Virtual Library

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Background:
Incidental stage IIIA non-small cell lung cancer (NSCLC) cases have positive N2 mediastinal lymph node involvement discovered at the time of surgery, resulting in stage reclassification. These patients represent a small group within the stage III patient spectrum with limited data regarding their outcome. This study’s aim is to characterize the survival of incidental stage IIIA disease and compare these outcomes to patients diagnosed with stage II and IIIA disease.

Methods:
Using the Glans-Look Lung Cancer database and electronic patient charts, a retrospective review identified patients consulted at the Tom Baker Cancer Center from 1999 to 2012 who were defined as incidental stage III NSCLC. Their outcome was compared with stage II patients who underwent resection and stage IIIA patients treated with concurrent chemotherapy and radiation (CCR). These groups were selected for comparison because they represent patients who received the recommended standard of care for their respective diagnosis. A Kaplan-Meier analysis was conducted to compare overall survival (OS) among the groups.

Results:
Fifty-eight incidental stage III NSCLC patients were identified: median age was 63 years (SE ±10.3), 46.6% male, and 63.8% received adjuvant therapy. There were 225 individuals treated with CCR; median age 64 years (SE ±9.0), 56.0% male. The stage II group contained 248 individuals, the median age was 64 years (SE ±10.2), 53.6% were males, and 30.6% received adjuvant therapy. The OS of the incidental group was 47.4 months (95% CI 20.0-74.7). The OS for patients treated with CCR only was 24.0 months (95% CI 20.8-27.2) and 55.3 months (95% CI 43.7-66.9) for stage II resected cases. There was a significant difference in OS between CCR-treated stage IIIA and incidental cases (p = .001) but not between stage II and incidental (p = .264). The five-year survival rates were 44.6% (SE ±6.5) for incidental IIIA, 21.0% (SE ±2.7) for CCR-treated IIIA, and 46.9% (SE ±3.2) for resected stage II.

Conclusion:
This study demonstrates that incidental stage IIIA-N2 patients are a distinct group whose median OS closely resembled stage II patients. The benefit of resection for stage IIIA patients suggests that the traditional influence of stage in dictating treatment is changing. Further investigation is needed to identify which stage IIIA patients benefit the most. Ongoing analysis will include a comparison of progression-free survival between the three groups, impact assessment of post-operative treatment on OS, and a description of the diagnostic process evolution over time leading to an incidental N2 diagnosis.

Background:
Complete histopathological response or downstaging has been reported as a good prognostic factor for locally advanced non-small cell lung cancer (NSCLC) patients who received neoadjuvant therapy and underwent surgical resection. However, it is yet to be known if the prognosis of pStage I patients is similar to that of ypStage I cases. In this study we aimed to compare the long-term survival following surgical excision between locally advanced NSCLC that have been downstaged to stage I after neoadjuvant therapy versus stage I NSCLC treated by direct surgery.

Methods:
In this is multi-centered study we retrospectively analyzed the medical data of NSCLC patients undergoing surgery (segmentectomy or more) between January 1998 and December 2014. According to the histopathological results patients with Stage 1 (T1-2aN0) disease (n=427) were included into the study. Patients were divided into two groups Group 1: patients who underwent direct surgical resection without any preoperative therapy (n=291), Group 2: Patients who had locally advanced disease (T3-4N0-1 or T1-3N2) and received neoadjuvant treatment (chemotherapy or chemoradiation) for locally advanced NSCLC (n=136). The survival rates and effecting factors were analyzed.

Results:
All but 64 patients were male with a mean age of 60y (20-87y). According to tumor type; 192(45%) patients had squamous cell carcinoma, 158(37%) adenocarcinoma and 77 (18%) patients NSCLC. Neoadjuvant treatment consisted of chemotherapy in 89 (65,4%) and chemoradiation in 47(34,5%) patients. Histopathological investigation of the resected specimen revealed stage Ib (T2aN0) in 205 patients (group 1; n=140, group 2;n= 65, p=0,95). Overall morbidity rate for all patients was 30,9% (132/427) with 1.8% mortality. Five year survival rate in all patiens was 71% (77% in group I and 57% in group 2). The difference was statistically different between the groups, p<0,001.

Conclusion:
This study showed that survival of patients after surgical excision was different in ypStage 1 compared to pStage 1. Histopathological staging does not reflect to the survival figures. Our impression is that IASLC recommendations for staging of NSCLC should be subdivided or revised according to ypTNM staging following neoadjuvant treatment.

Background:
In IIIa(N2) Non-small cell lung cancer (NSCLC), various strategies to cure have been tried but the major cause of mortality is still the recurrence. Therefore, understanding of the dynamics of recurrence is important to improve the treatment outcome. We investigated the timing and patterns of recurrence after treatment of IIIA(N2) NSCLC with trimodality treatment (neoadjuvant chemoradiotherapy and surgery).

Methods:
An institutional database of consecutive patients between 1997 and 2013 (N = 574) was reviewed retrospectively. Eligible patients had pathologically proven N2 disease of NSCLC and completion of a planned trimodality treatment. First events involving the development of loco-regional recurrence, distant metastases or both were considered. The hazard rate function was used to evaluate the dynamics of recurrence.

Results:
The 5-year overall survival rate was 47% and the 5-year recurrence free survival rate was 29%. Among the 299 patients (52.1% of total) who experienced recurrence, 26 (8.7%) had loco-regional recurrences, 248 (82.9%) had distant metastases, and 25 (8.4%) had both. The most frequent sites of distant metastases were lung (n=102, 41%), brain (n=63, 25%), and bone (n=63, 25%). The hazard rate function for the overall recurrence revealed the peak at approximately 8 months after surgery then the down-slope pattern before 38 months. A similar risk pattern was found in distant metastasis but low and steady risk pattern was detected in loco-regional recurrence. In distant metastases, similar patterns were found in individual organs, however, earlier peak at approximately 5 months presented in brain metastasis. A comparison of histology showed that adenocarcinoma exhibited higher recurrence hazard rate of distant metastasis than squamous cell carcinoma with similar pattern of recurrence (p=0.03). The status of nodal clearance after induction therapy exhibited that ypN2 patients (n= 229, 39.9%) had highest hazard rate (p=0.03). The recurrence hazard rate of ypN0 was the least, but the extent was not smaller, they showed approximately one of third of ypN2 at peak.

Conclusion:
The hazard rate of loco-regional failure after trimodality therapy was low. But the hazard rate of distant metastasis was considerably high yet and shifted to left with the peak within 12 moths after surgery. This study guides the intensive surveillance immediate after completion of trimodality therapy to identify risk groups of early recurrence and to develop therapeutic strategy.

Abstract not provided

Background:
In all current non-small cell lung cancer (NSCLC) guidelines it is advised to screen all stage III patients for brain metastases, preferably by magnetic resonance imaging (MRI), or otherwise a contrast-enhanced computed tomography (CE-CT). Access to MRI can be problematic and a dedicated brain CE-CT can be incorporated in the staging [18]Fluodeoxoglucose-positron-emission-tomography ([18]FDG-PET)-CT scan. The additive value of a brain MRI after a dedicated brain CE-CT scan is unknown.

Methods:
In this observational prospective multicentre study all consecutive stage III NSCLC patients scheduled for treatment with curative intent from three Dutch hospitals who underwent a dedicated brain CE-CT incorporated in the staging [18]FDG-PET and an additional brain MRI were included. Patients with another primary tumour within 2 years of NSCLC diagnosis were excluded. Data regarding patient characteristics and imaging results were collected. Primary endpoint was the percentage of patients diagnosed with brain metastases on MRI without suspect lesions on CE-CT. 118 patients were needed to show a clinically relevant considered difference of 2%.

Results:
Between December 14[th] 2012 and July 15[th] 2016, 264 consecutive patients had an extracranial stage III NSCLC based on [18]FDG-PET. 111 out of these 264 patients (42.0%) were excluded because of no dedicated brain CE-CT 57 (51.4%) had only a low dose CT for attenuation correction, 54 (48.6%) had a CE-CT but without dedicated brain imaging protocol). Fourty (26.1%) of the remaining 153 patients were excluded because of asymptomatic brain metastases on dedicated CE-CT brain (N=8), second primary (N=6) or no brain MRI (N=26). 113 stage III patients were included (updated results of 118 patients will be presented). 57.5% of the included patients were male; mean age was 67.0 years, 84.1% had WHO PS 0-1, 60.2% had stage IIIA (before MRI brain) and 42.5% had an adenocarcinoma. Median time (range) between [18]FDG-PET-CE-CT and MRI was 2.0 (0.0 -8.1) weeks. 5/113 (4.4%) patients had a solitary brain metastasis on MRI despite no suspect brain lesions on CE-CT. In retrospect, in one of these five patients a solitary brain metastasis could be identified on the [18]FDG-PET–CE-CT.

Conclusion:
Although asymptomatic brain metastasis were detected in staging CE-CT, MRI brain is in daily practice clinically relevant superior to a CE-CT in screening for brain metastases in stage III NSCLC

Background:
Tumor-infiltrating lymphocytes (TILs) and tumor budding were all the markers of tumor microenvironment. This study aimed to explore the potential association of tumor microenvironment with brain metastases (BM) in patients with completely resected stage IIIA(N2) NSCLC.

Methods:
301 consecutive patients with pathological stage IIIA(N2) NSCLC who underwent complete surgery were reviewed between January 2005 and July 2012. Full-face hematoxylin and eosin-stained sections from surgical specimens for each case were evaluated for the density of TILs. Patients were stratified into TIL- and TIL+ groups based on pathologic evaluation. Tumor budding was defined as single cancer cells and clusters composed of up to four cancer cells. According to the number of tumor budding per field, the cases were classified into two groups: grade 1, up to five budding foci; and grade 2, six or more budding foci. The relationship between tumor microenvironment and BM at the initial presentation was analyzed.

Results:
Brain was the most common site of distant failure, and 92.5% BM developed in 3 years after the complete resection. 53 (17.6%) patients had BM as the first failure. Although, univariate analysis showed that TIL was not significantly associated with an increased risk of developing BM as the first site of failure in 3 years (P=0.196), a higher density of TILs was associated with improved postoperative survival time (P=0.058). Patients with the tumor budding >5 experienced increased BM in 3 years versus patients with the tumor budding ≤5 (P=0.068). Multivariate analysis showed that adenocarcinomas and multiple N2 stations were significantly associated with the high risk of BM as the initial site of failure in 3 years. Figure 1



Conclusion:
In patients with completely resected stage IIIA(N2) NSCLC, tumor budding >5 had a tendency to experience more BM. TIL seems to be a potential role in predicting survival of patients in completely resected stage IIIA(N2) NSCLC.

Background:
Type 2 Diabetes Mellitus (T2DM) has been associated with an increased risk of relapse and mortality in several cancer locations, but the prognostic value of T2DM or its metabolic control (MC) in patients (pts) with stage III non-small cell lung cancer (NSCLC) have not been studied yet. The purpose of this study is to evaluate the influence of T2DM and its MC on the prognosis of pts with NSCLC treated with concurrent chemoradiotherapy (cCT-RT).

Methods:
170 pts with NSCLC stage III treated with cCT-RT at the Catalan Institute of Oncology from 2010-2014 were retrospectively reviewed. The overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier method and multivariate Cox model was adjusted by: age, histology, stage, ECOG PS and smoking history.

Results:
Patient characteristics: median age 64y (37-87), male 87%; ECOG≤1 92%; smoking history: current 49%, former 46%, never 5%; histology: adenocarcinoma 34%, squamous 43%, NOS 23%. Platinum doublet CT: Cisplatin 64%, Carboplatin 36%. RT between 60-70 Gys: 94%. At a median follow-up of 38 months (m), 108 patients relapsed (63%), mPFS; 13m (95% CI 10-16) and mOS: 28m (95% CI 22-34). 54 pts (32%) had been diagnosed with T2DM before NSCLC diagnosis. In the overall population mean baseline glycemia was 6.75 mmol/L (3-17). OS and PFS were significantly shorter in patients with T2DM (mOS 17m vs 31m, p=0,005; mPFS 10m vs 16m; p =0,003). T2DM pts were classified into 3 groups of MC based on glycated hemoglobin (HbAc1) before treatment: good MC (HbAc1 <7%), n=26pts; moderate MC (HbAc1 between 7.1-8.5%), n=18pts and poor MC (HbAc1 >8.6%), n=10pts. Poor MC was significantly associated with shorter mOS (11m) as compared with moderate MC (20m) and good MC (28m; p=0.029). T2DM pts treated with insulin had shorter mOS (8m vs 20m; p=0.002) and mPFS (7m vs 12m; p=0.002) than non-insulin treated pts. However there were no differences based on whether pts were taking metformin or not. T2DM was not associated with higher risk of treatment toxicity (pneumonitis or esophagitis). In the multivariate analysis, baseline glycemia and T2DM were both independent prognostic factors for OS (HR 1.2; IC95%1.17-1.3 and HR 1.51; IC95% 1.02 -2.27, respectively).

Conclusion:
Our data suggest that T2DM and poor MC is associated with worse prognosis in pts with stage III NSCLC treated with cCT-RT. Optimal control of T2DM and prevention of hyperglicaemia might benefit those pts, and further studies are warranted.

Abstract not provided

Background:
This study aims to compare efficacy and safety of two widely used combinations of cisplatin (P) in this setting: as etoposide (E) and vinorelbine. This last, in its oral formulation (oV) which has achieved comparable results as the IV formulation and patients (pts) prefer it.

Methods:
Pts between 18-75years, with histologically proven untreated and unresectable locally-advanced NSCLC (LA-NSCLC), adequate respiratory function, V20≤35% and ECOG-PS 0-1, were randomized 1:1 to oV-P arm: 2 induction cycles (cy) of oV-P followed by 2 cy more with RT; or to E-P arm: 2 cy of E-P concomitants to RT. Both arms with a total radiation dose of 66Gy administered 2 Gys daily. Primary endpoint was progression free survival (PFS) by RECIST 1.1. Secondary endpoints: overall response rate (ORR), overall survival (OS) and safety. With α-error of 0.05 (one-tailed test) and 0.1 β-error, median PFS unacceptable for the oV-P arm of 10 months (m) (p0) and a very acceptable of 15 m (p1), 122 eligible pts were required.

Results:
140 pts from 23 institutions of SLCG were randomized between 08/2011-12/2014. 134 pts were treated (66 in oV-P and 68 in E-P arms). Results based on this 134 pts are presented. Median age 62 years [39-76]; PS 0/1, 45%/55%; current smoker 51%; squamous cell 51%; stage IIIB 54%. 244 and 131 cy were given in the oV-P and E-P arms, respectively. All irradiated pts in oV-P arm received at least 60Gy, 7 pts in the E-P arm received less than 60Gy (4 due to toxicity). 1 pt (1.5%) in oV-P arm and 12 pts (17.6%) in E-P arm presented esophagitis G3/4 (p=0.002). 121 confirmed eligibility for efficacy analysis. ORR were 39 (64%) and 40 pts (67%) in the oV-P and E-P arms, respectively (p=0.889). After 16 m [1-43] of follow-up, 66% pts progressed and 43% pts died. Median PFS is 11.4 m (IC95%; 6-17) in oV-P arm and 11.8 m (IC95%; 7-16) in E-P arm (p=0.374).

