and 6 weeks, did NOT predict for disease control rate (DCR) at the first tumour response evaluation (TRE). A LDH ≥ upper limit of normal at 6 weeks DID predict disease progression at the first TRE (P-value=0.04), with an OR of 3.58 (95% CI 1.11 – 11.52). The neutrophil-lymphocyte ratio (NLR) at baseline and 6 weeks, and the change-in NLR>10% at cycle 2 and 6 weeks did NOT predict for DCR at the first TRE. A NLR ≥5 at cycle 2 DID predict for disease progression at the first TRE (P-value=0.008), with an OR of 3.92 (95% CI 1.48 – 10.39). Receiver operator curve analysis of the early LDH/NLR score (1 point each for 6 week LDH ≥ upper limit of normal and cycle 2 NLR ≥5) predicted for disease progression at the first TRE (C-index 0.77, P-value <0.0001).

Conclusion:
The LDH greater than upper limit of normal at cycle 2 and NLR ≥5 at 6 weeks predicts for disease progression at the first TRE. These routine early predictive biomarkers could be used to identify non-responders when treating with PD-1/PD-L1 inhibitors prior to a CT scan. This data needs validation in a larger cohort.

Background:
Checkpoint inhibitors targeting PD-1 and PD-L1 have emerged as the standard of care for patients with NSCLC. While generally well tolerated, immune related adverse events (irAEs) are a known complication and when serious, may require use of systemic corticosteroids. The impact of steroid use on checkpoint inhibitor efficacy remains unclear. Previous data suggest comparable response rates among patients who require steroids and those who do not. Here, we seek to confirm those findings and explore the impact of systemic steroids for irAEs on time to treatment failure (TTF) in patients with NSCLC.

Method:
Retrospective analysis was performed on all patients with advanced NSCLC at five institutions who received a checkpoint inhibitor (anti-PD-1 or anti-PD-L1 antibody) between January 1, 2011 and April 1, 2017. TTF was defined as the time from initiating therapy to start of a new therapy, last day of follow up or death. Development of any irAE and use of systemic corticosteroids was noted and median TTF and RR were compared between subgroups.

Result:
We identified 141 eligible patients with NSCLC treated with checkpoint inhibitors. Nineteen patients were excluded from the final analysis due to lack of any follow up or receipt of investigational agents or combinations. For the 122 evaluable patients, median TTF and RR were 169 days and 18%. A total of 30 (25%) patients developed any irAEs with median TTF and RR of 497 days and 32%. A total of 11 (9%) patients received systemic corticosteroids for irAEs. Among the patients who received steroids for irAEs, the median TTF and RR were 502 days and 27%. Our observation failed to demonstrate a statistically significant difference in median TTF among patients who received steroids and those who did not (p=0.4155).

Conclusion:
These retrospective data do not demonstrate a difference in response or treatment failure among patients who received steroids for irAEs and support the use of steroids when necessary.

Background:
Immune checkpoint inhibitors have revolutionized the field of oncology. nivolumab, pembrolizumab, ipilimumab, and atezoluzimab have been approved by the United States Food and Drug Administration for various malignancies. Because these antibodies rely on activating the host immune system, unique autoimmune side effects have been discovered, including reactions against the cardiovascular system. We would like to summarize our institutional experience with immune checkpoint inhibitor associated cardiotoxicity and review the current literature on this subject.

Method:
Retrospective review of the patient medical record and review of PubMed indexed literature on immune checkpoint inhibitor associated; cardiotoxicity, cardiomyopathy, autoimmune myocarditis, heart failure.

Result:
To date we have experienced two cases of immune checkpoint inhibitor associated cardiotoxicity in our patients treated at Markey Cancer Center, Lexington Kentucky. Both these patients were treated for metastatic non-small cell lung cancer who had previously progressed on frontline chemotherapy. Both patients received nivolumab. One of the patient developed congestive heart failure within couple of days after first dose of nivolumab. Extensive cardiac workup for ischemia was negative. On returning of cardiac functions to baseline he was re-challenged with second dose of nivolumab. Patient again developed decomensated CHF with ejection fraction of 30-40%. Subsequent therapy was aborted. Patient continues to have stable disease off therapy for the past 8 months. Our second patient developed moderate to severe pericardial effusion after fifth dose of nivolumab. Pericardial fluid cytology was negative for malignancy and CT scans showed stable visceral metastatic disease. He is currently off therapy and will get a prolonged 8 week steroid taper. Our literature review revealed only nineteen documented cases of immune checkpoint mediated cardiotoxicity. Seventeen of the 19 patients had metastatic melanoma; the remaining two had non-small cell lung cancer (one adenocarcinoma and one squamous cell). Six of the 19 patients developed cardiotoxicity within five weeks of treatment initiation. One of the patients developed biopsy confirmed immune mediated cardiotoxicity 31 weeks after initiation of treatment. Seven patients were treated with ipilimumab alone, four with nivolumab, one with pembrolizumab and the remaining seven patients received a combination of PD1/PDL-1 and CTLA-4 antibody either sequentially or concurrently. Six out of 19 patients died from toxicity of the respective drugs.

Conclusion:
Immune checkpoint associated cardiotoxicity is rare but well defined in literature. Patients can present with decompensated heart failure, arrhythmia or pericardial effusions. Early recognition, prolonged steroid taper and optimization of cardiac function with diuretics, ACE inhibitors and beta blockade are critical steps for the successful management.

Background:
Immunotherapy has brought new therapeutic options to non-small cell lung cancer. PD-L1 has been established as the primary clinical biomarker for PD-1/PD-L1 targeting antibodies, with higher expression correlation with superior therapy responses. Tumor mutational burden and other biomarkers have been similarly implicated in prediction of immunotherapy responses. These markers are obtained from tumor tissue based on immuno-histochemistry or next generation sequencing. Availability of tissue has remained a significant clinical challenge. Mutations in KRAS have been reported to correlate with improved survival. We interrogated our data base to investigate whether KRAS detected in blood could serve as a surrogate marker for immunotherapy selection.

Method:
We screened a total of 239 cases of non-small cell lung cancer with positive tissue evaluation. 89/239 cases tested positive for presence of a KRAS mutation. 56 KRAS mutant cases of NSCLC, matched tissue (NGS and PD-L1) and blood (NGS) analyses were available. 17 cases had PD-L1 expression of greater than 50% on IHC. 39 cases had PD-L1 expression of less than 50%, defined as low expression. 34 patients had received single agent, PD-1 targeting immunotherapy (nivolumab or pembrolizumab). We reviewed these cases with low PD-L1 expression treated with immunotherapy in a retrospective analysis for clinical outcomes.

Result:
In the cohort with low PD-L1 low/KRAS mutant status, a response rate (PR+CR) of 53% (n=18) was observed, including 13% (n=5) complete responses. The average progression-free survival in this subset was 11.1 month. KRAS status correlated expectedly with prior or current smoking history (97%), and elevated tumor mutational load (16 mutations per megabase).

Conclusion:
Selection of appropriate candidates for immunotherapy has remained a clinical challenge. In our analysis, liquid biopsy was obtained without complication and correlated strongly between blood and tissue. Compared to historical controls, KRAS mutant status appears to have a higher response rate and prolonged progression-free survival independent of PD-L1 status. In addition to previously established PD-L1 and TML markers, our data supports a role of KRAS as a surrogate marker for immunotherapy response that should be investigated in prospective clinical trials.

Background:
We experience secondary cancer merging after anticancer medications. Also, as a mechanism of resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors to patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR, conversion to small cell lung cancer is well known. However, little is known about the occurrence of secondary cancer during the use of immune checkpoint inhibitors.

Method:
We report a 71 years old man who was diagnosed small cell lung cancer during nivolumab administration as second line treatment for advanced squamous cell lung cancer.

Result:
He suffered from diffuse large B-cell Lymphoma (DLBCL) at the age of 65 years old. He received eight cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone combined with rituximab), and he remitted DLBCL. During his follow up by a hematologist, he pointed out a new nodule in left upper lung and small nodules in right lung with CT scan. He was diagnosed with squamous cell lung cancer by bronchoscopic biopsy. He received four cycles of carboplatin and nanoparticle albumin-bound paclitaxel combination chemotherapy as first line treatment, and he obtained partial response (PR). After 12 months of this treatment, the primary tumor re-increased and relapsed, he received nivolumab as a second line treatment. Although he obtained stable disease by nivolumab, another new lung nodule appeared in right lower lobe gradually. After 12 cycles of nivolumab, he was diagnosed with small cell lung cancer by endobronchial ultrasound transbronchial biopsy with guide-sheath. He received four cycles of combination chemotherapy with carboplatin and etoposide, and he obtained PR. We plan to resume nivolumab as the next line treatment.

Conclusion:
We reported a case of small cell lung cancer complicated during immune checkpoint inhibitor (nivolumab) administration as second line treatment for squamous cell lung cancer. In this case, monotherapy with nivolumab failed to suppress the emergence of small cell lung cancer.

Background:
Immunotherapy is changing the therapeutic perspective and expectations for solid tumors and constitutes a major therapeutic advance for advanced non-small cell lung cancer (NSCLC). We assessed the cost-effectiveness of pembrolizumab (anti-PD-1 antibody) as compared to platinum-doublet chemotherapy as first-line therapy for advanced NSCLC.

Method:
We developed a Bayesian Markov model of disease states with a 5-year horizon. We retrieved survival, progression, and safety data comparing pembrolizumab to contemporaneous platinum-doublet chemotherapy as first-line therapy for PD-L1 expression equal to or greater than 50%, EGFR non-mutated, ALK non-translocated lung carcinoma patients. Published estimated US and UK costs were applied to inform the incremental cost-effectiveness ratio (ICER). We estimated costs in USD and summarized effectiveness as discounted quality-adjusted life-years (QALYs).

Result:
Patients treated with pembrolizumab accumulated 0.65 QALYs (95% credible interval [95% CrI] 0.5-0.91) as compared to 0.19 QALYs (95% CrI 0.16-0.22) to 0.32 QALYs (95% CrI 0.27-0.37) for those treated with platinum-doublet chemotherapy. From a current US cost perspective, ICERs varied from $173,000 (95% CrI $163,000-$183,000) to $201,000 (95% CrI $182,000-232,000) for one end-of-life (EoL) adjusted QALY, while from a British National Health System (NHS) perspective, ICERs varied from $154,000 (95% CrI $144,000-$166,000) to $193,000 (95% CrI $165,000-$248,000) per EoL adjusted QALY gained.

Conclusion:
At current price, pembrolizumab is not cost effective considering the usual NICE threshold in the UK. In the US, these numbers would be considered cost-effective according to the WHO definition.