Conclusion:
Both regimens achieve similar efficacy however oV-P has less toxicity, especially esophagitis G3/4. Further follow-up is needed for the survival analysis.

Background:
Concurrent chemoradiotherapy (CCRT) is the standard treatment (TRT) for stage 3 NSCLC. Elderly patients (pts) are common, may have increased toxicity,& poorer results from CCRT

Methods:
Individual patient data (IPD) from NCTN phase 2/3 trials of CCRT for stage 3 NSCLC from 1990-2012 was collected. We compared the overall survival (OS), progression-free survival (PFS), & adverse events (AE’s) for pts age ≥70 years (yrs) (elderly) vs. <70 yrs (younger). Unadjusted & adjusted Hazard Ratios (HRs) for survival time & their confidence intervals (CIs) were estimated by single-predictor & multivariable Cox models. Unadjusted & adjusted Odds Ratio (OR) for AE’s & their CIs were obtained from single-predictor & multivariable logistic regression models

Results:
IPD from 16 trials were analyzed; 2,768 pts were younger & 832 were elderly. Median OS & PFS for elderly & younger pts are in the table. In the unadjusted & multivariable models elderly pts had worse OS (HR=1.23; 95%CI =1.13-1.35, and 1.20; 95%CI=1.10-1.32, respectively). In the unadjusted & multivariable models, elderly & younger pts had a similar PFS (HR=1.02; 95% CI=0.94-1.11 and 1.01, 95% CI=0.92-1.10, respectively). Elderly pts had a higher rate of grade ≥3 AE’s in the unadjusted & multivariable models (OR=1.25; 95% CI=1.00-1.57 and 1.30; 95%CI=1.03-1.62, respectively). A lower percentage of elderly pts compared to younger completed TRT (47% and 57%, respectively; P<0.0001) & higher percentage stopped due to AE’s (20% and 13%; P<0.0001). Grade ≥ 3 AE’s (occurring at a rate ≥ 2.5%) with a higher rate in the elderly: neutropenia, dyspnea, fatigue, anorexia, vomiting, dehydration, hypoxia, hypotension, & pneumonitis (P<0.05).

	Age ≥ 70yrs	Age < 70 yrs	P-value[a]
Median OS (months)	17.0	20.7	< 0.01
Median PFS (months)	8.7	9.1	0.68
All toxicities grade ≥3	86%	84%	0.04
Hematologic AE’s grade ≥3	65%	61%	0.04
Non-hematologic AE’s ≥3	68%	62%	<0.01
Grade 5 AE’s	9.0%	4.4%	<0.01
TRT related deaths[b]	3.2%	2.0%	0.12

a: Log-rank test for survival times, chi-square test for AE’s, and Fisher’s exact test for deaths. The P-values from these tests are unadjusted. b: Data available on 2,091 patients

Conclusion:
Elderly pts in CCRT trials had worse OS, similar PFS, & a higher rate of severe AE's.

Background:
Nimotuzumab, a humanized IgG~1~ monoclonal anti-EGFR antibody, is approved and widely used in patients (pts) with head and neck cancer or malignant glioma in combination with radiotherapy (RT) in several countries. On in-vitro and in-vivo experiments using NSCLC cell lines, nimotuzumab showed a radio-sensitizing effect.

Methods:
This phase II study evaluated the tolerability and efficacy of nimotuzumab in combination with concurrent CRT in pts with unresectable locally advanced NSCLC. All eligible pts received concurrent thoracic RT (60 Gy, 2 Gy/day, 6 weeks from day 1) and 4 cycles of chemotherapy (cisplatin 80 mg/m[2] on day 1, vinorelbine 20 mg/m[2] on days 1 and 8) once every 4 weeks as scheduled. Nimotuzumab (200 mg) was administrated once a week from cycle 1 to 4. The primary endpoint was tolerability in combination with concurrent CRT, which was measured by the percentage of pts who completed 60 Gy of RT within 8 weeks, completed 2 cycles of chemotherapy and received more than 75% of nimotuzumab.

Results:
Of 40 pts enrolled between June 2009 and May 2010, 39 eligible pts received the study treatment. The pts characteristics were as follows: 62 years (median); male/female, 34/5; stage IIIA/B, 21/18; PS0/1, 25/14. Thirty-four pts met the criteria for treatment tolerability, and 38 pts completed 60 Gy of RT within 8 weeks. Infusion reaction, >grade 3 skin rash, >grade 3 radiation pneumonitis, or >grade 4 nonhematological toxicity were not observed. The 3-year and 5-year overall survival rates for the 39 pts were 66.4% and 58.4%, respectively. The median PFS was 16.9 months, and the 5-year PFS rate for pts with squamous cell carcinoma (Sq; n = 16) was 50%, while that for pts with non-squamous cell carcinoma (non-Sq; n = 23) was 13.7%. In terms of the first relapse site, in-field relapse rates were low for both Sq (4/16; 25%) and non-Sq (4/23; 17%). However, the distant relapse rate was significantly higher for non-Sq (15/23; 65%) than that for Sq (4/16; 25%). Cytologic or histologic specimens were examined for the expression of EGFR protein/mutations using the EGFR IHC/FISH methods in 20 pts. EGFR 2+/3+ expression was shown more frequently in sq (8/10) than non-sq (4/10). EGFR mutation was observed in only 2 pts with non-sq.

Conclusion:
Addition of nimotuzumab to the concurrent CRT in this setting was well tolerated with clinical benefit to the patients. The low in field relapse rates may be attributed to the radio-sensitizing effect of nimotuzumab.

Abstract not provided

Background:
Immunotherapy based on PD-1/PD-L1 immune checkpoint inhibitors has emerged as a powerful tool for the treatment of lung cancer. To further enhance the antitumor efficacy of individual treatments, numerous ongoing studies are trying to identify synergistic combinations that simultaneously block more than one immunomodulatory pathway. C5aR1 is a G protein-coupled receptor activated by C5a, an anaphylatoxin released during the activation of the complement system, a major component of innate immunity. We have previously shown in a murine model of lung cancer that pharmacological blockade of C5aR1 reduces cancer progression by reversing the immunosuppressive microenvironment. Thus, we hypothesized that a combined inhibition of C5aR1 and PD-1 may have a synergistic effect in the treatment of lung cancer.

Methods:
We characterized the immunosuppressive activity of C5aR1 and evaluated the therapeutic efficacy of the dual administration of PD-1 and C5a/C5aR1 antagonists in syngeneic non-small cell lung cancer mouse models. The RMP1-14 monoclonal antibody was used to block PD-1, and a PEG-modified L-aptamer, which binds to complement C5 and C5a, was used to inhibit the C5a/C5aR1 interaction.

Results:
Kras[G12D/+] mice deficient for C5aR (Kras[G12D/+];C5aR1[Δ/Δ]) had a lower lung tumor burden and survived longer than Kras[G12D/+];C5aR1[wt/wt] littermates. Interestingly, Kras[G12D/+];C5aR1[Δ/Δ] mice showed a significant reduction of myeloid-derived suppressor cells (MDSCs), a subpopulation of immune cells that profoundly influences the effectiveness of cancer immunotherapies. We therefore evaluated whether C5a/C5aR blockade may enhance the efficacy of anti-PD-1 therapy by reversing the immunosuppressive microenvironment. In the Kras/Tp53 mutant 393P syngeneic lung cancer model, the combination of C5a and PD-1 blockade dramatically reduced in vivo tumor growth, as compared to the effect of each treatment alone. Similarly, this combination showed a remarkable synergistic antitumor effect in Lewis lung carcinoma (3LL)-bearing mice. Survival analysis confirmed the benefit of the combined treatment. Finally, the therapeutic combination significantly diminished the in vivo metastatic capacity of the highly aggressive Lacun3 lung cancer cell line in syngeneic BALB/c mice, as compared to the effect of anti-PD-1 or anti-C5a drugs as monotherapy.

Conclusion:
Our study supports the notion that the efficacy of anti-PD-1 therapy is limited by the immunosuppressive tumor microenvironment. In this context, C5a/C5aR1 blockade concomitant to anti-PD1 therapy obliterates the resistance mechanisms mediated by MDSCs, improving antitumor immune responses. These findings provide a framework for the clinical evaluation of this therapeutic strategy.

Background:
Platinum doublet chemotherapy ± bevacizumab is standard first-line therapy for patients with advanced non–small cell lung cancer (NSCLC) without genetic aberrations. Single-agent pembrolizumab exhibits robust antitumor activity in PD-L1–positive advanced NSCLC. Cohort G of the multicenter, open-label, phase 1/2 multicohort KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated the efficacy and safety of pembrolizumab + carboplatin and pemetrexed compared with carboplatin and pemetrexed in patients with treatment-naive advanced nonsquamous NSCLC with any PD-L1 expression.

Methods:
Cohort G enrollment criteria included patients with stage IIIB/IV nonsquamous NSCLC, no activating EGFR mutation or ALK translocation, no prior systemic therapy, measurable disease, ECOG performance status 0-1, and adequate tumor sample for assessment of PD-L1 status, regardless of PD-L1 expression. Patients were randomized 1:1 to 4 cycles of pembrolizumab 200 mg Q3W + carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W or carboplatin AUC 5 (5 mg/mL/min) + pemetrexed 500 mg/m[2] Q3W alone, followed by maintenance pemetrexed ± pembrolizumab. Pembrolizumab was given for ≤35 cycles. Randomization was stratified by PD-L1 expression (positive [tumor proportion score, or TPS, ≥1%] vs negative [TPS <1%]). Crossover to pembrolizumab monotherapy was allowed for eligible patients who experienced disease progression (RECIST v1.1) on chemotherapy. Response was assessed by central imaging vendor review every 6 weeks for first 18 weeks, every 9 weeks through year 1, and every 12 weeks in year 2. The primary end point was objective response rate (ORR); secondary end points included progression-free survival (PFS), duration of response, and overall survival (OS). Comparison between arms was assessed using the stratified Miettinen and Nurminen method (ORR) and stratified log-rank test (PFS, OS).

Results:
As of January 2016, 123 patients (60 in the pembrolizumab + chemotherapy arm, 63 in the chemotherapy arm) had been enrolled in cohort G. Data on ORR, duration of response, safety, and preliminary PFS and OS results will be available by August 2016.

Conclusion:
The conclusion will be updated at the late-breaking submission stage.

Background:
Immune checkpoint inhibitors are now established therapies in many advanced cancers. Preliminary studies suggest combining immune checkpoint inhibitors with platinum-based chemotherapy may enhance anti-tumour activity. The primary objective of this multi-centre study was to evaluate the safety and tolerability of durvalumab (Du), a PD-L1 inhibitor, ± tremelimumab (Tr), a CTLA-4 inhibitor, in combination with one of four standard platinum-doublet regimens (pemetrexed (pem), gemcitabine, etoposide (each with cisplatin) or nab-paclitaxel (with carboplatin)), in order to establish a recommended phase II dose (R2PD) for each combination. This abstract focuses on the pem / cisplatin cohort in non-squamous non-small cell lung cancer (NSCLC).

Methods:
Patients (pts) with advanced NSCLC (no prior treatment for advanced disease) who were eligible for treatment with cisplatin and pemetrexed were enrolled into one of four dose levels, regardless of tumour PD-L1 status. Concurrent with chemotherapy, dose level (DL) 0 added Du 15 mg/kg IV q3wks; DL1 added Du 15mg/kg q3wk + Tr 1mg/kg x1 dose; DL2a added Du 15mg/kg q3wk + Tr 1 mg/kg q6wk x multiple doses; DL2b added Du 15mg/kg q3wk + Tr 3 mg/kg q6wk (1 dose with cycle 1 and 2 doses with maintenance pem). Pemetrexed and Du maintenance continued after completion of 4-6 cycles of pemetrexed and cisplatin.

Results:
Twenty-four pts (median age=61 (range 37-78); 50% female, 95% ECOG PS≤1, were enrolled (5 pts to each of DL 0 and 1 and 7 pts each to DL2a and 2b). Thus far 121 cycles have been administered. The majority of drug-related adverse events (AEs) were ≤ grade 2. Most AEs were related to chemotherapy; other AEs were chemotherapy or immune-related (renal, hepatic, skin and pulmonary toxicity). AEs that were considered related to Du or Tr were mainly ≤ grade 2, the most common of which were fatigue (46%), nausea/vomiting (25%), anorexia (21%) and diarrhea (13%). Two pts (DL2a) had serious related AEs (febrile neutropenia related to chemotherapy and lung infection/pneumonitis related to both chemotherapy and Du + T (considered a DLT)). Seventeen of the 24 patients are currently evaluable for response. The provisional objective response rate is 52.9% (95% CI: 28 -77%).

Conclusion:
In this PD-1 unselected patient population, Du 15mg/kg q3w and Tr 1mg/kg (multiple doses q6w) or 3mg/kg (3 doses q6w) can be safely combined with full doses of platinum-doublet chemotherapy. Additional studies with this combination are being planned.

Abstract not provided

Background:
Patients with SCLC and disease progression during/after first-line platinum-based chemotherapy have poor prognoses and limited treatment options. Nivolumab alone and in combination with ipilimumab has shown survival benefit and durable responses in multiple tumor types. Here we present updated results for the SCLC cohort of the phase 1/2 CheckMate 032 trial (NCT01928394), which was designed to evaluate nivolumab or nivolumab/ipilimumab in advanced solid tumors.

Methods:
Patients with advanced SCLC that progressed following ≥1 platinum-based chemotherapy regimens were assigned to receive nivolumab monotherapy (nivolumab-3 Q2W) or nivolumab/ipilimumab combination therapy (nivolumab-1/ipilimumab-3 or nivolumab-3/ipilimumab-1 Q3W for 4 cycles, then nivolumab-3 Q2W). Patients were eligible regardless of platinum sensitivity or tumor programmed death ligand 1 (PD-L1) expression. The primary endpoint was ORR. Additional endpoints were duration of response (DOR), OS, PFS, safety, and correlation of tumor PD-L1 expression with activity.

Results:
214 patients have been enrolled to date (nivolumab-3, n=98; nivolumab-1/ipilimumab-3, n=61; nivolumab-3/ipilimumab-1, n=55), including 96 and 118 patients treated with 1 or ≥2 prior regimens, respectively. Efficacy and safety data are shown (table). In the nivolumab-1/ipilimumab-3 cohort, ORR was 23% and 1-year OS was 43%. The proportion of patients with PD-L1–expressing tumors was substantially lower in previously treated SCLC in this study than that previously observed with pretreated NSCLC (16% vs 53%–54% with ≥1% PD-L1 expression). In SCLC, responses were observed regardless of PD-L1 expression. ORR and median OS were similar in patients treated with 1 or ≥2 prior regimens. Rate of discontinuation due to treatment-related AEs ranged from 5% to 11%; there were 3 treatment-related deaths. Figure 1



Conclusion:
Durable objective responses were observed with nivolumab and nivolumab/ipilimumab in patients with previously treated SCLC, and safety profiles were consistent with other tumor types. Updated efficacy (including 2-year OS and DOR), safety, and additional subgroup analyses will be presented from the August 2016 DBL.