Background:
Treatment with immune checkpoint inhibitors (ICIs) improves overall survival with lower toxicity when compared to classic chemotherapy in the management of advanced non-small cell lung cancer (NSCLC). While emerging, the role of PD-L1 expression as a biomarker remains controversial. In addition, all clinical trials that included previously treated patients compared ICIs with docetaxel and there is a lack of data comparing each agent against each other. This network meta-analysis aims to (i) compare overall survival (OS) with nivolumab, pembrolizumab, and atezolizumab against docetaxel in previously treated advanced non-small cell lung cancer (NSCLC) patients and (ii) to perform indirect comparisons between ICIs in the PD-L1 unselected population and by PD-L1 expression levels.

Method:
We searched Pubmed for randomized controlled trials comparing the ICIs nivolumab, pembrolizumab and atezolizumab in the treatment of patients with previously treated advanced NSCLC. Two independent reviewers screened each study. We performed network meta-analyses of survival outcomes in the PD-L1 unselected population and by PD-L1 expression levels <1%, ≥1%, ≥5%, ≥10%, and ≥50%. Head-to-head indirect comparisons of nivolumab, pembrolizumab and atezolizumab were constructed and treatment rankings provided in terms of SUCRA and probability that a treatment is best. We also assessed the potential survival benefits of selecting patients by PD-L1 expression level as compared to a PD-L1 unselected population.

Result:
Five trials with 3,024 total patients were included in the meta-analysis. ICIs improved OS in previously treated advanced NSCLC patients across PD-L1 expression levels compared to docetaxel with HRs of 0.70 (95% CrI 0.61-0.81), 0.79 (0.65-0.97), 0.67 (0.57-0.77), 0.55 (0.44-0.69), 0.43 (0.30-0.63), and 0.49 (0.37-0.63) for PD-L1 expression levels as follows: unselected, <1%, ≥1%, ≥5%, ≥10%, and ≥50%. However, for individual ICIs nivolumab and atezolizumab in PD-L1<1%, there was only weak evidence of benefit with HR of 0.77 (0.57-1.04) and 0.81 (0.62-1.08) respectively compared to docetaxel. Nivolumab, pembrolizumab and atezolizumab showed little survival differences between each other (nivolumab vs pembrolizumab HR 0.94 (0.63-1.39), nivolumab vs atezolizumab 0.91 (0.62-1.35), and pembrolizumab vs atezolizumab 0.97 (0.68-1.41) in PD-L1 ≥1%). When interpreting these data, it is important to note that while nivolumab and pembrolizumab trials used tumor cells for PD-L1 cutoffs, atezolizumab used both tumor and/or immune cell cut-offs and PD-L1≥50% in atezolizumab trials comprised patients with tumor cell PD-L1≥50% or immune cell PD-L1≥10%.

Conclusion:
ICIs improve survival across PD-L1 expression levels compared to docetaxel. None of the available ICIs, nivolumab, pembrolizumab and atezolizumab, seem to be better than the others.

Background:
Improving the outcome of locally advanced non-small cell lung cancer (NSCLC) is one of the major challenges in thoracic oncology. SAKK substantially contributed to establish a standard of care for patients with stage III NSCLC: The trial SAKK 16/96 established neoadjuvant chemotherapy with three cycles of cisplatin and docetaxel. The randomized trial SAKK 16/00 showed no benefit by adding radiotherapy as third treatment modality to chemotherapy and surgery. Our results consistently showed a 5-year overall survival (OS) of 37%. However, it seems very difficult to further improve the OS by conventional therapies.

Method:
This is a single-arm phase II clinical trial designed to evaluate the addition of perioperative immunotherapy with the anti-PD-L1 antibody durvalumab to the previously established standard of care for stage IIIA(N2) patients, which is based on the trials SAKK 16/96 and SAKK 16/00. Eligible patients with WHO performance status 0-1 and age of 18-75 years must have pathologically proven NSCLC stage IIIA(N2) (T1-3 N2 M0) according to the 7th edition of the TNM classification, irrespective of histological subtype, genomic aberrations or PD-L1 expression status. Tumor tissue has to be available for the mandatory translational research. Patients whose tumor is deemed resectable at diagnosis receive three cycles of chemotherapy with cisplatin 100 mg/m[2 ]and docetaxel 85 mg/m[2] every three weeks followed by two cycles of durvalumab 750 mg every two weeks. Following surgery, patients will be treated with durvalumab 750 mg every two weeks for 12 months. Patients with R1/R2 resection and patients with extracapsular spread of mediastinal lymph node metastases may undergo standard radiotherapy prior to adjuvant treatment with durvalumab. The primary endpoint of the trial is event-free survival at 12 months. Secondary endpoints include OS, objective response, nodal down-staging, complete resection, pattern of recurrence and toxicity. Additionally, a large translation research program accompanies the trial investigating potential predictive biomarkers of anti-PD-L1 therapy.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Checkpoint inhibitors showed satisfactory efficacy in treating lung cancer. We conducted this meta-analysis to explore the therapeutic efficacy and safety of anti-PD-1/PD-L1 antibodies combine with chemotherapy or CTLA4 antibodies as first-line treatment on advanced lung cancer.

Method:
A quantitative meta-analysis was performed through a systematic search in PubMed, Web of Science, the conference abstracts and so on. The pooled ORR, 6-month progression-free survival rate (PFSR6m), and 1-year overall survival rate (OSR1y) were calculated and compared. 9 trials were included in this meta-analysis.

Result:
Our analyses demonstrated the pooled ORR and DCR of anti-PD-1/PD-L1 antibodies combine with chemotherapy for non-small-cell lung cancer were 48.0% (40.2–56.0 %) and 84.8 % (78.1– 89.7%), respectively. The pooled OR and DCR of anti-PD-1/PD-L1 antibodies combine with chemotherapy for small-cell lung cancer were 42.9% (18.5–71.2 %) and 73.6 % (32.8–94.1%), respectively. The pooled PFSR6m of anti-PD-1/PD-L1 antibodies combine with chemotherapy for NSCLC and SCLC were 62.9% (46.3–79.6%) and 27.6 % (18.9–36.2 %), respectively. The OSR1y of anti-PD-1/PD-L1 antibodies combine with chemotherapy for NSCLC and SCLC were 70.1 % (57.4%-82.8 %) and 32.0 % (25.2–38.9 %). In addition, the pooled ORR and DCR for anti-PD-1/PD-L1 antibodies plus CTL4 antibodies treatment group was 29.6% (11.4%-657.8%) and 48.7% (16.8%-81.7%), respectively.

Conclusion:
Anti-PD-1/PD-L1 antibody plus chemotherapy can serve as a promising treatment option for lung cancer. While patients treated anti-PD-1/PD-L1 antibodies plus CTLA4 antibodies may benefit less compare with anti-PD-1/PD-L1 antibodies combine with chemotherapy. Encouraging activity with tolerable adverse effect was observed.

Background:
JNJ-64041757 (JNJ-757) is a live attenuated, double-deleted (LADD) Listeria monocytogenes (Lm)-based immunotherapy engineered to induce adaptive immune responses against the tumor-associated antigen mesothelin. The goals of Part 1 of this first-in-human (FIH) study were to establish the recommended phase 2 dose (RP2D), characterize the safety profile, and evaluate the immunological activity of JNJ-757 in patients with adenocarcinoma of the lung.

Method:
This is an ongoing FIH trial in patients with advanced adenocarcinoma non-small cell lung cancer (Stage IIIb or IV) who have progressed after standard therapy (ClinicalTrials.gov: NCT02592967). Patients were treated at 1 of 2 dose levels (10[8] CFU or 10[9] CFU), infused over 1 hour every 3 weeks until disease progression or unacceptable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first cycle. Disease response was assessed every 3 cycles according to RECIST 1.1. Post-infusion blood, urine, fecal, and saliva samples were evaluated for the presence of JNJ-757. Immunological activity of JNJ-757 was assessed by evaluation of peripheral cytokines and immune cells as well as ELISPOT analysis to defined antigens.

Result:
Nine subjects were enrolled; 6 at 10[8] CFU and 3 at 10[9] CFU. There were no DLTs in either dosing cohort, and 10[9] CFU was identified as the RP2D. Most adverse events (AEs) were of grade 1/2 severity, with fatigue, headache, nausea, and vomiting as the most reported events. One drug-related AE of grade ≥3 severity (hypokalemia, grade 3) was reported in the 10[8] CFU cohort. Best response was stable disease. Four patients had received at least 7 cycles (range, 1 to 14 cycles). JNJ-757 was quickly cleared after infusion, with 7/9 patients showing negative blood cultures at 2 hours; all were negative after 24 hours. Correlative studies demonstrated activation of both innate and adaptive immune responses. Natural killer cell and T cell activation were observed 24 hours after infusion, coinciding with elevated cytokine production (i.e., IFN-γ, TNF-α). Specific T cell responses against Listeria listeriolysin O and mesothelin antigens were documented in a subset of patients, consistent with the mechanism of LADD to prime new immune responses.

Conclusion:
The RP2D of JNJ-757 is 10[9] CFU, with a safety profile consistent with other LADD Lm-based agents such as CRS-207. Both innate and mesothelin-specific adaptive immune responses were demonstrated in multiple patients. Recruitment in the trial continues to further characterize the safety profile and immune response, and a phase 1b/2 trial with JNJ-757 and nivolumab is planned.

Background:
GMCI is a tumor-specific immune-stimulator through local delivery of aglatimagene besadenovec, an adenovirus-based vector expressing the HSV-1 thymidine kinase gene (AdV-tk) followed by anti-herpetic prodrug. We conducted a phase I dose escalation trial of intrapleural administration of aglatimagene besadenovec followed by standard chemotherapy in patients with MPE.

Method:
The primary end-point of this dose escalation trial was safety. Eligibility included patients with MPE or MPM with a clinical indication for placement of pleural catheter, age > 18 yrs, ECOG PS 0-1, FEV1> 40% predicted and adequate end organ function. Intra-pleural (IP) AdV-tk was administered at doses of 1x 10[12 ]viral particles (vp) (Cohort 1); 1x10[13 ]vp (Cohort 2); and 1x10[13 ]vp plus celecoxib (Cohort 3). Three patients were treated per cohort with 10 patients in the expansion phase. Valacyclovir (2 gm PO TID x 14 days) started the day after AdV-tk followed by chemotherapy. Secondary end-points included response rate, progression free survival, overall survival and immune response.

Result:
From 2013 to 2015, 19 patients were enrolled and completed therapy: median age 69.5 years (range 41-89), 14 malignant mesothelioma (MM) (9 epithelioid, 3 sarcomatoid, 2 biphasic), 4 non-small cell lung cancer (NSCLC) and 1 breast cancer. Eight patients received IP AdV-tk upon diagnosis, 7 prior to 2[nd] line and 4 prior to 3[rd] line chemotherapy. Safety results have previously been reported. Response according to RECIST was evaluable for 17 pts. Best response was PR in 4 patients (3 with MM, and one pt with NSCLC), 9 SD and 4 PD. As of 05/2017, three patients are alive and in active follow up (one with NSCLC, and 2 with MM), range of follow up 21-32 months. Of the 4 patients with NSCLC, 3 had prolonged disease stabilization (median overall survival 25.7 months post-GMCI), and one patient is still alive 3.6 years from initial diagnosis (29 month post-GMCI).

Conclusion:
We previously reported that GMCI can be safely administered at high-doses IP in combination with chemotherapy. With median follow up of 31 months, we report that the majority of the patients experienced clinical benefit and sustained disease stabilization was seen in patients with NSCLC. Three patients are still alive and in active follow up. Phase II studies are warranted to further determine efficacy based on these preliminary encouraging observations; NCT01997190.

Background:
LIPI is a score that combine dNLR (neutrophils/(leucocytes-neutrophils) and lactate dehydrogenase (LDH) and correlate with prognosis of NSCLC patients treated with immune checkpoint inhibitors (ICI). We report the predictive role of LIPI on response and in various subgroups of patients.

Method:
Baseline dNLR and LDH were retrospectively collected in 431 patients treated with ICI from Nov. 2012 to Jan. 2017, from 8 European centers. LIPI delineates 3 groups: good (dNLR<3+LDH3 or LDH>ULN), poor (dNLR>3+LDH>ULN). Response rate (RR) and disease control rate (DCR) were assessed according to the investigator’s criteria. The subgroup analysis was performed according to the age, histology, performance status (PS) and PD-L1 status by immunohistochemistry (positivity if ≥ 1% on tumor cells).

Result:
With a median follow-up of 12.8 months (m.) [95%CI 11.9-14], 431 patients were included. Baseline characteristics are summarized in table 1. The median overall survival (OS) and progression-free survival (PFS) were 10.5m. [95%CI 9.5-13] and 3.9m. [3-4.4], respectively. The median OS was 4.8m. vs. 10 m. vs. 16.5m., and median PFS was 2m. vs. 3.1m. vs. 5m. for the poor, intermediate and good LIPI groups, respectively (both p<0.0001). LIPI was correlated with response rate (p<0.0001). In multivariate analysis, the intermediate and poor group were associated with progressive disease, with an OR of 2.20 [CI95% 1.26-3.84] p=0.005) and an OR of 3.04 [CI95% 1.46-6.36] p=0.003), respectively. LIPI was correlated with OS, regardless the age (<70 years (p<0.0001) vs. older (p=0.0006) and the histology non-squamous (p<0.0001) vs. squamous (p=0.02). In PS 0-1 and in smoker population, LIPI correlated with OS (both p<0.0001), but not in PS ≥2 (12%) and non-smokers (8%). LIPI was correlated with OS for positivity (p=0.01) and unknown PD-L1 (p=0.0001), but not negativity.

	LIPI 0 Good (N=162, 37%)	LIPI 1 Intermediate (N=206, 48%)	LIPI 2 Poor (N= 63, 15%)	All population cohort N = 431 (%)
Sex
Male	102 (63)	131 (64)	42 (67)	275 (64)
Age at diagnosis
Median (years, range)	62 (36;86)	63 (29;86)	62 (39;84)	62 (29;86)
Smoking status
Non-smoker	13 (8)	18 (9)	5 (8)	36 (8)
Former	80 (49)	115 (56)	46 (73)	241 (56)
Current	67 (42)	69 (33)	11 (17)	147 (34)
Unknown	2	4	1	7
Histology
Non-squamous	111 (69)	132 (64)	41 (65)	284 (66)
Squamous	51 (31)	74 (36)	22 (35)	147 (34)
Molecular alteration
EGFR mutation	3 (2)	13 (6)	3 (5)	19 (4)
ALK rearrangement	2 (1)	2 (1)	1 (2)	5 (1)
KRAS mutation	34 (21)	31 (15)	8 (13)	73 (17)
PDL1 status
Negative	16 (36)	14 (25)	1 (5)	31 (25)
Positive	28 (64)	43 (75)	20 (95)	91 (75)
Unknown	118	149	42	337
Performance Status
0	51 (32)	45 (22)	10 (16)	106 (25)
1	96 (60)	132 (64)	42 (67)	270 (63)
≥ 2	12 (8)	28 (14)	11 (17)	51 (12)
Stage at diagnosis
IIIb	18 (11)	33 (16)	14 (22)	65 (15)
IV	101 (62)	135 (66)	38 (60)	274 (64)
Metastases sites
Median (Range)	2 (0;6)	2 (0;7)	2 (1;7)	2 (0-7)
Bone	43 (27)	58 (28)	20 (32)	121 (28)
Liver	28 (17)	39 (19)	16 (25)	83 (19)
Brain	22 (14)	19 (9)	9 (14)	50 (12)
Immunotherapy
PD1 inhibitor	133 (82)	167 (81)	48 (76)	348 (81)
PDL1 inhibitor	19 (12)	34 (17)	12 (19)	65 (15)
PDL1 inhibitor- CTLA4 inhibitor	10 (6)	5 (2)	3 (5)	18 (4)
Immunotherapy line
Median (Range)	2 (1;11)	2 (1;12)	2 (1;8)	2 (1-12)
Response rate
Complete response (CR)	6 (4)	3 (1)	0 (0)	8 (2)
Partial response (PR)	42 (26)	53 (26)	18 (28)	113 (26)
Stable disease (SD)	66 (41)	59 (29)	8 (13)	133 (31)
Progression	40 (25)	81 (39)	33 (52)	154 (36)
NA	8	10	4	25
Dissociated response	14 (9)	15 (7)	2 (3)	31 (7)

Conclusion:
Baseline LIPI predicts response to ICI, and was correlated with OS regardless of age and histology.

Background:
: Nivolumab is a PD-1 inhibitor that has been approved as a treatment in adenocarcinoma and squamous cell lung cancer. This study examines the experience with nivolumab as a compassionate use in Mexican patients.

Method:
Descriptive, observational, retrospective and unicentric study that analyzed 38 patients diagnosed with stage III and IV lung cancer who progressed to one or more line of chemotherapy and received nivolumab from April 2016 to March 2017 at the National Institute of Respiratory Diseases. The primary endpoint was overall survival and secondary progression-free survival and response rate measured based on RECIST 1.1.

Result:
The sample was formed by 12 men (35.3%) and 22 women (64.7%), that had an initial ECOG of I in 23.5%, II in 58.5% and III in 17.6% and clinical stages was III 2.9% and IV 97.1%. They were smokers in 52.8% of the patients, with an average of 9.1 packs/year and 47.1% had exposure to smoke from wood, with an average of 62.1 hours/year. The 88.2% had adenocarcinoma, 5.9% squamous, from which 54.4% received nivolumab in second line and 45.6% in third line or more. The median progression-free survival was 8.1 months. The average overall survival, has not been able to achieve since 12 moths of treatment, the 51.4% of patients still alive. The response to the treatment by RECIST 1.1 was 38.2% for partial response (13 patients), stable disease in 41.2% (14 patients) and complete response 20.6% (7 patients).

Conclusion:
The use of nivolumab in patients with non-small cell lung carcinoma in advanced clinical stages (III and IV) progressing to a first line or more of chemotherapy demonstrated a better progression-free survival and overall survival in Mexican patients.

Background:
Abundance and functional quality of tumor infiltrating lymphocytes are positively linked with tumor response and improved survival with checkpoint inhibitors. NKTR-214 is a CD122-biased agonist that targets the IL2 pathway and is designed to provide sustained signaling through the heterodimeric IL2 receptor pathway (IL2Rβɣ) to preferentially activate and expand NK and effector CD8+ T cells over CD4+ T regulatory cells within the tumor microenvironment. NKTR‐214 is administered on an outpatient basis as a 15-minute IV infusion and has been administered to 28 patients with advanced solid tumors. Single-agent NKTR-214 demonstrates a substantial increase in both CD8+ T and NK cells within the tumor microenvironment in those patients with prior immune checkpoint therapy (Bernatchez et al, SITC poster 2016). Given the favorable safety profile and strong biomarker data, a trial combining NKTR‐214 and nivolumab was initiated.

Method:
PIVOT‐02 is a phase 1/2 open‐label trial in patients with locally advanced or metastatic melanoma (MM), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma, or triple‐negative breast cancer (TNBC). Approximately 250 patients will be enrolled across 5 tumor types and 8 indications, with 26-38 patients per indication. Patients who are immunotherapy naïve will be studied for all 5 tumor types. MM, RCC, or NSCLC patients who are relapse/refractory on one prior anti-PD-1/PD-L1 containing regimen will be studied separately. The primary objectives are to evaluate safety and tolerability, determine the recommended phase 2 dose (RP2D), and assess tumor response by RECIST 1.1. The dose-escalation portion of the trial has enrolled 23 patients (MM= 8, RCC= 11, NSCLC=4), in 5 different cohorts including NKTR-214 at 0.003 (q2w), 0.006 (q2w or q3w), or 0.009 (q3w) mg/kg in combination with a flat dose of nivolumab at 240 (q2w) or 360 (q3w) mg. Extensive blood and tumor tissue samples are being collected in both escalation and expansion phase to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T-cell clonality and gene expression analyses. Based on safety/tolerability, PK/PD and early biomarker data, the recommended phase 2 dose of NKTR-214 is 0.006 mg/kg q3w with nivolumab 360 mg q3w. The expansion phase of the study is now open for accrual.

Result:
Section not applicable

Conclusion:
Section not applicable

Background:
Safety of PD-1/PD-L1 pathway inhibitors in patients with preexisting autoimmune disease is not well defined since these patients are generally excluded from immunotherapy trials. In this study we aimed to provide our institutional experience for the safety of PD-1 inhibitors in NSCLC patients with a history of autoimmune diseases.

Method:
In a retrospective study we collected genomic, demographic, clinical and pathologic data from patients with a history of autoimmune disease who received PD-1 inhibitors for their stage IV NSCLC as standard of care at MD Anderson Cancer Center (MDACC). Qualifying autoimmune diseases included autoimmune thyroiditis, rheumatologic, neurologic and dermatologic autoimmune conditions.