Background:
Viagenpumatucel-L (HS-110) is an allogeneic whole-cell vaccine, selected for high expression of adenocarcinoma tumor antigens, transfected to secrete gp96-Ig. Prior studies with HS-110 (and related gp96-Ig vaccines) have shown a correlation between increases in CD8+ tumor infiltrating lymphocytes (TIL) and tumor response. The DURGA trial was designed evaluate the combination of HS-110 and nivolumab, in an attempt to increase tumor inflammation and improve the response rates observed with nivolumab alone. Clinical Trial identifier: NCT02439450

Methods:
Patients with advanced lung adenocarcinoma who received at least one prior line of therapy were assigned to two cohorts based on baseline levels of TIL in patient biopsies: low TIL (≤10% CD8+ T cells) or high TIL (>10% CD8+ T cells). All patients received standard of care nivolumab 3 mg/kg every 2 weeks and weekly HS-110 for 18 weeks until intolerable adverse events, disease progression, or death. Each 9-patient Phase 1b cohort could be expanded to 30 patients in Phase 2 based on exhibited efficacy. The primary endpoint was safety and tolerability. Biopsies at baseline and Week 10 were used to track changes in TIL and PD-L1 staining. Peripheral blood mononuclear cells (PBMC) were evaluated by flow cytometry for detection of circulating leukocyte subsets. ELISPOT was used to track antigen-specific immune response.

Results:
HS-110 vaccine and nivolumab combination was well tolerated with a safety profile consistent with single-agent nivolumab. Among the 8 initial patients, only 4 had optimal biopsies which showed 2 patients with high and 2 with low TILs. PD-L1 was >1% in 3 patients. IFNγ ELISPOT assay defined 4 patients as immune responders (doubling of IFNγ-secreting cells after re-stimulation with total vaccine antigen and individual cancer antigens, IR) and 4 patients as non-immune responders (NIR). The overall response rate (ORR) was 50% in the IR patients and 0% in the NIR patients. At the time of the data cutoff, 6 patients remain alive, including the 4 IR patients, with ongoing responses for 150 to 326 days. Patients with objective response also exhibited injection site reactions and maculopapular rash consistent with HS-110 mechanism of action, decreased Myeloid Derived Suppressor Cells (MDSC) in the blood, and increased markers of activated CD8+ T cell subsets by flow cytometry (CD8+CTLA-4+, CD8+Tim3+). Although the pathology specimens were sub-optimal in the two responding patients, the limited tissue available showed lower baseline TILs in both patients.

Conclusion:
Allogeneic gp96-based vaccination may have synergistic activity in combination with immune checkpoint inhibitors.

Background:
Intratumoral (IT) infiltration by activated immune effector cells is associated with a significantly better prognosis, however, tumor-associated immune suppression commonly occurs in non-small cell lung cancer (NSCLC). CD8[+ ]T cell or dendritic cell (DC) infiltration is an independent favorable prognostic indicator. CCL21 is a lymphoid chemokine that chemoattracts both lymphocytes and DC. Our aim was to investigate anti-tumor specific systemic immune responses and tumor-infiltrating CD8[+] T cells (CD8[+] TIL) in NSCLC patients in response to in situ vaccination via IT administration of autologous DC transduced with a replication-deficient adenoviral (Ad) vector expressing the secondary lymphoid chemokine (SLC/CCL21) gene. Here, we conducted a phase I trial and evaluated safety and immune responses following in situ vaccination.

Methods:
Sixteen stage IIIB/IV NSCLC subjects received two vaccinations (1 x 10[6], 5 x 10[6], 1 x 10[7], or 3 x 10[7] dendritic cells/injection) by CT- or bronchoscopic-guided IT injection (days 0 and 7). Immune responses were assessed by tumor antigen-specific peripheral blood lymphocyte induction of IFN-γ in ELISPOT assays. Tumor biopsies were evaluated for CD8[+ ]T cells by immunohistochemistry (IHC).

Results:
Twenty-five percent (4/16) of patients had stable disease at day 56 follow-up by RECIST criteria. Median survival was 3.9 months. Four possible vaccine-related grade 1 adverse events (AE) occurred in 3 patients with no clear association to dose or schedule; the AE included flu-like symptoms, blood-tinged sputum after each injection, nausea, and fatigue. ELISPOT assays revealed 38% (6/16) of patients had systemic responses against tumor associated antigens (TAA). Tumor CD8[+] T cell infiltration was induced in 54% of subjects (7/13; 3.4 fold average increase in the number of CD8[+ ]T cells per mm[2]). Patients with increased intratumoral CD8[+ ]T cells following vaccination showed significantly increased PD-L1 mRNA expression (p=0.02).

Conclusion:
Intratumoral vaccination with Ad-CCL21-DC was well-tolerated and resulted in 1) induction of systemic tumor antigen-specific immune responses and 2) enhanced tumor CD8[+ ]T cell infiltration. DC-CCL21 in situ vaccination may be a promising approach to induce tumor CD8[+ ]T cell infiltration in combination with checkpoint inhibitor therapy.

Abstract not provided

Background:
The c-Met receptor is overexpressed in ~50% of patients with NSCLC. ABBV-399 is a first-in-class ADC composed of ABT-700, an anti–c-Met antibody, conjugated to monomethyl auristatin E (a microtubule inhibitor). Preclinical data support ABBV-399 as a unique strategy to deliver a potent cytotoxin directly to c-Met+ tumor cells.

Methods:
In a 3+3 dose-escalation design, ABBV-399 was administered at doses ranging from 0.15 to 3.3 mg/kg once every 21 days to patients with advanced metastatic solid tumors (NCT02099058). ABBV-399 was then studied in a dose-expansion cohort in 16 patients with advanced c-Met+ (immunohistochemistry [IHC] H-score ≥150) NSCLC that had progressed on ≥2 prior lines of therapy. ABBV-399 was also studied in combination with erlotinib in 10 patients with NSCLC, 8 of whom were c-Met+. Overexpression of c-Met was assessed by an IHC assay utilizing the SP44 antibody (Ventana; Tucson, AZ, USA).

Results:
As of June 27, 2016, 48 patients with solid tumors received ≥1 dose of ABBV-399. The dose-limiting toxicity (DLT) for ABBV-399 was febrile neutropenia, which occurred in 2 patients (1 each at 3 and 3.3 mg/kg). There were no treatment-related deaths. Monotherapy treatment-related adverse events (AEs) occurring in ≥10% of patients (including all dose levels and all grades) were fatigue (25.0%), nausea (22.9%), neuropathy (14.6%), decreased appetite (12.5%), vomiting (12.5%), and hypoalbuminemia (10.4%). Based primarily on safety and tolerability, a 2.7-mg/kg dose was chosen for dose expansion in patients with c-Met+ advanced NSCLC. Three of 16 (19%) ABBV-399–treated c-Met+ NSCLC patients had a confirmed partial response (PR) with duration of response (DOR) 3+, 3, and 4.5 months. At week 12, 6 of 16 patients treated (37.5%) had disease control. Ten patients received ABBV-399 in combination with erlotinib. No DLTs were observed and AEs related to ABBV-399 occurring in ≥2 patients were acneiform rash (40.0%), fatigue (30.0%), and dry skin (20.0%). Three of 8 (37.5%) evaluable ABBV-399 + erlotinib-treated c-Met+ patients had a confirmed PR with DOR 2+, 4+, and 5+ months. Two of the 3 patients with PR had EGFR-mutated tumor, and previous TKI- and platinum-based chemotherapy had failed.

Conclusion:
ABBV-399 is well tolerated at a dose of 2.7 mg/kg every 21 days and has demonstrated antitumor activity in patients with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Updated data of antitumor activity and safety of ABBV-399 as monotherapy and in combination with erlotinib in c-Met+ NSCLC patients will be presented.

Background:
The sodium-phosphate transporter NaPi2b is expressed at high levels in a majority of non-squamous non-small cell lung cancers (NSCLC), suggesting it may be an attractive therapeutic target for antibody-drug conjugate (ADC) development in this disease. However, NaPi2b is also expressed at high levels in type II alveolar cells, raising the potential for normal tissue toxicity with this approach. XMT-1536 is an ADC comprised of a humanized antibody against NaPi2b and approximately 15 auristatin-derived payload molecules per antibody conjugated via a multivalent hydrophilic polymer (Fleximer). The auristatin payload is enzymatically cleaved upon ADC trafficking to the endosome/lysosome compartment, releasing a cytotoxic auristatin-derivative that is capable of bystander effect killing.

Methods:
The anti-tumor activity of XMT-1536 was evaluated in seven patient-derived xenograft models of NSCLC adenocarcinoma, chosen for high NaPi2b-expression and representing a spectrum of oncogenic driver mutations prevalent in NSCLC adenocarcinoma (including tumors without oncogenic drivers). The standard dose of XMT-1536 used across models was 3 mg/kg administered intravenously once weekly for 3 weeks (last dose on Day 14). Experiments ran until tumor growth past a pre-specified endpoint or Day 60. XMT-1536 was also evaluated for tolerability in a cynomolgus monkey study.

Results:
At the 3 mg/kg dose, XMT-1536 was active in 6/7 models: complete tumor regression in 3 models, partial tumor regression in 1 model, and significant tumor growth inhibition in 2 models. In 3 of the 4 models where XMT-1536 induced tumor regression, regressions were durable, with a majority of the animals maintaining partial or complete regression at Day 60. The antibody component of XMT-1536 is cross-reactive with cynomolgus NaPi2b with similar affinity as human NaPi2b. XMT-1536 was well tolerated up to 5 mg/kg (4294 mg/m[2] auristatin payload equivalents), the highest dose tested. There was no body weight loss, no clinical observations attributable to XMT-1536, and no evidence of neutropenia. On pathology, there was minimal mixed inflammatory cell infiltrate in the lung in 1 high dose animal at each necropsy time point, but no evidence of significant lung toxicity. Exposure to XMT-1536 indicated good conjugate stability, low exposure to free drug payload in plasma (<1 ng/mL), and supported the 3 mg/kg dose level in mouse studies as a potentially clinically-relevant dose.

Conclusion:
These results indicate XMT-1536 can achieve durable tumor regressions in murine patient-derived NSCLC adenocarcinoma models at doses associated with good tolerability in cynomolgus monkey, and support evaluation of XMT-1536 in patients with NSCLC.

Background:
Trials of anti-EGFR necitumumab and anti-PD1 pembrolizumab demonstrate the anti-tumor activity of each agent in NSCLC.

Methods:
Single-arm, multicenter Phase 1b study to investigate effectiveness and safety of necitumumab combined with pembrolizumab in patients with Stage IV NSCLC (NCT02451930). In Part A, escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W. In the absence of dose limiting toxicity, Part B (expansion cohort) was planned with necitumumab 800 mg in 27 squamous and 27 nonsquamous NSCLC patients. Major eligibility criteria included: progression after ≥1 platinum-based chemotherapy, and ECOG PS 0-1. Study objectives were to evaluate tolerability and ORR by RECIST 1.1. PD-L1 status was centrally assessed using PD-L1 IHC 22C3 pharmDx assay (considered negative, weak positive, strong positive if <1%, 1-49%, ≥50% of tumor cells were stained, respectively).

Results:
The interim analysis population includes 34 nonsquamous patients (median age 61 years, 68% men, 21% never smokers, PD-L1 status: negative, 50% [17/34]; positive weak/strong, 15% [5/34]/15% [5/34]; unknown 21% [7/34[BJ1] ]). Median follow-up was 6.0 months. Ten patients (29.4%) had PR (confirmed and unconfirmed) (PRs by PD-L1 status: negative, 18% [3/17]; positive weak/strong, 60% [3/5]/40% [2/5]; unknown status, 2 patients). DCR was 67.6%. PFS rate at 6 months was 55.1% (95% CI, 36.2-70.6); median PFS was 6.9 months (95% CI, 2.7-NR). Most common Grade ≥3 AEs were skin rash (9%), hypomagnesemia (9%), VTE (9%) and increased lipase (9%); 1 patient died due to an AE (respiratory tract infection). Five patients (14.7%) discontinued therapy because of an AE. Figure 1



Conclusion:
Safety profile corresponds to individual profiles for both drugs, with no additive toxicities. These preliminary data suggest activity of this combination in a pretreated nonsquamous NSCLC population, irrespective of PD-L1 status.

Abstract not provided

Background:
Immune checkpoint inhibitors (ICPIs) nivolumab and pembrolizumab have been FDA-approved in non-small cell LC (NSCLC). Current IHC based diagnostics are challenged by assay and slide scoring issues and modest predictive value, and more robust and comprehensive biomarkers of ICPI efficacy are needed. A discovery set of 64 NSCLCs treated with ICPIs suggested that high TMB (≥15 mutations/Mb) significantly correlated with longer time on drug (Spigel et al., ASCO 2016, Abstract:9017).

Methods:
Comprehensive genomic profiling (CGP) was performed during the course of clinical care. TMB was assessed as the number of somatic, coding, base substitution and indels per Mb of genome. Microsatellite instability-high (MSI-H) or stable (MSS) status was determined using a proprietary algorithm.

Results:
15,529 LCs: 66% adenocarcinoma, 1% sarcomatoid, 14% NSCLC NOS, 11% squamous, 5% small cell, and 2% large cell were assessed. TMB was similar across all lung histologies (median: 6.3, 8.1, 9.0, 9.9, 9.9, and 10.8); the median was 7.6 for all LC cases (TMB ≥15 in 24% of cases), compared to 4.5 for 80,000+ samples of diverse tumor types in the database. Of LCs assessed 0.3% were MSI-H, of which 30/31 were TMB-high; however, 24% of MSS-stable cases were also TMB-high. PD-L1 amplification and DNA repair pathway mutation (MLH1, MSH2, POLE) were found in 1.0% and 1.1% of LC cases analyzed, respectively. Tumors harboring known drivers (ALK, ROS1, EGFR, BRAF V600E, MET splice) had low TMB (median: 2.5, 3.6, 3.8, 3.8, 4.5), whereas tumors with KRAS mutation, non-V600E BRAF mutation, PD-L1 amplification, or DNA repair alterations were more likely to be TMB-high (median: 9.0, 10.8, 14.4, 21.6).

Conclusion:
High TMB may be a predictive biomarker of response to ICPIs. Several factors including lack of a known driver, MSI-H status, PD-L1 amplification, and DNA repair mutation correlated with high TMB (P<0.0001 for all cases). However, 95% of TMB-high cases assessed were MSS and lacked both PD-L1 amplification and DNA repair mutation, and thus would likely not be selected for immunotherapy by assessment of individual genomic alterations or MSI status alone. A validation cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapies including analysis of clinical outcome, TMB, genomic profile, and available clinicopathologic characteristics will be presented. CGP of LC to simultaneously determine TMB, MSI status, PD-L1 amplification, and the presence of driver alterations may provide clinically useful predictors of response to ICPI and other targeted therapies using a single platform, but prospective clinical trials are needed to confirm these observations.

Background:
Currently the immune system is considered an important target of study within the therapeutic alternatives for many tumors that have developed resistance in lung cancer. Many molecules called checkpoints regulate antitumor immunity as PD-L1 it is expressed in tumour cells and is a biomarker for anti PD-L1/PD-1 therapy. PD-1 / PD-L1 is expressed on exhausted activated T cells. This signaling pathway is involved in tumor evasion of the immune system. It has recently been demonstrated that the blockade of PD-1 or its ligand PD-L1 and PD-L2, restore the antitumor immune response leading to a durable tumor regression. However, the expression of PD-1/PD-L1 in T cells from peripheral blood of patients with non-small cell lung cancer has not been widely studied.

Methods:
We investigated the expression of PD-1 and its ligands PD-L1 and PD-L2 on peripheral blood T cells subpopulations (CD3+ CD4+ / CD8+) of patients with non-small cell lung cancer. We included 50 NSCLC patients (stage IIIB and IV) naive to treatment and 10 healthy subjects. Immunophenotyping was performed using multiparametric flow cytometry. Analyzing its prognostic significance regarding outcome analysis as well as its potential biomarker.

Results:
Our results showed that the percentage of PD-1, PD-L1 and PD-L2 expression in peripheral blood cells in NSCLC patients was lower compared to healthy subjects [P<0.005] and the Mean Fluorescence Intensity (MFI) was higher in patients compared to the control group [P<0.001]; The expression of PD-1 in T-helper or CD4+ of NSCLC patients was significantly higher than in cells from control subjects [P<0.001]. Similarly, the expression of PD-1 in T cytotoxic cells or CD8+ patients was significantly higher than in controls [P<0.001]. In the clinical analysis, we found that a higher percentage of PD-1+ CD3+ cells was statistically associated with tobacco exposure [P=0.0160], and de MFI was associated with the non-adenocarcinoma histology [P=0.0001] additionally, the presence of 3 or more metastases was associated to a higher MFI of PD-1 on CD3+ CD8+ [P=0.0490]. In the overall survival (OS) analysis the percentage of CD3+/CD4+/PD-1+ ≤20.91 was associated with a higher median OS [P= 0.045].

Conclusion:
Several studies demonstrate the importance of infiltrating PD-1+ T cells within tumors; however these results showed that the PD-1/PD-L1/PDL-2 expression in peripheral blood cells could be used also as a potential biomarkers in NSCLC patients.

Background:
EGFR mutations define a distinct subset of NSCLC characterized by clinical benefit from tyrosine kinase inhibitors. The impact of genomic alterations that coexist with EGFR mutations is not fully understood. In addition, the responsiveness of EGFR mutant NSCLC to immune checkpoint blockade is not well defined.

Methods:
We queried our prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI Database to identify EGFR mutant NSCLC patients. We analyzed the genomic landscape of these tumors derived from next generation sequencing, performed as part of routine clinical care, to comprehensively describe the concurrent genomic aberrations in EGFR mutant NSCLC and their impact on clinical outcomes. We used log rank and Fisher’s exact tests to identify associations between co-concurrent mutations and clinical outcomes.

Results:
1958 non-squamous NSCLC patients were identified in the GEMINI database. The frequency of EGFR mutations was 14.1% (n=276). Among EGFR mutant patients, 188 underwent targeted next generation sequencing of a minimum of 46 cancer related genes. The majority of EGFR mutant patients (77.6%, n=146) had at least one coexisting mutation. The most frequent co-mutations identified were TP53 (47%, n=88), CTNNB1 (7.5%, n= 14) and PIK3CA (6.5%, n=12). ALK and ROS1 translocations were found to coexist with EGFR mutations in one patient each. Of patients treated with a first or second generation TKI, concurrent TP53 mutations were associated with a shorter progression free survival (HR= 1.81, P= 0.039). Eight patients with EGFR/CTNNB1 co-mutations developed acquired TKI resistance with T790M secondary mutation being the resistance mechanism in six (75%) of them suggesting that coexisting mutation can dictate emerging resistance mechanisms. Twenty patients were treated with anti PD1/PD-L1 agents (nivolumab n= 18, pembrolizumab n=2). Only two (10%) patients achieved confirmed radiological response, one lasting for 6 months and the second ongoing at 6 months. Both patients were never smokers, one with EGFR exon 20 insertion and no concurrent mutations, and the other with EGFR exon 19 deletion and TP53 mutation. Sixteen patients developed confirmed progressive disease. Finally, one patient with 17 pack-year smoking history, EGFR G719/S768I double mutation and concurrent PIK3CA mutation achieved stable disease lasting for four months. The median progression free survival for the cohort treated with immunotherapy was 2 months (range: 1-not reached).

Conclusion:
Concurrent genomic aberrations may predict response duration to TKIs and may be associated with particular emerging resistance mechanisms to TKIs in EGFR mutant NSCLC. Immunotherapy results in durable clinical benefit in a subset of EGFR mutant NSCLC patients.

Abstract not provided

Background:
The KEYNOTE-010 (KN010) clinical trial, a multi-center, worldwide, randomized Phase II/III trial of pembrolizumab 2m/kg every 3 weeks and docetaxel 75mg/m2 every 3 weeks in patients with previously treated advanced NSCLC with PD-L1 positive tumors showed a significant overall survival (OS) advantage for patients receiving pembrolizumab. We examined the improvement in prognoses for patients who elect to learn their PD-L1 biomarker results using extrapolative survival modeling.

Methods:
Partitioned survival models to project long-term outcomes were developed using data from patients enrolled in KN010, with treated patients in the pembrolizumab 2m/kg and docetaxel 75mg/m2 arms included in these analyses. As OS for docetaxel patients is not dependent on PD-L1 status, KN010 results were assumed to represent docetaxel efficacy in all patients irrespective of PD-L1 status.The model projected expected lifetime using Kaplan Meier estimates of PFS and OS from the trial with extrapolation based on parametric functions and long term registry data.

Results:
Results directly from KN010 showed for patients with TPS≥50%, median survival to be 8.2 months (6.4, 10.7) and 14.9 months (10.4, NA) for docetaxel and pembrolizumab, respectively (HR= 0.54 (0.38, 0.77)). Model-based projections show that should all patients be treated with docetaxel, expected mean lifetime is 1.0 years. For patients receiving a PD-L1 biomarker test per KN010 28.49% will be identified as PD-L1 strong positive (TPS≥50%). PD-L1 (TPS ≥50%) predicts a life expectancy with biomarker directed pembrolizumab of 2.25 years on average.

Conclusion:
Use of PD-L1 biomarker identification can significantly improve OS prognoses for patients considering pembrolizumab and docetaxel with advanced NSCLC based on both clinical trial results and model-based projections from KN010.

Background:
Nivolumab is the first checkpoint inhibitor approved for the treatment of Sq-NSCLC to show a survival benefit vs the standard of care docetaxel in the randomised, phase III, CheckMate 017 study. In the nivolumab development program, a greater clinical benefit was shown in current and former smokers than in never smokers. Nevertheless, no data are available in this respect from a real world setting. For this reason, we decided to use the data collected in the EAP in order to assess the effectiveness and tolerability of nivolumab treatment in the never smoker patient population.

Methods:
Nivolumab was provided upon physician request for patients aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events using Common Terminology Criteria for Adverse Events.

Results:
Of 372 patients with Sq-NSCLC participating in the EAP in Italy, 38 (10.2%) were never smokers, a proportion very similar to the one observed in Checkmate 017 (10%). With a median number of doses of 8 (range, 1–22) and a median follow-up of 5.6 months, the disease control rate in this group was 50%, including 9 patients with a partial response and 10 with stable disease. Eight patients were treated beyond RECIST-defined progression, with 4 of them achieving disease control. As of April 2016, median progression-free survival and overall survival were 3.5 months and not reached, respectively. 17 patients (44.7%) discontinued treatment for any reason except toxicity and 5 (13.1%) discontinued due to AE.

Conclusion:
These preliminary results, although obtained from a small sample size, suggest that nivolumab is effective and well tolerated in a never smoker group of patients with advanced Sq-NCLCS in the real life and warrant further investigation in this area.

Background:
Randomized phase III trials have shown that the PD-1 blocking monoclonal antibody Nivolumab is effective in advanced NSCLC. Nivolumab is registered by the FDA and EMA for treatment of NSCLC. However, approval in The Netherlands was put on hold because of Nivolumab's high price per quality adjusted life year (QALY). From August 2015, Nivolumab was provided through a compassionate use program. Here we present our experience in treating NSCLC patients with Nivolumab in real life.

Methods:
Efficacy and safety of Nivolumab was assessed in patients with advanced NSCLC, previously treated with at least one line of platinum-based chemotherapy and an ECOG-PS of ≤2. Nivolumab was administered 2-weekly at a dose of 3 mg/kg intravenously. Response evaluation took place according to RECIST 1.1 at 12 and 24 weeks after start of treatment.

Results:
In the 10-month period in a single center 189 patients started treatment with Nivolumab, with a mean follow up time of 106 days after start of treatment. Mean age was 62 years (range 29–83), 57% male, 18,5% never smoked, 68% had adenocarcinoma, 20% had squamous histology and 12% were other, mixed or unspecified types. Figure 1 Twenty-four percent of patients experience immunotherapy related toxicity, most toxicities were short-term or easily manageable. No grade 5 toxicities, one grade 4 hepatitis and one grade 3 hypophysitis were observed. Hypothyroidism was most frequently observed (gr.1-2; 9,5%), followed by skin-reactions (gr.1-3; 3,8%) and colitis (gr.1-2; 3,2%). Other immune related toxicities were hepatitis (gr.1-4; 2,5%), infusion reactions (gr.1; 2,5%), pneumonitis (gr.2; 1,9%), hyperthyroidism (gr.1; 1,3%), arthritis (gr.2; 0,6%), hypophysitis (gr.3; 0,6%) and diabetes mellitus type 1 (gr.3, 0,6%).



Conclusion:
Although follow up is short and response data not yet mature, real-life efficacy and safety data from Nivolumab are comparable to phase III trial data.

Abstract not provided

Background:
Immuno-oncology (IO) therapies offer the possibility of long-term survival to metastatic cancer patients. Prior analyses have shown that lung cancer reduces life expectancy by an average of 11.8 years (Burnet NG, et al. Br J Cancer. 2005;92:241‒245.). We aimed to investigate the impact of IO therapies on life extension of patients with non-small cell lung cancer (NSCLC).

Methods:
We used The Health Economics Medical Innovation Simulation (THEMIS) alongside available clinical trial data to estimate the anticipated increase in NSCLC patient survival post-diagnosis resulting from the introduction of IO therapy. THEMIS is an established microsimulation with a 50-year time horizon that tracks a representative sample of patients aged ≥51 years to project longevity. These outcomes were estimated for metastatic NSCLC patients under a pre-IO scenario and compared to a post-IO scenario where IO is available for either first- or second-line treatment. Patients were classified as either heavy, medium, or light responders, corresponding to reductions in mortality hazards of 96.5%, 64.4%, and 0%, respectively, based on extrapolations of clinical trial results for nivolumab (see table). Health state transitions probabilities and medical expenditures were estimated from nationally representative datasets. Mortality and disease stage were estimated using the Surveillance and Epidemiology End Results (SEER) database.

Results:
In the pre-IO simulation, metastatic NSCLC patients lose 11.3 years of life (comparable with the published 11.8 years). The results from the post-IO scenarios are shown in the table. For comparison, SEER data suggest that survival in metastatic NSCLC patients has only increased by 0.3 years since 1998.

Population	Heavy Responder Prevalence	Medium Responder Prevalence	Heavy Responder Hazard Reduction	Medium Responder Hazard Reduction	Light Responder Hazard Reduction	Additional Life Years
Second-line monotherapy, All patients	20%	30%	96.5%	64.4%	0%	2.1
First-line monotherapy, PD-L1 >1%	30%	40%	96.5%	64.4%	0%	3.25
First-line monotherapy, PD-L1 >50%	50%	40%	96.5%	64.4%	0%	4.72
First-line combination therapy, PD-L1 >1%	60%	30%	96.5%	64.4%	0%	4.22
First-line combination therapy, PD-L1 >50%	100%	0%	96.5%	N/A	N/A	7.06

Conclusion:
Current IO therapies represent a significant step towards extending life expectancy for metastatic NSCLC patients.

Background:
This study aimed to understand the impact on disease management costs beyond drug acquisition costs in the context of an economic evaluation of pembrolizumab compared with docetaxel in patients in patients with previously treated PD-L1 positive (TPS>=50%) advanced NSCLC. The analysis was conducted from a US third-party payer perspective.

Methods:
A partitioned-survival model was developed using data from patients from the KEYNOTE-010 (KN010) clinical trial. The model used KM estimates of PFS and OS from the trial for patients treated with pembrolizumab 2mg/kg and docetaxel 75kg/m[2] with extrapolation based on fitted parametric functions and long-term registry data. Costs of clinical management of advanced NSCLC along with drug acquisition/administration and adverse event management costs were included in the model. The base-case analysis used a time horizon of 20 years. Costs and health outcomes were discounted at a rate of 3% per year.

Results:
Base case results project for PD-L1 positive (TPS>=50%) patients treated with pembrolizumab a mean survival of 2.25 years. For docetaxel, a mean survival time of 1.07 years was estimated. Weekly disease management costs observed in KN010 for the progression-free state were $866 and $1,298 for pembrolizumab and docetaxel, respectively. Weekly disease management costs for the progressive disease state were $1,938 based on a US healthcare claim database. Results projected total disease management costs to be $166K per patient treated with pembrolizumab compared with $93K for docetaxel because of extended progression-free and post-progression survival with pembrolizumab. Nearly half (45%) of total expected cost differences between pembrolizumab and docetaxel are due to the incremental disease management costs. Further analyses that exclude drug treatment costs show that the additional disease management costs associated with extended progression-free and overall survival exceed $50,000 per LY gained ($61,864).

Conclusion:
Pembrolizumab improves outcomes compared to docetaxel in PD-L1 positive (TPS>=50%) pre-treated advanced NSCLC patients in the US. The improved overall survival with pembrolizumab is accompanied by the economic reality of additional non-pembrolizumab costs that represent their own substantial economic burden.

Background:
Delivering high quality cancer care at an affordable cost is one of the main challenges for health care professionals and policy makers, especially in low- and middle-income countries. The objective of our study is to assess the economic impact of nivolumab and pembrolizumab with and without the use of PD-L1 as a biomarker in Brazil.

Methods:
We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and the second-line treatment with NIVO or PEMBRO versus docetaxel. The model used outcomes data from randomized clinical trials and drug acquisition costs were estimated using current prices in Brazil. Thereafter, we used Brazilian epidemiologic data to estimate the economic impact.

Results:
We included three RCTs (two with NIVO and one with PEMBRO). The estimated number of cases eligible for therapy with immune checkpoint inhibitors is 4,733. Treating all patients with NIVOLUMAB would cost US$ 173 million dollars each year, representing an increase of 21% in current Brazilian expenses for cancer drugs acquisition. Treating only patients with PD-L1 > 1% with NIVOLUMAB would cost 93 million dollars every year, leading to an increase of 11.3% in expenses for cancer drugs acquisition. However, with such selection, up to 46% of cases would not be treated and 315 years of life would be lost compared to treating all patients regardless of PD-L1 expression. The cost of each year-of-life saved was improved by PD-L1 selection (from US$ 196,000 to US$ 164,000). Table 1 summarizes our findings for five different scenarios of treatment. The results were similar with NIVOLUMAB and PEMBROLIZUMAB.