Result:
Between March 2016 and February 2017, 975 NSCLC patients were treated with PD-1 inhibitors, as standard of care at MDACC and 14 of those patients had preexisting autoimmune disease (5 rheumatoid arthritis, 3 seronegative arthritis, 3 psoriasis, 2 hashimoto thyroiditis, and 1 polymyalgia rheumatica). Three patients experienced flare of the autoimmune disease (2 psoriasis, and 1 rheumatoid arthritis) while on therapy and two of those patients were symptomatic from their preexisting autoimmune disease prior to the treatment. Median duration of exposure to therapy prior to flare was 21.4 weeks (range 7-48 weeks). These patients did not require treatment break or steroid use for autoimmune disease flare. 35% (5/14) of patients developed at least one immune related adverse effect (irAEs, one grade 2 and four grade 3) unrelated to the underlying autoimmune disease. There were no grade 4-5 irAEs observed. Updated results from larger patient cohort will be reported at the conference.

Conclusion:
In our single center experience, symptomatic flare of underlying autoimmune diseases was uncommon. However, patients with history of immune disease may be at higher risks for immune related toxicities during therapy with PD-1 pathway inhibitor. Further studies are needed to identify the safety profile of the PD-1 directed therapies in patient subsets with preexisting autoimmune diseases.

Abstract not provided

Abstract not provided

Background:
Loss of muscle mass and function is common in patients with non-small cell lung cancer. Handgrip strength is a simple screening measure of general limb muscle function which is clearly associated with mortality in the general population and in some chronic disease populations. It is largely unclear to what extent handgrip strength provides prognostic information in patients with non-small cell lung cancer.

Method:
Handgrip strength was bilaterally assessed with a Jamar handheld dynamometer before initiation of radiotherapy. Normative values for handgrip strength have been proposed based on centile scores in over 224,000 healthy adults, adjusted for age, sex, height and measurement side. Patients were defined as weak if handgrip strength at one side (left or right) was below the tenth centile of the general population. Cox proportional hazard models were used to assess the relationship between handgrip weakness and mortality. Follow-up time was calculated from the day of assessment. Results are reported unadjusted and adjusted for disease stage (I to IV), World Health Organization Performance Score (WHO PS), gender and age.

Result:
We included 1497 patients for analysis (age 68±10; 63% male; stage I:17%; II:9%; III:60%; IV:14%). During follow-up 1109 patients (74%) deceased (time to death 18 ±17 months); mean follow-up in survivors was 46±25 months. Baseline weakness was present in 29% of patients. Unadjusted analysis shows an association between handgrip weakness and mortality (HR 1.64 (1.45-1.86; p<0.001; see figure 1). After covariate adjustment, handgrip weakness remained significantly related to mortality (HR 1.46 (1.27-1.68; p<0.001). Figure 1. Figure 1



Conclusion:
Our findings suggest that handgrip strength provides prognostic information in addition to well-established prognostic markers including disease stage, functional performance score and age in NSCLC patients who undergo radiotherapy. The detection of handgrip weakness is easy and quick and therefore might have a role in routine pre-treatment screening in this patient group.

Background:
Stage IIIA/N2 non-small-cell lung cancer (NSCLC) is a heterogeneous condition with multidisciplinary approaches involved. For operable IIIA/N2 NSCLC, surgery combined with chemotherapy is considered as an optimal management. Yet no solid evidences to conduct appropriate treatment modality for operable IIIA/N2 NSCLC and patients through curative treatment still surfer unsatisfactory prognosis.

Method:
329 pathologically confirmed IIIA/N2 NSCLC patients through curative treatment were enrolled. Multivariate analysis was performed to select highly correlated clinical characters for nomogram. C-index and further survival analysis were given to validate the efficacy of the model.

Result:
Multivariate analysis indicate independent factors for overall survival including clinical stage, T stage, N stage, N2 status and tumor position which were then integrated into the model. The calibration curves showed moderate concordance between nomogram prediction and actual observation. Linear predictor of 3.5 was set to be the cutoff of the model through X-tile plot, and patients with linear predictor over 3.5 revealed significant longer median survival than those under 3.5 (59.90 vs. 24.90, log-rank P=0.0005). Figure 1Figure 2





Conclusion:
We established a nomogram that may well distinguish the potential subgroup of patients benefit from curative treatment modalities. Further perspective study should rigorously clarify the issue of which multimodality treatment to be chosen for IIIA/N2 NSCLC patients.

Background:
Concurrent chemoradiotherapy is the standard non surgical management of locally advanced NSCLC. Radiation pneumonitis is a well recognized complication of lung radiotherapy. This retrospective study examines the clinical outcomes and treatment toxicities of patients treated with chemoradiotherapy(CRT) for NSCLC in 2014 at the LCC in UK.

Method:
Data was retrospectively collected from patients with locally advanced NSCLC treated with concurrent CRT from 1/1/14-31/12/14 at LCC. Patients received 3-D conformal radiotherapy to a dose of 60-66Gy/30-33# over 6-6.5 weeks. Individual patient’s clinical data was reviewed on Patient Pathway Manager for tumour and patient demographics. Radiotherapy dosimetric data were studied with V20, mean lung dose(MLD) and PTV volume. Treatment associated haematological toxicities and radiation pneumonitis were analysed. Overall and progression free survival were calculated. In addition, correlations between clinical/dosimetry parameter and clinical diagnosis of radiation pneumonitis were analysed.

Result:
58 patients were included in the study. Median follow up was 18.6 months. 66% of patients received weekly carboplatin/paclitaxel and the rest received 3 weekly cisplatin or carboplatin with etoposide. 78% of patients completed both chemotherapy and radiotherapy. For all radiotherapy plans, median V20 was 20.9Gy (range 3.4-29.8Gy), median MLD was 12.8Gy (range 2.3-16.5Gy) and median PTV was 395cc (range 73-819cc). 34% of patients developed grade 3-4 neutropenia, 64% grade 3-4 lymphopenia and 5% grade 3-4 thrombocytopenia. Neutropenic sepsis occurred in 10% of patients with one grade 5 toxicity. Radiation pneumonitis was diagnosed in 17% of patients, all below grade 3. Median time to pneumonitis was 133 days post radiotherapy. Radiation pneumonitis correlated strongly with V20(r = 0.93). Correlations with MLD and PTV were less. There were no correlations with neutropenia, lymphopenia or thrombocytopenia during treatment. 2/3 of the recurrences were distant metastases. 90 day mortality was 5%(three patients died from oesophageal perforation, colitis and pneumonia). The median progression free survival was 20.1 months. The median overall survival was not reached.

Conclusion:
At the LCC, chemoradiotherapy has been a safe and effective treatment for locally advanced lung cancer. Consistent with existing evidence, V20 remains the most powerful predictor of radiation pneumonitis following lung radiotherapy.

Background:
Pathological complete response (pCR) after trimodality therapy in locally advanced non-small cell lung cancer (NSCLC) is associated with favorable long-term survival (LTS). The implication of pCR into daily practice is poorly defined. The aim of the study was to identify the correlation of pCR and different prognostic factors influencing long-term survival (LTS), tumor recurrence pattern and progressive-free interval (PFI).

Method:
A cohort of patients with locally advanced stage III NSCLC treated with induction chemoradiation (CRT) and subsequent surgery at a single center was retrospective reviewed. The subgroup of patients with pCR after the initial CRT, combined with application of 45Gy radiation dose, was extracted for further analysis. The statistical analysis stratified by descriptive statistics, Kaplan-Meier survival curves and estimated 3- and 5-years survival time combined with long-rank tests and Cox multivariate-analysis.

Result:
Between March 2008 and December 2016, a total of 24 patients with proven pCR were included in the retrospective analysis. The median age was 58.8 years [range, 46.4-76]. Fourteen patients (63.6%) were younger than 65. The median radiation dose applied was 50.4 Gy (range 45-56 Gy). The mean interval between the induction therapy and operation was 7.4±3.3 weeks and complete (R0) resection was achieved in 22 (91.6%) patients. The prognostic influence of gender, age, initial tumor stage and grade, histological subtype on pCR was analyzed using log-rank test and multivariate Cox regression model. The estimated 3- and 5-year survival rates for LTS were 64% and 57%, respectively. The estimated 3- and 5-year rates for PFI were 53% and 48%, respectively. Figure 1



Conclusion:
Favorable LTS is associated with pCR after CRT and followed by curative surgical resection. During the analysis pCR was identified as an independent prognostic factor. The distant tumor control remains the main limiting factor for LTS.

Background:
The incidence of local failure and residual tumor after definitive chemoradiation therapy (dCRT) for locally advanced non-small-cell lung cancer is even as high as 30%, irrespective of applied radiation dose (>59 Gy). So-called salvage surgery has been suggested a feasible treatment option after failure of definitive chemoradiation for locally advanced non-small cell lung cancer. Experience with salvage lung surgery is limited and long-term survival is rarely reported. The aim of this retrospective study was to assess postoperative survival and perioperative morbidity/mortality in order to identify prognostic factors and to define patient selection criteria.

Method:
Records of 13 consecutive patients with locally advanced non-small cell lung cancer, who underwent salvage lung surgery for local recurrence and persistent tumor after definitve chemoradiation therapy at a single institution between March 2011 and November 2016, were reviewed. Descriptive statistics were applied for patient characteristics, surgical and oncological outcome. Survival rates were calculated using Kaplan-Meier method and compared with long-rank test.

Result:
All patients initially received curative-intent definitive chemoradiation with median radiation doses of 66 Gy (range 59.4-72) and concurrent platin-based chemotherapy. Clinical tumor stage before definitive chemoradiation was IIIA in 9, IIIB in 3, IV in 1 patients. The indication for salvage surgery were in 6- a local recurrence and in 7 patients a persistent primary tumor. Median interval between definitive chemoradiation and salvage surgery was 6.7 months. Perioperative morbidity and 30-days-mortality was 38% and 7.7%, respectively. The median postoperative survival and estimated 5-year survival rate were 29.7 months and 46%, respectively.

Conclusion:
Salvage lung surgery for local failure in patients with locally advanced non-small cell lung surgery following definitive chemoradiation therapy is feasible, prolongs long-term survival and allows local tumor control. Selection criteria remain undefined and patients should be considered surgical candidates during multidisciplinary team conference.

Background:
The immune microenvironment of locally advanced non-small cell lung cancer (NSCLC) has not been systematically studied. Our aim was to determine the prognostic value of immunological biomarkers expression in a cohort of patients (pts) in this clinical setting.

Method:
We retrospectively reviewed 46 bronchial biopsies from locally advanced NSCLC. Pts were treated between 2010 and 2014 with concurrent chemo-radiotherapy (cCRT) at the Catalan Institute of Oncology. The following immunological markers were assessed by immunohistochemistry: PD-L1, ≥5% membrane expression on tumor cells was considered positive (+); HLA-Class I expression was classified into 0,1+,2+ according to membrane intensity; CD8+ tumor infiltrating lymphocytes (CD8 TILs) classified into low ≤5% or high >5% intratumoral infiltration. Chi-square test for assessing correlation and survival analysis by Kaplan-Meier method were used.