SCENARIO	QALY GAIN	ICER (US$)	LIFE-YEARS SAVED	YEARS OF LIFE NOT SAVED	% NOT TREATED	TOTAL COST (US$)	IMPACT ON TOTAL CANCER DRUG EXPENDITURE	COST/LYS (US$)
NIVO ALL COMERS	0.148	129 K	885	0	0%	173 Million	21.1%	196 K
NIVO PD-L1 > 1%	0.201	108 K	570	315	46%	93	11.3%	164 K
PEMBRO PD-L1 > 1%	0.138	137 K	666	NA	34%	100	12.1%	150 K
NIVO ALL SQ/ > 1% NSQ	0.216	99 K	738	147	35%	116	14.0%	157 K
PEMBRO PD-L1 > 50%	0.164	116 K	285	NA	72%	43	5.2%	151 K

Conclusion:
The use of PD-L1 expression as a biomarker for treatment with immune checkpoint inhibitors decreases the overall economic impact and the cost per life-year saved. Further study and societal discussion is needed in order to find the optimal strategy for patient selection.

Abstract not provided

Background:
Rab25, a member of Rab family of small GTPases, is associated with progression of various types of human cancer including lung cancer that is the leading cause of cancer-associated deaths around the globe.

Methods:
Figure 1In this study, we report the gene therapeutic effect of short hairpin Rab25 (shRab25) on 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorgenesis in female A/J mice. Initially, Mice (six-week-old) were injected with single dose of NNK (2 mg/0.1 ml saline/mouse) by intraperitoneal injection to induce the tumor. 8 weeks later, shRab25 was delivered with GPT-SPE (glycerol propoxylate triacrylate (GPT) and spermine) complex into tobacco-induced lung cancer models through a nose-only inhalation system twice a week for 2 month.



Results:
Figure 1Remarkably, aerosol-delivered shRab25 significantly decreased the expression level of Rab25 and other prominent apoptosis related proteins in female A/J mice. The apoptosis in these mice were determined by detecting the expression level of Bcl-2, PCNA, Bax and further confirmed by TUNEL assay.



Conclusion:
Our results strongly confirm the tumorigenic role of Rab25 in tobacco carcinogen induced-lung cancer and hence demonstrate aerosol delivery of shRab25 as a therapeutic target for lung cancer treatment.

Background:
GLORY is a global registry of patients with RET-rearranged non-small cell lung cancer (NSCLC). In order to complement ongoing prospective studies, the registry’s goal is to provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial. We previously reported results from our first interim analysis (Gautschi, ASCO 2016). Following additional accrual into the registry, updated results are presented here, with a focus on an expanded efficacy analysis of various RET inhibitors.

Methods:
A global, multicenter network of thoracic oncologists identified patients with pathologically-confirmed NSCLC harboring a RET rearrangement. Molecular profiling was performed locally via RT-PCR, FISH, or next-generation sequencing. Anonymized data including clinical, pathologic, and molecular features were collected centrally and analyzed by an independent statistician. Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST1.1 (data cutoff date: April 15, 2016). In the subgroup of patients who received RET TKI therapy, the objectives were to determine overall response rate (ORR, primary objective), progression-free survival (PFS), and overall survival (OS).

Results:
165 patients with RET-rearranged NSCLC from 29 centers in Europe, Asia, and the USA were accrued. The median age was 61 years (range 28-89 years). The majority of patients were female (52%), never smokers (63%), with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent metastasic sites were lymph nodes (82%), bone (51%) and lung (32%). KIF5B-RET was the most commonly identified fusion (70%). 53 patients received at least one RET-TKI outside of a clinical protocol, including cabozantinib (21), vandetanib (11), sunitinib (10), sorafenib (2), alectinib (2), lenvatinib (2), nintedanib (2), ponatinib (2) and regorafenib (1). In patients who were evaluable for response (n=50), the ORR was 37% for cabozantinib, 18% for vandetanib, and 22% for sunitinib. Median PFS was 3.6, 2.9, and 2.2 months and median OS was 4.9, 10.2, and 6.8 months for cabozantinib, vandetanib, and sunitinib, respectively. Responses were also observed with nintedanib and lenvatinib. Among patients who received more than one TKI (n=10), 3 partial responses were achieved after prior treatment with a different TKI.

Conclusion:
RET inhibitors are active in individual patients with RET-rearranged NSCLC, however, novel therapeutic approaches are warranted with the hope of improving current clinical outcomes. GLORY remains the largest dataset of patients with RET-rearranged NSCLC, and continues to accrue patients.

Abstract not provided

Background:
EGFR tyrosine kinase (TKI) showed better progression free survival (PFS) in EGFR-mutant non-small cell lung cancer (NSCLC), but the overall survival (OS) benefit were not clear so far. Treatment sequence may contribute to OS, but there are little data so far. We aimed to analyze the impact of treatment sequence of EGFR TKI and chemotherapy on outcomes in EGFR-mutant NSCLC.

Methods:
Among NSCLC patients who had EGFR exon 18–21 mutation test results between 2009 and 2014 at Seoul St. Mary’s Hospital, 114 patients who had recurrent or metastatic disease, EGFR mutation positive excluding T790M mutation, and received both EGFR tyrosine kinase inhibitor (TKI) and chemotherapy as the 1[st] or 2[nd] line of treatment were included. Patients were categorized into two groups according to the treatment sequence: 1[st] line EGFR TKI followed by chemotherapy (group A), 1[st] line chemotherapy followed by EGFR TKI (group B). The median follow-up duration was 64.6 (15.8–202.8) months.

Results:
Among total 114 patients, 69 patients received EGFR TKI first and then chemotherapy (group A), and the remaining 45 patients received vice versa (group B). Group A was younger (P = 0.029) and less frequently received platinum-doublet agents than Group B (P <0.001). Performance status and EGFR mutation status were not different. Overall response or disease control rate were significantly better for EGFR TKI comparing to chemotherapy regardless of treatment sequence. However, PFS on both treatment were longer in group B (P = 0.008), especially for patients with exon 19 deletion (P = 0.002). On multivariate analyses, performance status (P = 0.006 for PFS, P <0.001 for OS) and treatment sequence [hazard ratio (HR) = 0.027, P = 0.027 for PFS; HR = 0.64, P = 0.065 for OS] were related to prognosis.

Conclusion:
For exon 19 deletion subtype of EGFR-mutant NSCLC patients, the sequence of cytotoxic chemotherapy followed by EGFR TKI showed better PFS comparing with the reverse sequence, EGFR TKI followed by cytotoxic chemotherapy . We will present the data from larger cohorts the WCLC meeting.

Background:
AC0010 was designed specifically to inhibit EGFR active mutations and the T790M acquired resistant mutation. The purpose of the study is to determine the safety, antitumor activity and recommended phase II dose of AC0010 in T790M-postitive NSCLC patients after the first generation EGFR TKIs treatment.

Methods:
This is a dose escalation and expansion phase I/II study. Oral AC0010 was administered on a 28-day cycle with the starting dose at 50 mg BID. In any given dose cohort, if 1 out of 3 patients was evaluated as PR at the first cycle, and no DLT determined, up to 20 patients will be enrolled. Plasma samples were collected to evaluate pharmacokinetics of AC0010. T790M in biopsy samples was detected by a central laboratory. NCT02330367.

Results:
As of 10 Jul 2016, 136 patients have been treated across 7 cohorts (50, 100, 150, 200, 250, 300, and 350 mg BID). At the 30 Jun 2016 cutoff, 124 pts were evaluable. MTD has not been reached. The most common adverse events (AE) regardless of study drug relationship were diarrhea (38%), rash (26%) and ALT/AST elevation. Most AEs were grade 1 and 2. The most common Grade 3/4 drug-related AE was diarrhea (2%) rash (2%) and ALT/AST elevation (4%, 2%). All patients with AEs of the grade 3/4 were recovered after either stopped the treatment or reduced the dose. As of the cutoff date, there is no Grade 2,3 hyperglycemia, and grade 3 QTc prolongation. RECIST responses were observed at all dose levels except 50 mg BID. Amongst 124 evaluable patients in all cohorts, ORR (including unconfirmed responses) and disease control rate (DCR) was 44% and 85% respectively. In the dose cohorts between 150 mg BID and 300 mg BID (n=95 pts), the ORR and DCR were 51% and 89%. PK shows rapid absorption with a T~max~ of 2-4h and a median T1/2 of 8 h. At 300 mg BID, total 32 patients were treated and ORR and DCR are 53% and 90% respectively. Based on the efficacy, safety and PK results, the 300 mg BID was selected as RP2D. The phase II, AEGIS-1 study has started.The Phase II result will be presented.

Conclusion:
AC0010 shows a safe profile and antitumor activity against T790M mt NSCLC. Phase II, AEGIS-1 study is ongoing to evaluate therapeutic outcomes as a second line treatment for T790M positive NSCLC patients. Clinical trial information: NCT02330367

Background:
Approximately 10% of EGFR mutant NSCLCs have an in-frame insertion in exon 20 of EGFR resulting in innate resistance to 1[st] generation TKIs. The reported response rate of patients with EGFR exon 20 insertions to gefitinib and erlotinib is 5% with a median progression free survival of 1.5 months. It has been shown that exon 20 insertions stabilize the active conformation of EGFR and increase affinity to ATP over TKIs. We hypothesize that exon 20 insertions induce conformational changes to the drug binding pocket resulting in EGFR TKI resistance which can be overcome by covalently binding TKIs.

Methods:
Ba/F3 cells expressing 7 different clinically observed EGFR exon 20 insertion mutations spanning the helix (residues 763-766) and loop (residues 767-773) regions were generated and screened against 1[st], 2[nd], and 3[rd] generation EGFR inhibitors including erlotinib, gefitinib, afatinib, dacomitinib, neratinib, poziotinib, ibrutinib rocilentinib, EGF816, and osimertinib. Computational modeling was conducted to analyze the conformational changes and drug binding affinity.

Results:
In Ba/F3 cells with EGFR exon 20 insertions, most 1[st] and 3[rd] generation TKIs failed to inhibit growth of EGFR exon 20 insertions after residue 767 with IC~50 ~values above 100nM. However, poziotinib significantly inhibited cell growth of all EGFR exon 20 insertions tested across the helix and loop regions with an average IC~50~ value of 2.9nM, as compared to osimertinib and rocilentinib (IC~50~ values =103nM and 850nM, respectively). Further characterization using three-dimensional modeling revealed that exon 20 insertions induce conformational changes which cause a decreased affinity for 1[st] generation TKIs and steric hindrance of C797 reducing the ability of 3[rd] generation TKIs to covalently bind. A significant shift of the c-helix and p-loop result in a sterically hindered binding pocket. Therefore, the smaller, more flexible 1,2-dichloro-3-fluorobenzene terminal group of poziotinib can overcome the structural changes induced by the exon 20 insertions, whereas the ridged 1-methylindole terminal group of osimertinib cannot.

Conclusion:
EGFR exon 20 insertions induce a shift of the p-loop and c-helix resulting in steric hindrance of the binding pocket thereby preventing binding of 1[st] generation and 3[rd] generation EGFR inhibitors including rocilentinib and osimertinib. A smaller, more flexible inhibitor such as poziotinib can overcome the steric hindrance of the drug binding pocket. Currently, in vivo studies of the EGFR D770insNPG GEMM, and EGFR H773insNPH PDX model with poziotinib are underway, and a clinical trial testing poziotinib in EGFR exon 20 mutant NSCLC patients will begin enrollment this year.

Abstract not provided

Background:
MET alterations leading to exon 14 skipping occur in ~4% of non-squamous non‑small cell lung cancer (NSCLCs) and 20–30% of sarcomatoid lung carcinomas, resulting in MET activation and sensitivity to MET inhibitors in vitro.[1–4] Crizotinib, initially developed as a MET inhibitor, is currently approved for the treatment of ALK-rearranged and ROS1-rearranged advanced NSCLC. We present crizotinib antitumor activity and safety data in patients (pts) with MET exon 14-altered advanced NSCLC.

Methods:
Advanced NSCLC pts positive for MET exon 14-alteration status determined locally by molecular profiling were enrolled into an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195) and received crizotinib at a starting dose of 250 mg BID. Objective responses were assessed using RECIST v1.0.

Results:
As of the data cut-off of Feb 01, 2016, 21 pts with MET exon 14-altered NSCLC received crizotinib treatment (18 response-evaluable, 3 not yet evaluable). Median age was 68 y (range: 53−87). Tumor histology was: 76% adenocarcinoma, 14% sarcomatoid adenocarcinoma, 5% adenosquamous carcinoma, and 5% squamous cell carcinoma. Sixty-two percent (62%) of pts were former-smokers, 38% never-smokers, and there were no current smokers. Duration of treatment ranged from 0.2 to 12.2 mo, with 76% of pts (16/21) still ongoing. Five pts discontinued treatment (1 due to AE, 3 due to clinical or disease progression, and 1 preferred alternative treatment formulation). PRs were observed in 8 pts, for an objective response rate of 44% (95% CI: 22–69); 9 pts had stable disease. Median time to response was 7.8 weeks (range: 7.0–16.3), which was the approximate time of the scheduled first on treatment tumor scans for patients. Median progression-free survival could not be calculated. The most common (≥25%) treatment-related AEs (TRAEs) were edema (43%) diarrhea (33%), nausea (33%), vision disorder (33%), and vomiting (29%). Most TRAEs were grade 1/2 in severity and consistent with the known safety profile of crizotinib. Four grade 3 TRAEs (edema, bradycardia, anemia, and weight increased) and no grade 4 or 5 TRAEs were reported. Enrollment of pts with MET exon 14-altered NSCLC continues, and updated data will be available at the time of presentation.

Conclusion:
Crizotinib has clinically meaningful antitumor activity in pts with MET exon 14-altered advanced NSCLC. The drug has a tolerable AE profile, consistent with that previously reported for pts with ALK-rearranged or ROS1-rearranged advanced NSCLC. Further study of crizotinib in this pt population is warranted.

Background:
Lung-MAP (S1400), is a master protocol that incorporates genomic testing of tumors through a next generation sequencing (NGS) platform (Foundation Medicine) and biomarker-driven (matched) therapies for patients with squamous cell lung cancer (SCCA) after progression on first-line chemotherapy.

Methods:
The Lung-MAP trial, activated June 16, 2014, includes 3 matched- and 1 non-match study. Matched studies include: S1400B evaluating taselisib, a PI3K inhibitor, S1400C evaluating palbociclib, a CDK 4/6 inhibitor and, S1400D evaluating AZD4547, an FGFR inhibitor. The non-match study S1400I tests nivolumab + ipilimumab vs. nivolumab. Two studies have closed: S1400E evaluating rilotumumab an HGF monoclonal antibody + erlotinib closed 11/26/2014 and S1400A evaluating MEDI4736 in non-match pts, closed 12/18/2015.

Results:
From June 16, 2014 to June 15, 2016, 812 pts were screened and 292 pts registered to a study: 116 to S1400A, 27 to S1400B, 53 to S1400C, 32 to S1400D, 9 to S1400E and 55 to S1400I. Demographics: Screening was successful for 705 (87%) of screened eligible pts. Median age 67 (range 35-92); male 68%; ECOG PS 0-1 88%, PS 2 10%; Caucasian 85%, Black 9%, other 5%; never/former/current smokers 4%/58%/36%. Table 1 displays biomarker prevalence; 39% of pts matched; 33.9%, 4.8%, and 0.3% with 1, 2, and all 3 biomarkers, respectively. Tumor mutation burden (TMB) was available for 636 (90.4%) of eligible pts. The distribution of TMB is: 126 (19.8%) low (≤5 mutations Mb), 415 (65.1%) intermediate (6-19 mutations/Mb), and 96 (15.1%) high (≥20 mutations/Mb). The median TMB was 10.1.

Conclusion:
Genomic screening is feasible as part of this master protocol designed to expedite drug registration, confirm anticipated prevalence of targeted alterations in SCCA and reveal intermediate or high TMB in most (80.2%) pts. Treatment results are not yet available as patients continue to accrue. Clinical trial information: NCT02154490

Total	FGFR	CDK	PIK3CA
FGFR (15.9%)	12.9%	2.4%	0.6%
CDK (18.8%)		14.6%	1.8%
PIK3CA (8.8%)			6.4%
Biomarker prevalence and overlap.

Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.

Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.

Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.

Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.

Abstract not provided

Background:
The identification and development of tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have revolutionized and greatly improved the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). Unfortunately, acquired resistance (AR) to these agents remains a major clinical problem hindering durable responses. Although significant work has been done to identify particular mechanisms of acquired resistance, little is known regarding the global mutational landscape of EGFR mutant tumors before therapy or at the manifestation of acquired resistance.

Methods:
Using specimens obtained in the IRB approved, Yale Lung Rebiopsy program, we completed whole exome sequencing of 15 EGFR mutant tumors with paired tissue obtained pre-treatment and at the time of AR to EGFR TKIs. An additional 5 unpaired AR samples were also analyzed. The mutational burden and copy number profile of the specimens were studied.

Results:
We found that the mutational burden of pre-treatment EGFR mutant tumors varies widely between tumors. TKI treatment, however, does not significantly alter the overall or non-synonymous mutation load at AR. Interestingly, EGFR[L858R]tumors had a significantly higher mutation burden at acquired resistance to EGFR TKIs than EGFR[Δ19] tumors. The higher mutation burden in EGFR[L858R] tumors compared to those harboring EGFR[Δ19 ]mutations was further confirmed through analysis of TCGA data. Recurrently altered genes shared in the pre- and AR specimens include TP53, EGFR and AKT1. Alterations in EGFR (T790M), MYCBP2, WHSC1L1, AXL, MET, HGF, MYC and NTRK1 were found at exclusively at AR.

Conclusion:
Collectively, these data provide valuable insight into the mutational landscape of EGFR mutant NSCLCs as they evolve on TKIs and identify potential resistance candidate genes for further investigation.

Abstract not provided

Abstract:
Medical therapy in advanced NSCLC in 2016 is characterized by personalization, individualization, and therapy precision. Not only clinical factors are used for treatment differentiation but also the histological type (squamous versus non-squamous) and the molecular profile (mutant versus wild type). In addition, the complexity of the treatment algorithm has gradually increased over time by the incorporation of a number of approved molecules for 1[st], 2[nd] -, subsequent line therapy (Peters, 2012; Masters, 2015; NCCN, 2016). NSCLC – 1[st]-line-therapy - wild-type: For patients with wild-type non-squamous NSCLC it is generally accepted that upfront platinum based doublet chemotherapy (DCT) remains the backbone for individuals with good performance and that this approach should be modified according to feasibility and tolerability, co-morbidity, and age over 70 years. Progress has been made through pemetrexed, which is recommended as the favorite partner of platinum-based components (Scagliotti; 2008/2011). In addition, it has lately been demonstrated that the extension of induction chemotherapy by single agent pemetrexed until progression - in case of non-progression under four cycles of DCT not containing pemetrexed (switch maintenance) (Ciuleanu, 2009) or containing pemetrexed (continuation maintenance) (Paz-Ares, 2012/2013) - prolongs survival. In this case survival may also be prolonged by erlotinib, when used in the switch maintenance setting, but erlotinib’s benefit seem to be restricted to patients, which have experienced disease stabilization to induction chemotherapy (Cappuzzo, 2010; Coudert, 2012). Bevacizumab, when added to platinum-based to DCT, significantly improves response rate, progression free survival, as well as overall survival in eligible patients (Sandler, 2006/2010; Reck, 2009/2010). In wild-type squamous NSCLC platinum based DCT (no pemetrexed, no bevacizumab) remains standard. Nonetheless, necitumumab has recently shown to improve survival when combined with cisplatin/gemcitabine (Thatcher, 2015). Maintenance therapy in squamous tumors with docetaxel or erlotinib (switch) or gemcitabine (continuation) may be justified in some patients even so study evidence is weaker than for non-squamous tumors (Fidas, 2009; Perol, 2012). NSCLC – 1[st]-line-therapy - mutant: For patients with advanced NSCLC expressing specific molecular features – mainly non-squamous tumors – 1[st]- line treatment with targeted agents has been established. In tumors with EGFR mutations gefitinib, erlotinib, and afatinib have shown to prolong progression free survival over standard chemotherapy (Mok, 2009; Rosell, 2012; Sequist, 2013). In tumors bearing ALK-/ROS1-gene-rearrangements crizotinib has also shown to prolong progression free survival when compared to platinum/pemetrexed. (Solomon, 2014). Therefore, erlotinib, gefitinib or afatinib should be prescribed for patients with tumors bearing EGFR-mutations. For patients with tumors bearing ALK-/ROS1 crizotinib should be prescribed. However, for these patients molecular testing is critical and should be used to select patients for EGFR/ALK/ROS1 targeted therapy. Patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics (ethnicity, gender, smoking status) (Lindeman, 2013). NSCLC - 2[nd] /subsequent-line therapy - wild-type: In patients with disease progression during or after completion of 1[st ] -line chemotherapy, 2[nd] -, subsequent-line therapy is indicated when the patient remains in good clinical condition. Approved older treatment options include docetaxel, pemetrexed and erlotinib. Two anti-angiogenic agents and two immune-checkpoint inhibitors have recently been added. These include nintedanib and ramucirumab (Reck, 2014; Thatcher, 2015), as well as nivolumab and pembrolizumab (Brahmer, 2015; Borghaei, 2015; Herbst, 2016). Nintedanib/docetaxel increases significantly survival in patients with adenocarcinoma who specifically progressed within 9 months after the start of 1[st]-line therapy, who have experienced disease progression as best response to 1[st]-line therapy and decreases tumor burden and decelerates tumor growth. Nintedanib/docetaxel has been approved in the EU for the treatment of patients with adenocarcinoma. Ramucirumab/docetaxel has also been approved in the US and EU for patients with disease progression on or after DCT for wild-type non-squamous and squamous NSCLC. This approval has been based on phase III study evidence indicating survival advantage in non-squamous NSCLC (statistically significant) and squamous NSCLC (numerically longer). Comparing head-to head nivolumab and docetaxel in patients with squamous and non-squamous NSCLC after failure of DCT has demonstrated superior overall survival in patients receiving nivolumab. Nivolumab has received US and EU approval for advanced NSCLC with progression on or after DCT. Nivolumab appears to be most effective in patients with more than 6 months from completion of the latest treatment regimen to randomization in comparison to patients with less than 3 months to randomization. Pembrolizumab has received approval in the US and EU for patients with advanced NSCLC who’s tumors expressed PD-L1 and who have disease progression on or after chemotherapy. Approval has been based on head-to-head comparison of pembrolizumab and docetaxel in patients with previously treated PD-L1 positive squamous and non-squamous NSCLC, which has demonstrated a significant survival benefit for pembrolizumab. NSCLC-2[nd]/subsequent-line therapy - mutant: Resistance to first and second generation EGFR-TKIs is a multifactorial process with a variety of clinically patterns. Its management requires different, case adapted approaches. Several strategies are currently under investigation, but some have already find its way into todays practice although study evidence is still rather weak. In case of oligoprogression the EGFR-TKI therapy may continue but local therapies (radiation, surgery) should be added. In case of diffuse progression EGFR-TKI therapy may continue, but in combination with chemotherapy; EGFR-TKI therapy may be switched to chemotherapy, but at the moment of chemotherapy resistance patients may be re-exposed to EGFR-TKI therapy; admission to clinical trials offering investigational agents may be a valid option for some patient. Osimertinib has just been approved and is recommended for tumors expressing P790M (Jänne, 2015). In tumors bearing ALK-/ROS-gene-rearrangements ceritinib is approved and recommended in case of crizotinib resistance (Shaw, 2014). Conclusion: During the past ten years the complexity of the treatment algorithm of advanced NSCLC has gradually increased by the incorporation of several approved molecules. Novel immunotherapies have recently changed the management of advanced wild-type NSCLC. Treatment by histo-type and geno-type has been established and it can be assumed by the given speed of growth of molecular information that the process of treatment differentiation will fast continue. Identification of new prognostic and predictive factors undoubtedly will accelerate this process.

Background:
Patients with extensive-stage disease (ED) small cell lung cancer (SCLC) have limited treatment options and poor survival following failure of platinum-based chemotherapy. Pembrolizumab, a humanized anti–programmed death 1 (PD-1) antibody, has demonstrated robust antitumor activity and a favorable safety profile in multiple tumor types. Here, we present updated safety and efficacy data, including survival, for patients with ED SCLC enrolled in the KEYNOTE-028 (ClinicalTrials.gov, NCT02054806) study.

Methods:
KEYNOTE-028 is a nonrandomized, multicohort phase 1b trial of pembrolizumab in patients with PD-L1–positive advanced solid tumors. Patients received pembrolizumab 10 mg/kg every 2 weeks for up to 2 years or until confirmed progression or intolerable toxicity, death, withdrawal of consent, or physician decision. Response was assessed per RECIST v1.1 by investigators every 8 weeks for the first 6 months and every 12 weeks thereafter. The primary end point was objective response rate (ORR; per RECIST v1.1, investigator assessed). Secondary end points included safety, tolerability, progression-free survival (PFS), and overall survival (OS).

Results:
24 patients with ED SCLC and tumor PD-L1 positivity were enrolled and received ≥1 dose of pembrolizumab. At the data cutoff date (June 9, 2016), median follow-up duration was 9.8 months (range, 0.5-24.0 months); 3 patients (12.5%) remain on treatment. The ORR was 37.5% (95% CI, 18.8%-59.4%), including 1 complete and 8 partial responses in 24 evaluable patients. Median duration of response was 9.0 months (range, 1.9-19.9+ months). Median PFS was 1.9 months (95% CI, 1.7-5.9 months); the 6- and 12-month PFS rates were 29.8% and 24.8%, respectively. Median OS was 9.7 months (95% CI, 4.1 months-not reached); the 6- and 12-month OS rates were 66.0% and 35.7%, respectively. No new safety concerns were noted. Sixteen of 24 (66.7%) patients experienced treatment-related AEs. Two patients experienced grade 3-5 treatment-related AEs: 1 patient had blood bilirubin increased (grade 3) and 1 patient experienced grade 3 asthenia and grade 5 colitis.

Conclusion:
Pembrolizumab demonstrated promising antitumor activity in this pretreated, PD-L1–positive ED SCLC population. The responses were found to be durable and may have led to an OS benefit for the subset of patients who achieved objective responses with pembrolizumab.

Background:
While the majority of small cell lung cancer (SCLC) patients succumb to their disease within a few months, there is a small group of patients who survive for many years after their diagnosis. Factors contributing to the SCLC long-term survivorship remain largely unknown. Herein, we compared tumors from exceptional survivors (EXS) and patients with the expected outcome (EOP) to determine genomic and immunological determinant of SCLC survivorship.

Methods:
In the Mayo Clinic tissue registry, we identified surgical blocks from 12 EXS who survived > 4 years after surgery and 14 EOP who died < 2 years of surgery. These cohorts were created to have no statistical differences in clinical TNM stage, curative versus non-curative intent surgery, age, gender, and smoking status between EXS and EOP. Tumor areas were macro-dissected for gene expression profiling by the Human Transcriptome Array (Affymetrix). Also, tissue sections were stained for key immunological markers, including CD8, CD4, CD3, CD279, FoxP3, CD138, CD20, CD21, CD14, CD68, and also LYZ. Concentrations of immune cells in intra-tumor areas (IE), stroma (ST), and tumor/non-tumor interface (IF) were assessed by an image processing program (Aperio). Staining patterns in each of the three zones in EXS and EOP tumors were compared.

Results:
More than 90% of differentially expressed genes were over-expressed in EXS compared with EOP. Furthermore, over 75% of the known over-expressed genes were either immunoglobulin or MHC related and a majority of the remaining genes were immune function related such as cytokines. We then performed IHC for key immunological markers and found significantly higher concentration of immune cells including CD8 and PD-1 positive cells in the tumor microenvironment, especially at the tumor stromal interface in EXS compared with EOP (p < 0.005 for both markers). Furthermore, the total number of infiltrating immune cells (T-cells, B-cells, Plasma cells, monocytes and macrophages was significantly higher in EXS in the interface region (p < 0.0005).

Conclusion:
Gene expression profiling revealed that anti-tumor immunity is an important factor for SCLC survival. Further studies by IHC suggested the presence of immune cells especially cytotoxic T-cells in the tumor microenvironment and particularly at the tumor-stromal interface to be major contributors to long term survivorship in SCLC. These findings suggest that immunotherapeutic strategies may be effective for patients with SCLC.

Background:
SCLC is one of the most deadly malignancies. Rovalpituzumab tesirine (SC16LD6.5, Rova-T) is a first-in-class ADC directed against DLL3, a novel target identified in tumor initiating cells and expressed in over 80% of SCLC cases.

Methods:
Seventy-four patients with progressive SCLC after at least one previous systemic therapy were enrolled in a first-in-human study (NCT01901653), irrespective of DLL3 expression, including 68 at active doses of 0.2-0.4 mg/kg administered intravenously every 3 or 6 weeks. Available archived tumor tissue (n=48) was assessed retrospectively by immunohistochemistry for DLL3.

Results:
Among 60 evaluable subjects, active dose levels resulted in a confirmed objective response rate (ORR) of 18% and a confirmed clinical benefit rate (CBR; stable disease or better) of 68%. Among 26 evaluable subjects with DLL3 expression in at least 50% of tumor cells (DLL3-high), confirmed ORR and CBR were 39% and 89%, respectively. Median duration of response was 5.6 months. One-year survival rates among all and DLL3-high subjects were 18% and 32%, respectively. Among primary sensitive relapse patients, confirmed ORR and CBR among all subjects were 24% (8/33) and 67% (22/33); and among DLL3-high subjects were 53% (8/15) and 100% (15/15), with one-year survival rates of 17% and 33%, respectively. Among primary resistant/refractory relapse patients, confirmed ORR and CBR among all subjects were 12% (3/25) and 72% (18/25); and among DLL3-high subjects were 18% (2/11) and 73% (8/11), with one-year survival rates of 21% and 29%, respectively. The most common grade 3 or higher toxicities included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%). ADC pharmacokinetics were linear with a terminal half-life of 10 - 14 days and anti-therapeutic antibodies did not develop

Conclusion:
Rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity with a manageable safety profile, including among patients with disease resistant or refractory to primary chemotherapy. Further development of rovalpituzumab tesirine in SCLC is warranted.

Abstract not provided

Background:
Alisertib, an investigational selective Aurora A kinase inhibitor, showed single-agent antitumor activity in preclinical in vivo SCLC models and was synergistic with paclitaxel in this setting. We report the efficacy, quality of life (QoL), and safety from this study.