Result:
From 46 pts: Median age was 65 (43-81); gender: male 94%, female 6%; ECOG≤1 96%; smoking status: current 67%, former 30%, never 3%; histology: squamous cell carcinoma (SCC) 63%, adenocarcinoma (ADC) 24%, NSCLC (NOS+large cell) 13%; cN0-1 30%, cN2 57%, cN3 13%. Platinum doublet CT: Cisplatin 57%, Carboplatin 43%. PD-L1 was positive in 38% of cases and was positively correlated with HLA-I expression (p= 0.015) and CD8-TILs (p= 0.008). No correlations between PD-L1/CD8 TILs status and G3-4 radio-induced toxicities (pneumonitis, esophagitis) were found. At a median follow-up of 48 months (m), 53% of pts had relapsed. According to immune phenotype, median overall survival (mOS) was 20m (PD-L1 +, CD8 high; n=10) vs 17 m (PDL1 negative, CD8 low; n=19) vs not reached (PD-L1 negative, CD8 high; n=5) (p=0.23). Considering CD8 TILs, mOS in high CD8 (n=15) was 35m vs 18 m in low CD8 (n=26) (p=0.22).

Conclusion:
PD-L1, HLA-I and TILs CD8 expression was positively correlated. The potential role of TILs CD8+ as a prognostic biomarker in this cohort of pts that comprised mostly SCC histology, is promising. These results should be investigated in a larger cohort.

Background:
Previous studies by our group showed that that increasing the radiotherapy (RT) dose in an overall treatment time (OTT) of less than 6 weeks on basis of the isotoxic principle is feasible and could potentially increase the overall survival (OS) with non-concurrent chemo-RT without increasing the toxicity. No data were yet available for IMRT treated patients.

Method:
From 04-05 2009 until 26-04-2012, 185 patients with stage III NSCLC, treated with concurrent chemo-RT were included in this single center phase II trial. OS update was done on June 7, 2017. The primary endpoint of this study was OS, with in-field nodal failures (INF) and toxicity as secondary endpoints. Patients received 1 cycle of cisplatin-etoposide followed by two cycles of the same chemotherapy with concurrent radiotherapy (IMRT, 45 Gy BID followed by 2 Gy QD to the maximal organ at risk constraint).

Result:
Patient characteristics: Gender: Male: 61.1 %, Female: 38.9 %. Age 63.9 ± 8.9 years (44-86). Smoking: Never 2.9 %, current 36.8 %, former 60.3 %. WHO performance status: 0 (36.2 %) 1 (56.8 %), 2 11 (5.9 %), 3: 1 pt , 4:1 pt. Histology: Squamous 55 (29.7 %), Adenocarcinoma 49 (26.9 %), Large cell 26 (14.1 %), NSCLC-NOS 55 (29.7 %). GTV (T+N) 120.4 ± 132 ml (16.8-708.5), Total Tumor Dose 66.0 ± 12.8 Gy (36.0-73.0).Number of fractions: 39.7 ± 3.4 (24-44). OTT 38.2 ± 26.8 days (16-93) MLD 17.3 ± 3.0 Gy (4.9-21,2). Mean Esophageal Dose 29.0 ± 9.3 Gy (6.3-54.1). OS: stage IIIA (n=42), median 16.7 Mo (8.7-24.7), 5-year 16.7 %; stage IIIB (n=143) 20.3 (16.2-24.4), 5-year 27.3 % (P=0.10). INF: 3/185 (1.6 %). Loco-regional failures: 59/185 patients (31.8 %) Toxicity: Dyspnea Grade Baseline Maximal score 0 102 (55.1 %) 71 (38.4 %) 1 68 (36.8 %) 103 (55.7 %) 2 15 (8.1 %) 5 (2.7 %) 3 0 6 (3.2 %) 88% of patients experienced any grade of dysphagia: 22% experienced grade 1 dysphagia, 44% grade 2, while 22% experienced grade 3 dysphagia.

Conclusion:
Isotoxic accelerated radiotherapy delivered with IMRT and concurrently with chemotherapy leads to low INF and toxicity is comparable to the best series using standard fractionation schedules. Long term OS remains low and therefore other strategies are needed.

Background:
Surrogate endpoints are commonly utilized in oncology clinical trials and have been adopted by regulatory agencies for the approval of many agents. To date, the effects of tumor size reduction on survival have not been determined for the only Food and Drug Administration (FDA)-approved regimen fo malignant pleural mesothelioma (MPM), but its widespread use mandates its validation. MPM is a challenging disease to assess and standard Response Evaluation Criteria for Solid Tumors (RECIST) were not optimized to measure pleural disease. Modified pleural RECIST (mRECIST) have been adopted by mesothelioma experts for the measurement of responses in MPM and mRECIST are the most commonly used response criteria in clinical trials for MPM. Although the gold standards for oncology outcomes are overall survival and quality of life, cross-over to subsequent therapies and competing risks influence survival outcomes. We sought to evaluate the relationship of response with survival in the clinical trial of the only FDA approved regimen for MPM.

Method:
We reviewed the clinical trial that randomized patients with MPM to receive cisplatin or cisplatin and pemetrexed. Patients with epithelioid MPM were categorized by whether or not they responded to cisplatin or the combination of cisplatin and pemetrexed accoring to the original study determination. Responders had >30% reduction in the thickness of the pleural rind measured at up to 3 points on 3 separate slices of the CT scan. Median progression-free (PFS) and overall survivals (OS) were determined and the hazard ratios for responders and non-responders were determined and compared by the logrank test.

Result:
We identified that patients with epithelioid MPM who responded to front-line therapy had a significantly longer overall survival (HR 0.341, 95% CI 0.239-0.486; median 20.6 months, 95% CI: 15.3-not reached) than those who did not respond (median 9.4 months, 95% CI: 8.1-11.0; p<0.001). Similarly patients who responded to front-line therapy had a significantly longer progression-free survival (HR 0.496, 95% CI: 0.385-0.639; median 7.8 months, 95% CI: 6.5-8.5) than those who did not respond (median 3.7 months, 95% CI: 2.9-4.3; p<0.001).

Conclusion:
Our findings demonstrate that a reduction in tumor burden was strongly associated with OS and PFS in epithelioid MPM treated with cisplatin or cisplatin and pemetrexed.

Background:
Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor. Age, stage (TNM) and histotype are the only recognized prognostic factors but the site of disease makes staging difficult to be defined. Pleural tumor volume (TV) was suggested as an alternative in prognostic evaluation but the evidence is limited. The aim of our study was to assess the prognostic role of TV compared to that of the TNM.

Method:
Fifty-two MPM patients (pts), diagnosed in 2002-012, were retrospectively collected. A baseline CT scan was performed. Stage was defined according to TNM (7th edition) and TV was calculated using a dedicated computer system. We divided pts in 2 groups according to mean value of baseline TV(483 cm3 ; range 18-2329 cm3). Information on age, sex, histology, and surgery were collected. We evaluated disease site based on the pleural localization: mediastinal-diaphragmatic-parietal. Kaplan-Meier analysis and log-rank test were performed on OS to determine significant prognostic factors. Cox regression analysis adjusted for the prognostic factors was used for investigating their effect on OS.

Result:
Thirty-five pts were men; mean age was 62 years (range:25-74). Forty-four pts had epithelioid and 8 had mixed histology. Twenty-five pts had radical surgery. Six pts were diagnosed in early stage(I-II), 20 in III stage and 26 in IV stage. Median overall survival(OS) was 20.8 months (range:0.3–94.3). OS was significantly associated to: TV, stage (I-II, III, IV), T (T1,1B;T2;T3;T4,4B). Cox models adjusted by age, histology, sex, surgery, were used for investigating the effect of stage group and T separately on OS to avoid multicollinearity. The effect of mean TV on OS was evaluated with the Cox regression adding the number of involved sites to the above covariates. Cox regression analysis showed that: stage III (HR 3.75,95%CI 0.99-14.18;p<0.05) and IV (HR 5.43, 95%CI 1.43-20.68; p<0.01) were predictive of survival. With respect to extent of tumor, T3 and T4 were associated with worse prognosis (HR 4.99, 95%CI 1.84-13.49; p<0.002; HR 4.65, 95%CI 1.61-13.47; p<0.005 respectively). Smaller TV was associated with better survival (HR=2.37, 95%CI 1.05-5.37; p<0.04) irrespective of tumor site.

Conclusion:
We reported a significant association between TV and prognosis. However, stage and T seem to be better prognostic factors compared to TV most likely because they provide information also on adjacent organs infiltration. Our results should be interpreted with caution, considering the retrospective nature of our series and the small sample. Further collaborative studies are needed.

Background:
Malignant pleural mesothelioma (MPM) is an unusual neoplasm, originated from the mesothelial surface of the pleural cavity. The disease is associated with occupational exposure to asbestos. Although it has low incidence, it carries an elevated morbimortality, determined by its aggressiveness and aggravated by the lack of efficient therapeutic strategies. Most patients are diagnosed at advanced stages and median overall survival (OS) remains around 9-17 months. In Brazil, some studies have suggested the number of new cases will increase till 2030, nevertheless there is no official epidemiologic data available.

Method:
Clinicopathological data from patients diagnosed with MPM and treated at A.C.Camargo Cancer Center between January/2000 and December/2014 were retrospectively collected from medical records. Demographics and clinicopathological variables were described using descriptive statistics. OS was calculated from the date of diagnosis to death. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of disease progression or death. Kaplan–Meier method was used to calculate survival curves. The impact of relevant variables on survival was evaluated by the log-rank test.

Result:
We identified 29 patients between 2000 and 2014. Median follow-up was 108 months. Median age at diagnosis was 68 years (43-85y). 72.4% was men and most were Caucasian (51.7%). Tobacco consumption reported (58.6%), history of asbestos exposure (44.8%) and positive family history of cancer (34.5%). The presenting symptom was dyspnea (44.8%); followed by chest pain (24.1%). Epithelioid subtype was reported (69%) and most patients were diagnosed in stage III (34,5%) and IV (24.1%). 79% of patients were submitted to surgery: pleural decortication (36,4%), pleurodesis (31,8%), and pleuro-pneumonectomy+mediastinal lymphadenectomy (31,8%). Chemotherapy was administered to 72.4% and radiotherapy to 24.1%. Median PFS was 8 months (95%CI 5.4-10.5) and the only factor associated with improved PFS was disease resectability (resectable vs. unresectable: 10mo vs. 7mo; p=0.041). Median OS was 12 months (95%CI 5.6-18.3). Variables associated with improved OS were lack of distant metastasis at diagnosis (M0 vs. M1-MX: 15mo vs. 6mo; p=0.008) and being able to receive further lines of chemotherapy (yes vs. no: 18mo vs. 6mo; p=0.016).

Conclusion:
Since there is no national official data in Brazil, collection of local data is extremely relevant to help unraveling the epidemiological scenario in our country. Our data reinforce the low prevalence of the disease, though it could also reflect issues regarding patient referral to specialized centers. As expected, we observed an association with occupational exposure to asbestos and a poor PFS and OS.

Background:
Malignant pleural mesothelioma (MPM) cells grow in the context of immune cells, either infiltrating the tumor or present in the associated pleural effusion. Specific immune cell subsets and immune-checkpoints on T-lymphocytes infiltrating the tumor have been proposed as possible prognostic factors (Uiije, DOI:10.1080/2162402X.2015.1009285; Awad, DOI:10.1158/2326-6066.CIR-16-0171) and therapeutic targets (Marcq, DOI:10.1080/2162402X.2016.1261241; Khanna, DOI: 10.1016/j.jtho.2016.07.033). The immune cells infiltrating MPM are however dynamically exchanged with those present in the pleural fluid (Lievense, DOI: 10.1016/j.lungcan.2016.04.015). The heterogeneity of tumor bulk, ranging from terminally differentiated cells to tumor-initiating cells (TIC), makes the interactions between tumor and immune cells even more jeopardized. Our study is the first that analyzes at the same time the immune-phenotype of MPM cells, immune cells infiltrating the tumor and present in the matched pleural fluid, to obtain a comprehensive signature of MPM immune-environment and precise indications for personalized immunotherapy-based interventions.

Method:
From June 2015 to June 2017, we collected 120 pleural fluids and biopsies from patients that undergone diagnostic thoracoscopy: 34 samples were diagnosed as MPM (25 epithelioid, 5 sarcomatoid, 4 biphasic MPM), 56 samples were reactive non neoplastic pleuritis, 30 samples were pleural localization of lung adenocarcinoma or other tumors. Cells of pleural fluids were analyzed by cell sorting and flow cytometry. Biopsies were cut and digested, and cell populations were analyzed as well. We isolated, expanded and analyzed the TIC-component from 5 epithelioid and 5 sarcomatoid MPM.

Result:
MPM significantly differed from non neoplastic pleuritis for the increased number of CD3[+]CD8[+]T-lymphocytes in pleural essudate coupled with the reduction of this population within the tumor (p<0.001). M2/M1-macrophages ratio was also higher (p<0.02). The increased number of T-regulatory cells and granulocytic/monocytic myeloid-derived suppressor cells in both pleural fluid and tumor significantly (p<0.005) differentiated MPM from non neoplastic pleuritis and other malignancies. Either CD3[+]CD8[+]or CD3[+]CD4[+]T-lymphocytes present in pleural fluid and infiltrating the tumor had higher expression of PD-1, LAG-3, TIM-3 immune-checkpoints (p< 0.02), coupled with increased expression of PD-1L, LAG-3, TIM-3 and GAL-9 on matched MPM (p<0.05) compared to non neoplastic pleuritis. Interestingly, immune-checkpoints were down-regulated in TIC, suggesting that immune-checkpoint inhibitors may be poorly effective against this MPM component.

Conclusion:
Our study identified an immune-signature that discriminates MPM from pleuritis secondary to other tumors or non malignant diseases. Such immune-signature will help to refine prognostic factors and define a precision immunotherapy for MPM.

Background:
Early data on immune-checkpoint blockade with PD-1 inhibitors show promising response rates and survival benefit mainly in PD-L1 positive malignant pleural mesothelioma (MPM) patients. Reported rate of PD-L1 positivity of MPM is between 20-40%. However, the role of PD-L1 protein expression positivity in prediction of a response to PD-1/PD-L1 inhibitors remains controversial. We assessed the prognostic value of PD-L1 expression in patients with MPM in central Europe.

Method:
We evaluated protein expression of PD-L1 in formalin-fixed paraffin-embedded surgical specimens of 176 MPM patients from Austria, Croatia, Hungary and Slovenia. PD-L1 antibody clone E1L3N (Cell Signaling) was used. Cut-off point of >10% of PD-L1-positive tumor cells at any staining intensity was correlated with clinicopathologic characteristics (age, gender, IMIG clinical stage, histology (epithelioid vs non-epithelioid) and survival).

Result:
There were altogether 49 females and 127 males, median age 63 years. PD-L1 protein expression of >10% was observed in higher proportion in a patient with higher IMIG stage (III+IV vs. I+II), as well as in patients with non-epithelioid histology, later being also statistically significant (p=0.0026). Median survival of patients with high PD-L1 expression (>10%) in tumor cells was significantly shorter in comparison with patients demonstrating lower PD-L1 expression (26 vs. 67 weeks respectively, p<0.001). PD-L1 expression (>10%) proved to be an independent prognostic factor in a multivariate cox regression analysis (hazard ratio [HR] 2.902; 95% confidence interval [CI] 1.425 to 5.937; p = 0.003).

Conclusion:
High expression of PD-L1 on tumor cells (>10%) is negative independent prognostic factor in malignant pleural mesothelioma regardless of histology.

Background:
Malignant pleural mesothelioma (MPM) is a devastating neoplasm. However, some patients show a good response to chemotherapy or multidisciplinary therapy. It is therefore important to investigate the factors that can be used to select patients who will benefit from such treatment. The C-reactive protein/albumin ratio (CAR) has been used to predict the prognosis in other diseases. The aim of this study was to elucidate the prognostic utility of the CAR in MPM patients.

Method:
The data of 83 patients, who were treated with surgery, chemotherapy, or multidisciplinary therapy at National Kyushu Cancer Center between 1995 and 2015, were analyzed in the present study. The CAR was calculated as C-reactive protein value divided by albumin value using the results of blood examination just prior to starting the treatments. A cut-off value of CAR was set to 0.58 according to the receiver operating characteristics (ROC) curve for 1-year-survival.

Result:
Thirty of the 83 (36.1%) patients were classified into the high CAR group. Twenty-seven (32.5%) and 56 (67.5%) patients underwent surgery and only chemotherapy, respectively. The ROC curve showed that the CAR had good diagnostic ability with 78.9% sensitivity and 68.0% specificity (AUC=0.761). A high CAR group was significantly correlated with advanced clinical stage (III/IV) (p=0.002) and chemotherapy alone (p=0.005). The high CAR group had significantly poorer overall survival (OS) (p<0.001) and disease or progression free survival (DFS/PFS) (p<0.001). The clinical stage and the CAR were independent predictive factors for the OS (I/II and III/IV, p=0.008; ≤0.58 and >0.58, p=0.034, respectively). The clinical stage and the CAR were also independent predictive factors for the DFS/PFS (I/II and III/IV, p=0.031; ≤0.58 and >0.58, p=0.019, respectively). In the subgroup analysis of the patients who underwent only chemotherapy, the high CAR group showed significantly poorer OS and DFS/PFS compared with the low CAR group (p=0.002 and p<0.001, respectively). However, the difference in OS and DFS/PFS of the patients who underwent surgery was not apparent between the high and low CAR groups (p=0.061 and p=0.187, respectively).

Conclusion:
The CAR was an independent predictor of a poor prognosis in the MPM patients. The high CAR group showed a significantly poorer prognosis in patients with MPM treated by only chemotherapy. This score provides useful information for selecting patients who will benefit from treatment, especially chemotherapy. These findings should be validated in further prospective studies.

Background:
While the mortality rate has markedly improved for primary lung cancer, a disease that used to be incredibly difficult to treat, the prognosis for malignant pleural mesothelioma (MPM) is as poor as ever, with a mean survival time (MST) after diagnosis of about 1 year. Therefore, it is thought that the most practical method of obtaining better survival times than those associated with currently available treatment options is diagnosing MPM at an earlier stage than is possible now. We performed a retrospective study to evaluate the clinical characteristics of early stage MPM.

Method:
The study included 83 patients with a definitive MPM diagnosis of International Mesothelioma Interest Group (IMIG) clinical stage T0-1a/1bN0M0. We selected 40 patients who did not exhibit significant fluorodeoxyglucose (FDG) accumulation (<2.5) in FDG-positron-emission tomography (PET) prior to starting treatment, and then retrospectively examined their clinical characteristics.

Result:
There were 4 women in this study, 5 patients with no history of asbestos exposure, 37 patients with epithelial histology, 3 patients with biphasic histology, and 3 patients with negative cytology. All patients had pleural effusion.

Conclusion:
Although this was a retrospective study, we found that among T0-1a/1bN0M0 and PET-negative MPM patients, positive cytology (class IV/V) and histology (biphasic) were factors associated with a poor prognosis.

Background:
Distinction between mesothelioma and reactive mesothelial proliferation is difficult because of cytological and morphological overlap between these conditions. It is also difficult to differentiate sarcomatoid mesothelioma from fibrous pleuritis on biopsy. However, separation of reactive mesothelial proliferation from epithelioid mesothelioma and that of fibrous pleuritis from sarcomatoid mesothelioma is important because of therapeutic option and prognosis of the patients. There are some reports claiming that ancillary techniques such as fluorescence in situ hybridization (FISH) analysis of p16 and immunohistochemistry of BAP1 improve the diagnostic accuracy of mesothelioma. However, reported sensitivity of p16 FISH and BAP1 loss is different depending on the subtype of mesothelioma and on studies from various authors. The aim of this study was to elucidate the frequency of p16 deletion and BAP1 loss in mesotheliomas by multiple institutions in Japan.

Method:
We collected 262 malignant pleural mesotheliomas, 29 malignant peritoneal mesotheliomas, 23 cases with reactive mesothelial proliferation, and 37 cases with fibrous pleuritis from Tokyo Women’s Medical University, Chiba Rosai Hospital, Fukuoka University, Hyogo Medical University, Kagawa University, and Kanagawa Cancer Center. FISH analysis was performed with p16 probe. Immunostaining was performed with anti-BAP1 antibody.

Result:
We analyzed 262 pleural mesotheliomas (170 epithelioid, 38 biphasic, and 54 sarcomatoid) with p16 FISH, and 92 pleural mesotheliomas (58 epithelioid, 20 biphasic and 14 sarcomatoid) with BAP1 immunohistochemistry. Homozygous deletion (HD) of p16 was observed in 74% of epithelioid, 92% of biphasic, and 100% of sarcomatoid mesotheliomas. BAP1 loss was observed in 64% of epithelioid mesotheliomas and 55% of biphasic mesotheliomas, but not in sarcomatoid mesotheliomas. Concordance of HD of p16 and BAP1 loss between epithelioid and sarcomatoid components of 19 biphasic mesotheliomas was 100%. We analyzed 29 peritoneal mesotheliomas (25 epithelioid, 2 biphasic, and 2 sarcomatoid) with p16 FISH and 9 peritoneal epithelioid mesotheliomas with BAP1 loss. HD of p16 was observed in 52% of epithelioid mesotheliomas, 50% of biphasic mesotheliomas, and 50% of sarcomatoid mesotheliomas. BAP1 loss was observed in 56% of epithelioid mesotheliomas. No case with reactive mesothelial proliferation or fibrous pleuritis harbored HD of p16 and showed BAP1 loss.