Methods:
Patients ≥18 years with SCLC relapsed <180 days after standard first-line platinum-based chemotherapy were randomized 1:1 to alisertib 40 mg orally twice-daily on days 1–3, 8–10, 15–17 + paclitaxel 60 mg/m[2] IV on days 1, 8, 15 (Arm A) or matched placebo + paclitaxel 80 mg/m[2] (Arm B) in 28-day cycles. Patients were stratified using an interactive voice response system (IVRS) by type of relapse post-frontline platinum (sensitive vs resistant/refractory) and presence/absence of brain metastases at baseline. Protocol Amendment 2 corrected the definition for relapse per standard guidance; stratification factors were corrected accordingly. Primary endpoint was progression-free survival (PFS) per stratified log-rank test. QoL outcomes were assessed per EORTC QLQ-C30 and -LC13.

Results:
178 patients were randomized, 89/89 to Arm A/B (median age 62/62 years). Survival, response, QoL, and safety results are presented in the Table. The analysis of PFS using IVRS stratification favored Arm A, as did the analysis per corrected stratification factors. Mean EORTC QLQ-C30 QoL scores were similar between arms, as were mean change-from-baseline values at end of treatment (-5.7 in Arm A vs -4 in Arm B). Figure 1



Conclusion:
Alisertib + paclitaxel shows favorable PFS over placebo + paclitaxel with both initial and updated IVRS stratification. A similar favorable trend was also observed for OS and ORR although not statistically significant. Comparable changes in QoL scores were observed from baseline in both arms. The alisertib + paclitaxel arm showed higher rates of AEs and discontinuation due to AEs. Updated survival analyses are pending.

Background:
A significant proportion of limited-stage small cell lung cancer are elderly. However, there is paucity of data on the efficacy and safety of concurrent chemo-radiotherapy in the elderly to guide treatment decision-making.

Methods:
Data from the CONVERT trial was retrospectively analysed to compare the outcome of patients 70 years or older to patients younger than 70 years. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks or 66Gy in 33 once-daily fractions over 6.5 weeks starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by Prophylactic Cranial Irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy.

Results:
Of 547 patients randomised between April 2008 and November 2013, 57 patients were excluded for the purposes of this analysis as they did not receive concurrent chemo-radiotherapy. Of the 490 included patients, 67 (13.7%) were age 70 years or older with median age of 73 years (70-82). Patients’ characteristics were well balanced apart from more male in the elderly group (p=0.02). There was no significant difference in the number of chemotherapy cycles administered in the two groups (p=0.24). A higher proportion of patients received 30 or 33 fractions of radiotherapy as per protocol in the younger group (85% vs. 73%; p=0.03). Neutropenia grade 3/4 occurred more frequently in the elderly group (84% vs. 70%; p=0.02) but there was no statistically significant difference in neutropenic sepsis (4% vs. 7%; p=0.07) and non-haematological acute/late toxicities. There were two vs. six treatment-related deaths in the elderly and younger group respectively (p=0.67). At median follow up of 46 months for those alive; two-year survival was 53% (95% CI 41-64) vs. 57% (95% CI 52-61), median survival was 29 months vs. 30 months in the elderly vs. younger group respectively. Hazard ratios for overall survival and progression free survival were 1.15 (95% CI 0.84-1.59; log-rank p=0.38) and 1.04 (95% CI 0.76-1.41; log-rank p=0.81) respectively. In the elderly group median survival was not significantly different in patients who received once vs. twice daily radiotherapy (p=0.91).

Conclusion:
Radiotherapy treatment delivery was higher in the younger group but toxicity and survival rates were similar in elderly compared to younger patients. Concurrent chemo-radiotherapy with modern radiotherapy techniques is a treatment option for elderly patients with good performance status.

Background:
Circulating tumour cells (CTCs) are prevalent in patients with small cell lung cancer (SCLC) (Hou et al. JCO 2012) but their clinical utility is not known for patients with limited disease (LD) who receive concurrent chemoradiation. Here we report on a patient subgroup who underwent CTC analysis and treatment on the Concurrent ONce-daily (OD) VErsus Twice-daily (BD) RadioTherapy (CONVERT) trial (Faivre-Finn Proc. ASCO 2016) that demonstrated a non-significant difference in the primary endpoint of two-year survival for the OD (51%) and BD (56%) arms.

Methods:
Blood samples (7.5mls) were collected at baseline, prior to any treatment from patients who were enrolled to the CONVERT trial at The Christie Hospital site, Manchester, UK. CTCs were enumerated prospectively using the Cellsearch platform. Patients were randomised 1:1 to receive 45Gy in 30 twice-daily fractions over 3 weeks (Arm 1) or 66Gy in 33 once-daily fractions over 6.5 weeks (Arm 2) starting on day 22 of cycle 1 chemotherapy (4 to 6 cycles of Cisplatin 25mg/m2 days 1-3 or 75mg/m2 day 1 with Etoposide 100mg/m2 days 1-3), followed by prophylactic cranial irradiation if indicated. Radiotherapy planning was with a 3D conformal technique or intensity modulated radiotherapy. Staging by Positron Emission Tomography (PET) was permitted. Standard statistical methods were used to examine associations between CTC number (CTC#), clinical factors and outcomes.

Results:
Of 547 patients randomised between April 2008 and November 2013, 79 patients (41 in Arm1 and 38 in Arm 2) underwent CTC enumeration (CTC subgroup). The clinical demographics and median overall survival (OS) of the CTC subgroup did not differ significantly from the overall study population. The median number (range) of CTCs per 7.5mls blood for all 79 patients was 1 (0-3750) and for arm 1 and arm 2 patients respectively, 12 (0-164) and 158 (0-3750) (p=0.495). There was a trend for association of CTC# with higher TNM stage. CTC# was significant for survival in univariate and multivariate analysis. The median (95% CI) OS for ≥15 CTCs (n=18) was 6.01 (4.2-11.5) months compared to 30.77 (19.7-39.3) months for < 15 CTCs (n=61), p <0.001. The positive predictive value of CTC# ≥15 for survival ≤ 2 years is 100%, and ≤ 1 year is 72%. CTC# also predicted for worse outcome in patients who had undergone PET staging.

Conclusion:
CTC# is highly prognostic for poor survival in patients with LD-SCLC, treated with concurrent chemoradiotherapy, and could aid treatment decision making for this disease.

Abstract not provided

Background:
This phase II, multi-institutional (Roswell Park Cancer Institute, Cleveland Clinic, and Upstate Medical Center) randomized study was conducted to compare incidence of RTOG grade 3 or higher adverse events (AEs) associated with 2 different, established SBRT regimens for NSCLC

Methods:
Patients with documented baseline medical conditions precluding lobectomy and biopsy-proven peripheral (greater than 2 cm from the central bronchial tree) T1/T2, N0 (clinically node negative by PET), M0 tumors were eligible. Patients were randomized to receive either 30 Gy in one fraction (arm 1) or 60 Gy in 3 fractions (arm 2) over at least 8 days. Heterogeneity corrections were not used. Randomization was stratified by treatment center and Karnofsky performance status (100, 90, 80 and below.) The study was designed to detect whether psAEs rate > 17% at a 5% significance level (1-sided) and 81% power. Secondary endpoints included: local control, greater than 1 year toxicity, overall survival (OS) and progression-free survival (PFS).

Results:
The study opened in September 2008, was suspended between April 2010 to June 2010 as well as October 2010 to April 2011 while RTOG 0915 was open, and closed on April 15, 2015 after accruing a total of 98 patients. All patients received planned SBRT treatment. Median follow-up was 27 months. In follow-up, 10 patients were lost to follow-up; 1 was in arm 1 and 9 in arm 2. Baseline patient and tumor characteristics were balanced between both arms. On arm 1, 13 (27%) patients and 16 (33%) patients on arm 2 experienced RTOG grade 3 AEs, there were no grade 4 AEs. Thoracic grade 3 AEs were experienced by 8 (16%) patients on arm 1 and 6 (12%) patients on arm 2. There were no differences in OS or PFS survival, logrank p= 0.44 and 0.99 respectively. OS at 2 years was 71% (95% CI, 55-82%) for arm 1 and 61% (95% CI, 44-78%) for arm 2. PFS at 1 year was 63% (95% CI, 46-75%) for arm 1 and 51% (95% CI, 34-65%) for arm 2.

Conclusion:
This randomized phase II study demonstrated that 30 Gy in one fraction was equivalent to 60 Gy in three fractions in terms of toxicity, progression free survival and overall survival. Acknowledgment: Supported by Roswell Park Alliance Foundation grant

Background:
Stereotactic body radiotherapy (SBRT) has been sometimes used as a curative treatment for both of medically operable patients with stage I non-small cell lung cancer (NSCLC). However, most of these patients are comparatively high-aged and not similar to the patients cohort generally operated with surgery. So, the purpose of this study was to collect results of SBRT for operable and young (70 years old or younger) patients with stage I NSCLC from multiple Japanese institutions.

Methods:
We organized a multi-institutional SBRT study group in Japanese Radiological Society (JRS-SBRTSG) and conducted a study for SBRT for stage I non-small cell lung cancer (NSCLC). This is a retrospective analysis to review 252 patients (male 168, female 84) who were medically operable and 70 years old or younger (range,40-74; median, 67 years) with stage I (IA 211, IB 41) NSCLC treated with curative intent by SBRT in 20 institutions of JRS-SBRTSG. Histology was proven in 177 patients (adenocarcinoma 121, squamous cell carcinoma 41, others 15), and the others were diagnosed clinically. Median tumor size was 22mm (range, 5-49mm). A total dose of 40 -70 Gy mainly was prescribed in 4-10fractions. Median calculated biological effective dose (BED) was 107 Gy (range, 75-134 Gy) based on alpha/beta = 10Gy).

Results:
The median follow-up period for all patients was 37 months. Overall survival rate (OS) at three and five year was 83.3% and 76.6%, respectively. Radiation pneumonitis of grade 3 or more was noted in 0.8% of the total patients. In the total patients, local control rate (LC) at three year was 89.5%, and LC was significantly better in the subgroup of adenocarcinoma than that of squamous cell carcinoma. According to univariate analysis, female, adenocarcinoma, no emphysema, and no pulmonary interstitial change were better prognostic factors for OS. According to multivariate analysis, pulmonary interstitial change was only a worse survival factor for OS. OS at three and five year in the subgroup of patients without pulmonary interstitial change was 89.7% and 84.0%, respectively.

Conclusion:
The outcomes of SBRT for the medically operable and young (75 years or younger) patients with stage I NSCLC in the Japanese large database of practice level was excellent and the overall survival rate would be comparable to that of surgery. The results will support a rationale of applying SBRT for younger and operable patients with operable stage I NSCLC.

Background:
Interstitial lung disease, such as idiopathic pulmonary fibrosis (IPF), have been widely known to be associated with lung cancer. Lung cancer patients concomitant with IPF sometimes develop a life-threatening acute exacerbation after surgery or radiotherapy. Percutaneous cryoablation is evolving as a potentially less invasive local treatment for lung cancer. The purpose of this study is to retrospectively analyze the outcomes of cryoablation for clinical T1N0M0 non-small cell lung cancer (NSCLC) patients for whom surgery or radiotherapy is contraindicated because of IPF.

Methods:
Between December 2003 to March 2016, 210 patients underwent computer tomography guided percutaneous cryoablation for lung tumors at our institution. Of these, 11 histologically proven clinical T1N0M0 NSCLC patients, for whom surgery or radiotherapy was considered contraindicated because of severe IPF, were retrospectively reviewed. Complications, local progression-free survival and clinicopathological factors were evaluated.

Results:
The cohort was composed of 11 men with a mean age of 74 years (range: 68 to 82). The median follow-up time was 20 months (range: 6 to 55 months). The mean Krebs von den Lungen-6 (KL-6) level was 1608 ±1025 U/mL. The mean tumor size was 24 ± 7mm. The mean percentage of predicted diffusing capacity for carbon monoxide (DLCO) was 37±27%. Thirty and 90-day mortality was 0 and 18%, respectively. Two patients required chest tube drainage because of severe pneumothorax. Acute exacerbation of IPF occurred in two patients (18%). The use of oral steroids and need for chest tube drainage were predictors of higher mortality (p < 0.05) and higher incidence of acute exacerbation of IPF (p < 0.05). However, higher level of KL-6 and low percentage of DLCO were not significant risk factors of mortality or acute exacerbation of IPF. Local progression-free survival at 1, 2 and 3 year was 51, 41 and 31%, respectively.

Conclusion:
Percutaneous cryoablation for lung cancer patients with IPF provoked acute exacerbation of IPF in 18% of patients. The use of oral steroids and need for chest tube drainage were predictors of higher mortality and higher incidence of acute exacerbation of IPF.

Abstract not provided

Background:
CT screening programs frequently detect early stage lung adenocarcinoma. Recent studies show that distinct subtypes of lung adenocarcinoma are associated with different prognosis and suggest that treatment should be tailored to histological subtypes as identified in the new WHO Lung Tumor Classification. To develop this personalized approach, it is important to have reliable tools to diagnose tumors before treatment, preferably non-invasively through image analysis. We have developed a CT-image analysis system (iBiopsy) that uses computerized deep learning and artificial intelligence. To validate the accuracy of a noninvasive CT-based image biopsy system (iBiopsy) in differentiating early stage lung adenocarcinoma subtypes of atypical adenomatous hyperplasia (AAH), adenocaricnoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC).

Methods:
We retrospectively identified 365 eligible patients from Zhongshan Hopsital Fudan University, diagnosed with AAH, AIS, MIA or IAC by surgical pathological diagnosis. The last high definition CT scan prior to the surgery of the lesion was analyzed using the iBiopsy system, blinded to pathological result. Based on a pulmonary nodule image feature set (PNIFS) in combination with classified pattern models, such as R-SVM, all the pulmonary nodules were classified into four groups. For diagnosis efficacy, area under the curve (AUC) of Precision-Recall score (PRS), receiver operating characteristic (ROC) of a classification model were calculated in each group.

Results:
365 patients were included in the analysis. The classification recognition rate of the PNIFS was 80.03%. The average value of PRS is 0.92, the mean of ROC is 0.95, and it is more than 0.80 for the cross validation value.

Conclusion:
iBiopsy system allows the non-invasive imaged based stratification of pulmonary adenocarcinoma nodules into four groups, from AAH to IAC. Our result suggest that iBiopsy system could ultimate facilitate the diagnosis and precision management of pulmonary nodules.

Background:
We have recently demonstrated that the presence of the Spread Through Air Spaces (STAS) and the variety of histologic subtypes increase the risk of recurrence after resection for small lung adenocarcinoma (ADC). Currently, the new World Health Organization classification of lung cancers was revised and newly prescribed to describe the presence of each histologic subtypes and STAS. The purpose of this study is to examine the risk factor for recurrence other than TNM staging analyzing clinical information retrospectively.

Methods:
All available tumor slides from patients with clinical stage I, therapy-naive, surgically resected solitary lung ADC ≤2 cm in size (1998-2015) were reviewed. Each tumor was evaluated by comprehensive histologic subtyping, and the percentage of each histologic component was recorded in 5% increments. STAS was defined as the spread of tumor cells into air spaces in the lung parenchyma adjacent to the main tumor according to the WHO classification. Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method.