Conclusion:
Separation of epithelioid or biphasic mesothelioma from reactive mesothelial proliferation may be possible with p16 FISH and/or BAP1 immunohistochemistry. Because all of the pleural sarcomatoid mesotheliomas but no cases with fibrous pleuritis harbor HD of p16, p16 FISH helps the separation of sarcomatoid mesothelioma from fibrous pleuritis, but BAP1 does not.

Background:
Video-assisted thoracic surgery (VATS) pleural biopsy is a most reliable diagnostic procedure for malignant pleural mesothelioma (MPM), however, its surgical outcomes are still unknown. The purpose of this study was to analyze the surgical outcome of VATS pleural biopsy in patients suspected of MPM.

Method:
A total of 377 patients received VATS pleural biopsy with suspected of MPM from March 2004 to December 2016 were included in the study. We evaluated their surgical outcome based on diagnostic accuracy, mortality, morbidity.

Result:
Of 377 patients, VATS pleural biopsy led to diagnosis as MPM in 250, carcinomatous pleurisy in 22 and chronic pleuritis in 105. However, of these 105 chronic pleuritis patients, 10 patients were received re-biopsy to establish the definitive diagnosis. Re-biopsy revealed 9 patients finally diagnosed as MPM, and 1 patient as carcinomatous pleurisy. The diagnostic accuracy of initial VATS pleural biopsy for MPM was 96.5% (250/259). The causes of miss-diagnosis were sampling error in all 9 cases, and the causes of sampling error as follows: no visible tumor in 4, complicated empyema in 2, severe adhesion in 2, and desmoplastic MPM in 1. The median postoperative stay was 5 days (1-114).Postoperative complication. Median age was 68 years (range, 40-85 years), with a 5- day (range 1-114 days) median length of stay. Postoperative complication occurred in 25 patients (5.7%), and 1 patient (0.26%) died due to postoperative empyema. Complications of this study included the following: injury of lung parenchyma in 7, wound infection in 4, re-expanding pulmonary edema in 3, empyema, gastrointestinal perforation and delirium in 2, fetal arrhythmia, cholecystitis hemothorax, liver dysfunction, acute respiratory failure in 1.

Conclusion:
VATS pleural biopsy could lead to definitive diagnosis in most case of MPM, but we should consider their limitation of diagnostic ability and the risk of VATS biopsy.

Background:
The differential diagnosis between epithelioid mesothelioma (EM) showing a solid histological pattern (solid EM) and poorly differentiated squamous cell carcinoma (SCC) can be challenging with conventional light microscopy (haematoxylin and eosin-stained specimen) alone. The role of immunohistochemistry in distinguishing pleural EM from lung adenocarcinoma (LAC) has received much attention. Currently, many immunohistochemical markers are available for distinguishing pleural EM from LAC. . However, there are only a few reports on the immunohistochemical differential diagnosis of EM and lung SCC. Ordonez et al. have reported the immunohistochemical analyses of 30 EMs showing a solid pattern and 30 pulmonary non-keratinizing SCCs, and have recommended the combination of two positive (Wilms' tumour gene product; WT1 and calretinin/mesothelin) and two negative (p63 and Epithelial-related antigen; MOC31) markers for differentiating EM from lung SCC. The aims of this study were to clarify the usefulness of immunohistochemistry in the differential diagnosis of solid EM and poorly differentiated SCC, and to confirm the validity of a specific type of antibody panel. Additio nally, we aimed to clarify the pitfalls of immunohistochemical analyses.

Method:
Formalin-fixed paraffin-embedded specimens from 36 cases of solid EM and 38 cases of poorly differentiated SCC were immunohistochemically examined for calretinin, podoplanin (D2-40), WT1, cytokeratin (CK) 5/6, p40, p63, carcinoembryonic antigen (CEA), MOC31, claudin-4, thyroid transcription factor-1 (TTF-1), and napsin A.

Result:
WT1 showed the highest diagnostic accuracy (85.1%) as a mesothelial marker, and CEA, p40 and claudin-4 showed higher diagnostic accurac ies (95.9%, 94.6%, and 93.2%, respectively) as carcinoma markers. Calretinin (diagnostic accuracy: 75.7%), D2-40 (diagnostic accuracy: 67.6%), CK5/6 (diagnostic accuracy: 63.5%), TTF-1 (diagnostic accuracy: 55.4%) and napsin A (diagnostic accuracy: 52.7%) could not differentiate between solid EM and poorly differentiated SCC. Among these markers, the combination of calretinin and WT1 showed the highest diagnostic accuracy (86.5%) as a positive marker, and the combination of p40 and CEA showed the highest diagnostic accuracy (97.3%) as a negative marker. The combin ation of CEA and claudin-4 also showed relatively high diagnostic accuracy (94.6%) as a negative marker.

Conclusion:
We recommend the combination of WT1 and calretinin as a positive maker, and the combination of CEA and claudin-4 as a negative marker, for diff erential diagnoses of solid EM and poorly differentiated SCC.

Background:
Lung cancer is the third incidence and first mortality of cancer disease in Taiwan. The survival time of lung cancer patients was extended. The overall 2 year survival rate from 29% to 49.8% at National Cheng Kung University Hospital (NCKUH). Factors associated with quality of life have become the issues of focus and need to be elucidated as the improvements of medical science prolong the survival of patients with lung cancer.The purpose of this study was to describe the long-term trend on the quality of life of patients with lung cancer, and to understand the related factors.

Method:
This was a retrospective study with secondary data analysis and chart review. The study samples were lung cancer patients who were diagnosed from 2005 to 2012 at NCKUH and joined WHOQOL interview research program. We assessed personal characteristic, health status, lung cancer disease status and treatment. The authors analyzed secondary databases included the NCKUH cancer registration database and the NCKUH Cancer QoL Study database. The analyzing protocol was also approved by the institutional ethics committee. Using SAS 9.3 software, the regression models and mixed-models were constructed to explore related factors and the time trend of QoL.

Result:
Total 1887 questionnaires were included in research. The proportion of female subject was 47.7%. Figure 1



Conclusion:
The physical, psychological, environment domains and global QoL among lung cancer patients was improved over time, which showed the promising quality of treatment and care in NCKUH. The factors associated with QoL among patients with lung cancer include gender, age, married status, employment status, income, and with chronic kidney disease or brain metastasis. More resources are to be explored for patients who are single or have lower income, and special attention should be paid to patients who are unemployed, female, elder, or to under radiotherapy that would improve their QoL.

Background:
Two papers showed that female lung cancer patients have poorer QoL. But others papers didn't have consistence conclusion. In author's NCKUH-10207013 study, the result showed that male patients improved more than female over time in the domains of physical, psychological and social quality of life. The purpose of this study was to understand the demographic status and characteristic of QOL in different gender. And to understand the related factors of the QOL in different gender.

Method:
The study design was to analyze secondary databases. The study samples were lung cancer patients who were diagnosed at National Cheng Kung University Hospital and joined WHOQOL interview in DOH100-TD-C-111-003 study. The databases included the cancer registration database, the diagnosis and treatment database for lung cancer, and the NCKUH quality of life database. Using SPSS and SAS 9.3 software, regression madel and mixed-models were constructed to explore the difference and related factors of quality of life between gender.

Result:
409 females and 446 males lung cancer patients were included this study. Female lung cancer patients were diagnosed with younger age, higher proportion of non-working status and single status. Female had lower score in psychological domain of QoL at 6th months after diagnosis. But female had better score than male in physical domain of QoL at 9th months after diagnosis. For the QoL details items of each domains, there were significant negative differences of female in pain, energy, active ability, sleep, daily activity, thinking, bodily image, self-esteem, negative feeling. Figure 1



Conclusion:
The larger significant differences between gender were pain and sleep of the physical domain, and bodily image and negative feelings of the psychological domain. The results of this study could understand the differences of QoL between gender. More resources and care plans should to be explored for different gender to improve their QoL and prevention QoL decrease.

Background:
Performance status (PS) scoring systems are of immense prognostic and clinical importance, however, the subjective evaluation of a patient’s global physical functioning is limited in sensitive prognostic stratification and existing literature present contradictory inter-rater reliability of PS assessments. The subjective assessment indicates the level of physical functioning, but does not provide a targeted treatment aim. Better treatment aims could be provided, if the level of decline in physical functioning was objectively collected and evaluated. To our knowledge, the significance of functional capacity in patients with lung cancer has never been evaluated prior to this review. Thus, the aim of this study was to identify and evaluate the evidence objectively examining 1) the decline in functional capacity in patients with lung cancer during cancer treatment, and 2) the prognostic value of functional capacity for patients with lung cancer.

Method:
The systematic review was reported according to PRISMA guidelines. A search in three databases: PubMed, EMBASE and Web of Science, generated 171 articles. Quantitative study designs, including case-series and case-controls, assessing functional capacity in patients with lung cancer were included. Self-reported functional capacity was excluded. No restrictions on publication date were imposed. Only articles published in English were considered for inclusion.

Result:
Eight studies on a total of 908 patients with lung cancer met the inclusion criteria. The majority of the studies were prospective cross-sectional studies (n=7), remaining was a case-control (n=1). Patients with lung cancer had already declined in functional capacity at baseline compared to healthy adults, and deteriorated further during initial cancer treatment. Functional capacity as a predictive measure was not associated with radiation induced lung injury. A 6-minute walking distance (6MWD) >400 m was associated with a 56 % reduction in the risk of death, and every 50 m improvement in 6MWD was associated with a 13 % risk reduction.

Conclusion:
The results of this review demonstrate that functional capacity (6MWD) declines following non-surgical NSCLC treatment as well as low functional capacity being associated with higher risk of mortality. By implementing an objective measure for functional capacity at the time of diagnosis, it could be possible to generate targeted treatment aims throughout the medical treatment and rehabilitation process. In addition, an objective measure for functional capacity could provide a better prognostic stratification.

Background:
Lung cancer, the most common metastatic tumor to the pleura, accounts for approximately 40% of all malignant pleural effusion (MPE). Regarding symptomatic MPE, local therapies including pleurodesis and treatment of primary malignancy are required to alleviate dyspnea and/or pleuritic pain. Helixor-M made from European mistletoe (Viscum album) has been used as adjuvant anticancer treatment by boosting immune system. We have used Helixor-M as sclerosing agent for pleurodesis to control MPE. The aim of this study is to evaluate efficacy and safety of Helixor-M to control MPE.

Method:
Between 2009 and 2015, we consecutively enrolled 52 patients with lung cancer who were treated with Helixor-M for MPE and analyzed retrospectively. For pleurodesis, we instilled 100mg of Helixor-M via pleural catheter at Day 1. After 3-hour of frequent repositioning we drained residual pleural fluid. If prior procedures were not effective, we repeated this procedure up to 5 times every second day with increasing dose by 100mg. Our primary study outcome was reappearance of pleural effusion 1-month after pleurodesis.

Result:
The median age was 63 years and 77% were male. Among 52 patients, 69% were adenocarcinoma, followed by squamous cell (13%), not otherwise specified (10%), and small cell lung cancer (8%). About 85% of MPE were cytogenetically malignant. Among 52 patients, 39 (75%) were evaluable for recurrence of MPE. The 1-month recurrence rate was 49% (19/39). Among 19 patients who experienced recurrent MPE, 6 required recurrent pleural drainage. One fourth of patients experienced significant pain after pleurodesis. Only 15% of patients experienced fever.

Conclusion:
Our results suggest that a pleurodesis with Helixor-M was effective and tolerable procedure to control MPE in advanced lung cancer patients.

Background:
Brain metastases (BM) are common in due course of lung cancer (LC). The clinical presentation of BM can be very distressing for family/caregivers and urges for immediate treatment. Despite the early diagnosis and multimodality treatment of BM, prognosis remains poor. Considering the fact that treatment options in developing countries are limited (WBRT, surgery and SBRT) individual approach and specific prognostic assessment is highly important for further disease management. Aim of this study was to gather information and make approximation of overall survival (OS) of LC patients with BM.

Method:
This observational trial was conducted at the Institute for Pulmonary Diseases of Vojvodina, Serbia in the period from March 2010 to April 2015 taking into account all newly diagnosed LC patients. All data were harvested from the hospital based data capture system. The survival estimations were calculated regardless of the therapeutic interventions applied. Median OS was determined via Kaplan-Meier curves for all subgroups of LC patients with BM.

Result:
BM were diagnosed in 336 (5.1%) out of 6.624 LC patients in this 5 year period. Out of them, 182 patients were eligible for evaluation in this trial, the rest were excluded due to missing data. Majority of patients were male 68.1% (124), older than 60 years 50.0% (91), smokers 73.6% (134) with ECOG PS 1 76.4% (139). Most frequent LC type was adenocarcinoma 59.3% (108) followed by small-cell, squamous cell, and other types; 19.2% (35), 13.2% (24) and 8.2% respectively (13). One BM was present in 63.0% (63), 2-3 BM in 52.0% (52) and more than 3 in 34.6% (63) of patients. Extra cranial metastases (ECM) were present in 60.4% (110) of patients Median OS of all patients with BM regardless the histology was 8.5 (95%CI: 7.8-12.2) months. Median OS of patients with NSCLC, SCLC and other tumour types was 8.5 months (95%CI: 6.0-10.9), 10.0 months (95%CI: 7.8-12.2), and 5.5 months (95%CI: 0.1-11.0) respectively. Lowest median survival period was observed in patients with ECOG PS >3; 3.60 (95%CI: 0.2-7.0) months.

Conclusion:
The survival results of this trial show consistency with historical survival times. These results may suggest that survival outcomes for LC patients with BM are independent of applied therapy. Approximate survival prognosis taking into consideration individual (age and ECOG) and objective (tumour type, number of BM and presence of ECM) patient characteristics is highly important for further disease management in order to decrease patients burden and increase cooperation with family/caregivers.

Background:
The aim of this study was to identify predictors of overall survival (OS) and recurrence after palliative pleural procedures in patients with malignant pleural effusion (MPE) and high-risk tumors according to the LENT Score Study.

Method:
Data was collected from our database between January 2013 and December of 2015 of patients high-risk tumors according to the LENT Score and MPE. All patients were followed-up at least 30 days after the pleural procedure. We studied radiological aspects, biochemical and hematimetric parameters beyond clinical features. To analyze OS, patients were divided into two groups. Group I included OS greater than 30 days and Group II included OS shorter than 30 days. Prognostic factors for pleural recurrence and OS were identified by univariate analysis, using Fisher's exact and Student's T-Test. Subsequently, the significant variables were entered into a multivariate logistic regression analysis (p < 0.05).

Result:
A total of 134 patients were included in the analysis. Median follow-up time for surviving patients was 56 (range 2 to 623) days. High-risk primary tumors included lung 66,4%, gastrointestinal 24,6%, sarcoma 3,7%, urological 3,7% and others 1,5%. There were 44 patients in Group I who had OS shorter than 30 days. Recurrence occurred in 22 patients of the entire cohort. Factors affecting OS in univariate analysis were: procedure, ECOG, albumin, leukocytes, neutrophil to lymphocyte ratio (NRL) e hemoglobin in peripheral blood. Factors affecting recurrence were: procedures, quimiotherapy line (QL), albumin and platelets. At the multivariate analysis in Group I, the type of procedure (therapeutic pleural aspiration – TPA) (p = 0.011), ECOG 3 e 4 (p = 0.004), NLR > 5 (p = 0.037) and leukocytes > 8000 (p = 0.042) were identified as independents predictors of OS. About recurrence, only QL further than first line (p = 0.042) was identified as independent predictor.

Conclusion:
Patients with MPE who underwent TPA, ECOG 3 and 4, with leukocytes > 8000, NLR > 5 were significantly associated with shorter OS, and QL greater than first line was associated with recurrence. The identification of those prognostic factors may assist the choice of the optimal palliative technique for high-tumors risk patients according LENT score study.

Background:
Lung cancer is second most common cancer in Indian men and is a leading cause of cancer deaths in India. Most lung cancer patients in India are diagnosed at an advanced or metastatic stage and predominantly receive palliative treatment. In patients with metastatic lung cancer quality of life (QOL) improvement is the main treatment goal since survival can be prolonged only marginally despite the use of several new therapeutic modalities.

Method:
We divided metastatic lung cancer patients into four groups depending on the treatment they received: Group A - palliative chemotherapy, Group B – palliative radiotherapy, Group C – both palliative chemotherapy and radiotherapy and Group D – only symptomatic therapy and best supportive care. All patients completed quality of life questionnaire for lung cancer (EORTC QLQ C30 version 3.0 and LC13) translated in the native language before treatment and on follow up after receiving the planned treatment. Apart from QOL questionnaires few other variables were also studied including age, gender, histology, smoking status, stage, performance status and financial status.

Result:
92 patients were prospectively included in the study with 23 patients in each group. All aspects of functioning were most preserved in patients who received palliative chemotherapy (physical, emotional, social, cognitive, role and global QOL) and were most disturbed in patients who received only symptomatic therapy. Chemotherapy reduced symptoms like dyspnea, insomnia, loss of appetite, dysphagia, and haemoptysis, but also increased nausea, vomiting, fatigue and alopecia. Radiotherapy reduced pain, coughing, dyspnea, dysphagia and hemoptysis but worsened physical and social functioning.

Conclusion:
Any modality of treatment is superior to the use of only symptomatic treatment in improving QOL in metastatic lung cancer patients and therefore some form of treatment should be offered if possible. Patients on chemotherapy have better QOL than those on radiotherapy or combined chemotherapy and radiotherapy.

Background:
The management of lung cancer (LC) in French Polynesia may pose problem, especially intercultural communication between patients (PT) and health professionals (HP).

Method:
Attractiveness, use and utility of a PT’s self-expression and follow-up cultural notebook “A Haere I Mua”, was evaluated among 171 HP (self-administrated questionnaires) and among 35 PT suffering from incurable LC (interview). Comparisons were made between PT and HP (Fisher’s test).

Result:
The notebook pleased PT and HP (77.4%, 81.3% respectively), especially its images (90.3%, 81.3%), texts (80.6%, 69.6%) and expression areas (87.1%, 63.7%) (p>0.05 for all). PT’s health representations were focused on hope and future (the canoe and "A Haere I Mua"), HP’s ones on care and present (storm and difficult times).The subgroup of the Polynesian PT better made the connection with the disease (p = 0.02) and have a better perception of expression areas (p = 0.004) than the HP. While 80.6% of PT consulted the notebook, only 38.7 % used it. The Polynesian PT were more likely than the HP to have found the notebook useful (13/15 items p≤ 0.05), expect for the items "say or write things that I do not dare to say" (p=0.32) and "be better understood" (p=0.11).

Conclusion:
The notebook “A Haere I Mua” is an intercultural communication tool adapted to the Polynesian PT. It could be used in the announcement program and supportive cares, but requires training of the HP and a greater awareness of the PT. It may also contribute to the emergence of a project of integrative medicine for lung cancer in French Polynesia.Figure 1

Background:
Due to significant advances in the treatment of the lung cancer, it has become possible now to live and work with the disease. However, keeping a good balance between work and treatment is still a challenge for many patients. The paper describes the coping strategies and positive effects of work on the condition and treatment outcomes for a stage 4 NSCLC patient.

Method:
Case study of a 56-year old Japanese male patient diagnosed with pulmonary adenocarcinoma NSCLC (stage 4) metastases in July 2010, and living and working with cancer for 7 years.

Result:
The patient’s treatment started with PTX CBDCA and Bev in July 2010. As EGFR was positive, Gefitinib was used for second and fourth line. Palliative care and cancer rehabilitation were also undertaken. The sixth line treatment was a clinical trial (1[st] Phase) of AZD9291 from Mar. 2014 to Jan. 2016. After a one-year interval, Osimertinib became again effective from Jan. 2017, especially for brain metastases. After diagnoses of cancer, the patient’s lifework became to create a society where people with cancer can live and work, even those with advanced stage cancer. He started the new project on “Working with Cancer” in his company and contributed to the publication of books and websites introducing various patient case studies. He has also helped to establish the Japan Lung Cancer Alliance in Nov. 2015. These activities provided fulfillment and motivation in the patient’s life and improved treatment outcomes.

Conclusion:
The experience of this patient indicated the link between the work and the longer survival. First, the patient identify his mission and remain conscious of it. We gain a sense of usefulness, of connection with society, and meaning in life through work. Second, the patient tried to manage his mindset and maintain his own QOLs. The life of the patient has had its ups and downs, but he never give up on the treatment. He kept the mindset not being too influenced or passive in the care, but more proactive and decisive. Third, the case shows the importance of cooperation from his co-workers and the patient effort to communicate with them. The patient's record about his treatment and condition helped his co-workers to adapt the situation. Fourth, the patient sought advice not only from the chief physician, but also from other specialized doctors, seeking second opinions, looking for clinical trial information. The patient tried to evaluate all the information and make his own decision.