Results:
354 patients met inclusion criteria (52.3% men; median age: 67yrs; median tumor size: 1.3cm; 325 stage IA/ 29 stage IB; 91 partial resection/ 22 segmentectomy / 241 lobectomy or pneumonectomy). The prognosis didn’t differ significantly between sublobar resection group and lobectomy or pneumonectomy group (5-year RFP: 88.4% (N=113) vs. 91.9% (N=241), P=.162). Presence of STAS was identified in 74 cases (20.9%) (36 Micropapillary pattern / 55 Solid pattern / 15 Single cells). STAS was significantly associated with recurrence (5-year RFP: 94.3% vs. 76.2%, P < .0001). Histologic subtypes were 62 adenocarcinoma in situ (18%), 110 minimally invasive adenocarcinoma (31%) and 182 invasive adenocarcinoma (51%). The recurrence after sublobar resection was seen in 13 cases (1 partial resection (4.5%) / 12 segmentectomy (13%), 5 STAS (+)/ 8 STAS (-), 6 solid predominant / 5 acinar predominant / 2 lepedic predominant, 5 pulmonary recurrence / 4 lymph node recurrence / 2 local recurrence / 2 others). Patients with solid component had significantly worse prognosis (5-year RFP: 71.7% (N=83) vs. 96.3% (N=271), P<.0001). Among them, patients with sublobar resection had significantly more recurrence than with lobectomy or pneumonectomy (5-year RFP: 51.4% (N=19) vs. 77.7% (N=64), P=.0021).

Conclusion:
The patients of small ADC with STAS or solid component had worse prognosis. The patients after sublobar resection with solid component should be made follow-up closely. We propose that the presence of those features should be considered a factor to upgrade the pathologically defined T stage.

Background:
The newly proposed International Association for the Study of Lung Cancer (IASLC) staging system reclassified T2aN0M0 tumors greater than 4 cm as stage IIA instead of stage IB. This study investigated the role of adjuvant chemotherapy in pathologic stage IB non-small cell lung cancer (NSCLC).

Methods:
The patients with pathologic T2aN0M0 NSCLC who underwent complete resection between 2001 and 2013 were identified from prospectively maintained databases, and classified into three groups based on tumor size: A (≤3.0 cm, n = 205), B (3.1-4.0 cm, n = 264), and C (>4.0 cm, n = 254). After propensity score matching, overall survival (OS) and freedom from recurrence (FFR) were compared between each group of paired patients who received platinum-based adjuvant chemotherapy and those who did not.

Results:
Among the 723 patients, 134 patients (18.5%) received adjuvant chemotherapy: Group A, 38 (18.5%) patients; Group B, 47 (17.8%); and Group C, 49 (19.3%). Matching based on propensity scored produced 38, 47, and 49 paired patients in Group A, B, and C, respectively. In Group A and B, there was no significant difference in OS and FFR between patients who received adjuvant chemotherapy and those who did not. In Group C, patients who received adjuvant chemotherapy experienced less recurrence and higher survival than those who did not. The 5-year FFR was 79.0% in in patients who received adjuvant chemotherapy and 66.1% in patients with surgery alone (p = 0.090). The 5-year OS was 95.8% in patients who received adjuvant chemotherapy and 68.9% in patients with surgery alone (p < 0.001). Figure 1



Conclusion:
Adjuvant chemotherapy was related with reduced recurrence and improved survival in patients with T2a tumors exceeding 4 cm. In considering the next upcoming 8[th ]edition of the TNM classification, adjuvant chemotherapy is a worthwhile and justified treatment for tumors greater than 4 cm with early stage disease.

Abstract not provided

Abstract:
Advances in Stereotactic Body Radiotherapy Matthias Guckenberger, Switzerland Stereotactic Body Radiotherapy (SBRT) has become the guideline-recommended treatment of choice for patients with early stage NSCLC, who are medically inoperable because of their comorbidities. This reflects that SBRT has transformed from an emerging technology practiced only by few and highly experienced centres to a mature treatment practice broadly in the radiation oncology community setting. Nevertheless, the methodology of SBRT has continuously evolved covering all aspects of patient selection, practice of SBRT planning and delivery and follow-up assessment. Patient selection: In many centres, SBRT has been introduced as a replacement for conventionally fractionated radiotherapy in patients considered fit enough for a six weeks long radical treatment but unfit for surgical resection. Recent data have demonstrated that SBRT is also well tolerated in very old (> 80 years) patients and patients suffering from severe comorbidities [1]. Simultaneously, the patient characteristics of age, performance status and patients comorbidities are not suitable to accurately predict a high risk of early non-cancer death such that these patients could be offered best supportive care and they would not benefit from SBRT as a curative treatment approach [2]. However, several studies have identified interstitial lung disease as a highly significant factor for severe post-SBRT radiation induced pneumonitis; these patients should be treated only with caution [3]. On the other end of the patient spectrum, there is an increasing amount of data comparing SBRT with surgical resection, lobectomy and sublobar resection: despite a growing evidence suggests equivalent outcome, lobectomy remains the standard of care for properly selected patients [4,5]. SBRT planning and delivery: Multiple advanced radiotherapy treatment planning and treatment delivery technologies as well as dedicated SBRT delivery machines have been developed and have become clinically available within the last years. Despite simulations studies showed a benefit for most these technologies, it remains unclear whether small improvements in accuracy and dosimetry will translate into a clinically meaningful improvements of patient outcome. The upcoming ESTRO ACROP practice guideline has therefore only identified few technologies as mandatory components of up-to-date SBRT practice (e.g. type B dose calculation algorithm, image guidance, 4D motion compensation strategy). SBRT dose and fractionation has been one of the most controversially discussed topics in lung SBRT and patterns-of-practice analyses reported a large variability between institutions. Comparison of different fractionation schedules requires radiobiological modelling and several recent studies suggested that the traditional linear-quadratic model (LQ-model) describes the observed outcome with sufficient accuracy [6]. Consequently, biological effective doses (BED) or 2-Gy equivalent doses are used by most studies for dose-effect modelling. Several studies consistently showed that a threshold dose of minimum 100Gy BED (alpha/beta ratio 10Gy) is required for a local tumor control probability of >90%. Furthermore, not only the minimum dose at the PTV edge but also the maximum dose within the GTV was shown as important predictor for local tumor control supporting the traditional SBRT concept of inhomogeneous dose distributions within the PTV. After central tumor location has been called a no-fly-zone for SBRT based on studies with “excessive” toxicity of very high dose SBRT, recent retrospective and prospective data suggest that lower total doses combined with more fractionated SBRT protocols improve the therapeutic ratio. Nevertheless, our understanding of the radiation tolerance of critical central structures is still insufficient and further research is necessary. Follow-up: The development of radiation induced fibrosis in the high dose region is well documented following SBRT. Only recently, algorithms for differentiation between local tumor recurrence and fibrosis have been developed and validated [7,8]: CT features of bulging margin and cranio-caudal growth appear to best differentiate between fibrosis and tumor recurrence. More advanced studies evaluate the value of mathematical image analysis methods, radiomics, but such studies strongly require external validation. 1. Takeda A, Sanuki N, Eriguchi T, et al: Stereotactic ablative body radiation therapy for octogenarians with non-small cell lung cancer. Int J Radiat Oncol Biol Phys 86:257-63, 2013 2. Klement RJ, Belderbos J, Grills I, et al: Prediction of Early Death in Patients with Early-Stage NSCLC-Can We Select Patients without a Potential Benefit of SBRT as a Curative Treatment Approach? J Thorac Oncol, 2016 3. Ueki N, Matsuo Y, Togashi Y, et al: Impact of pretreatment interstitial lung disease on radiation pneumonitis and survival after stereotactic body radiation therapy for lung cancer. J Thorac Oncol 10:116-25, 2015 4. Chang JY, Senan S, Paul MA, et al: Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol 16:630-7, 2015 5. Nagata Y, Hiraoka M, Shibata T, et al: Prospective Trial of Stereotactic Body Radiation Therapy for Both Operable and Inoperable T1N0M0 Non-Small Cell Lung Cancer: Japan Clinical Oncology Group Study JCOG0403. Int J Radiat Oncol Biol Phys 93:989-96, 2015 6. Guckenberger M, Klement RJ, Allgauer M, et al: Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer. Radiother Oncol 109:13-20, 2013 7. Huang K, Dahele M, Senan S, et al: Radiographic changes after lung stereotactic ablative radiotherapy (SABR) - Can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiother Oncol 102:335-42, 2012 8. Peulen H, Mantel F, Guckenberger M, et al: Validation of High-Risk Computed Tomography Features for Detection of Local Recurrence After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys 96:134-41, 2016

Abstract:
This session will focus on the use of proton beam radiation therapy for lung cancer. We will review the basic physics of proton beam therapy, why protons are different from photon-based radiation therapy, and the potential advantages of using proton beam therapy to treat lung cancer. We will review the current data about the use of protons, both published and unpublished, and provide updates about ongoing clinical trials testing proton therapy in lung cancer patients.

Abstract:
Introduction Approximately 65 particle therapy facilities are in operation worldwide. Among them, only 10 have carbon-ion therapy (CIRT) facilities (5 in Japan, 2 in Germany, 2 in China, and 1 in Italy), and the remainder have proton therapy facilities. More than 137,000 patients were treated with particle therapy worldwide from 1954 to 2014, including 15,000 in 2014, 86% of which were treated with protons and 14% with carbon ions and other particles. (from the Particle Therapy Co-Operative Group: http://www.ptcog.ch/). The National Institute of Radiological Sciences (NIRS) Chiba, Japan, has been treating cancer with high-energy carbon ions since 1994. Most of the patients who have been cured of cancer worldwide with carbon ions were treated at NIRS (1). From NIRS’s data, the efficacy of CIRT for non-small cell lung cancer (NSCLC) has been suggested. Here those results are reviewed, and the issue of this modern technology is discussed. Characteristics of carbon-ion therapy CIRT has better dose distribution to tumor tissue, while minimizing surrounding normal tissue dose, compared with photon radiotherapy. Moreover, carbon ions have potential advantages over protons. They provide a better physical dose distribution due to lessened lateral scattering. Further, their higher relative biological effectiveness and lower oxygen enhancement ratio are desirable features for targeting radioresistant, hypoxic tumors. The difference between densely ionizing nuclei and sparsely ionising x-rays and protons offers further potential radiobiological advantages, such as reduced repair capacity, decreased cell-cycle dependence, and possibly stronger immunological responses. Carbon-ion therapy of early non-small cell lung cancer Surgical resection with lobectomy has been the standard treatment of choice for early-stage NSCLC. In a 2004 study of a Japanese lung cancer registry comprising 11,663 surgical cases, overall survival (OS) rates at 5 years for stages IA and IB disease are 82.0% and 66.8%, respectively (2). Radiotherapy is an option for patients who are not eligible for surgery or refuse it. Recently, hypofractionated radiotherapy is regarded as an alternative to surgery for localized NSCLC, using x-ray stereotactic body radiotherapy (SBRT) or particle therapy using protons or carbon-ions. With regard to CIRT, for peripheral stage I NSCLC, the number of fractions was reduced in different trials from 18 to 9, then 4, and finally to a single fraction at NIRS (Table 1). The results with CIRT in stage IA NSCLC are similar to the best SBRT results reported worldwide. For stage IB disease, CIRT results appear superior to those reported for photon SBRT in terms of local control and lung toxicity. Despite high local control, disease-specific survival is much lower in stage IB than in stage IA because distant metastatic recurrences are common. A combination of CIRT with systemic therapy is therefore essential to improve survival. CIRT demonstrates a better dose distribution than both SBRT and proton therapy in most cases of early-stage lung cancer. Therefore, CIRT may be safer for patients with adverse conditions such as large tumors, central tumors, and poor pulmonary function. Multi-institutional retrospective study of CIRT for stage I NSCLC was completed and will be presented at ASTRO 2016 by the Japan Carbon-ion Radiation Oncology Study Group (J-CROS). Carbon-ion therapy of locally advanced non-small cell lung cancer There was only one report about CIRT for locally advanced NSCLC. A prospective nonrandomized phase I/II study of CIRT in a favorable subset of locally advanced NSCLC was reported from NIRS (9). They showed that short-course carbon-ion monotherapy (72GyE/16Fr) was associated with manageable toxicity and encouraging local control rates. Among them, cT3-4N0M0 patients were good candidates for CIRT. There is otherwise a lack of evidence currently for CIRT for locally advanced NSCLC, and more study is needed. Moreover, concurrent systemic therapy is essential to improve survival for locally advanced NSCLC. Future directions We organized a multi-institutional study group of carbon-ion radiation oncology in Japan (J-CROS). This group is currently conducting trials on several tumor sites which are thought to be most attractive for CIRT, including NSCLC, head and neck disease, locally advanced unresectable pancreatic cancer, hepatocellular carcinoma, locally recurrent rectal cancer, and others. The outcomes of CIRT for stage I NSCLC at all Japanese carbon centers were pooled and retrospectively analyzed. Consequently, CIRT may be considered a low-risk and effective treatment option for patients with stage I NSCLC. J-CROS has now begun a confirmatory multi-institutional prospective study to confirm these results. References: 1. Kamada T, Tsujii H, Blakely EA, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol 2015; 16: e93-100. 2. Sawabata N, Miyaoka E, Asamura H, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol 2011; 6: 1229-35. 3. Miyamoto T, Yamamoto N, Nishimura H, et al. Carbon ionradiotherapy for stage I non-small cell lung cancer. Radiother Oncol 2003; 66: 127-140. 4. Miyamoto T, Baba M, Yamamoto N, et al. Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen. Int J Radiation Oncol Biol Phys 2007; 67: 750-758. 5. Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol 2007; 10: 916-926. 6. Sugane T, Baba M, Imai R, et al. Carbon ion radiotherapy for elderly patients 80 years and older with stage I non-small cell lung cancer. Lung Cancer 2009; 64: 45-50. 7. Takahashi W, Nakajima M, Yamamoto N, et al. Carbon ion radiotherapy in a hypofractionation regimen for stage I non-small-cell lung cancer. J Radiat Res 2014; 55(suppl 1): i26–i27. 8. Karube M, Yamamoto N, Nakajima M, et al. Single-fraction carbon-ion radiation therapy for patients 80 years of age and older with stage I non-small cell lung cancer. Int J Radiation Oncol Biol Phys 2016; 95: 542-548. 9. Takahashi W, Nakajima M, Yamamoto N, and et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC). Cancer 2015; 121: 1321-7.

Ref.	Pts.	Mean age	T1: T2	Total dose (GyRBE)/ fractions	F/U (months)	5-yr local control	5-yr cause-specific survival	5-yr overall survival	Toxicity grade 3 <
3)	81	72	41: 41	59.4-95.4/ 9-18	52.6	76%	60%	42%	lung 3.7%
4)	50	74.1	30: 21	72/ 9	59.2	94.7%	75.7%	50.0%	skin 2%
5)	79	74.8	42: 37	52.8-60/ 4	38.6	90%	68%	45%	0%
6)	28	82	12: 17	52.8-72/ 4-9	NA	95.8%	NA	30.7%	0%
7)	151	73.9	91: 60	36-50/ 1	45.6	79.2%	NA	55.1%	0%
8)	70	83	39: 31	28-50/ 1	42.7	85.8%	64.9%	39.7%	0%

Abstract not provided

Abstract not provided