Virtual Library

Background:
Anti-PD1-monotherapy has activity in NSCLC with improved outcomes compared to chemotherapy. Preclinical, and early clinical data, suggests that combining immune checkpoint inhibitors and platinum-based chemotherapy may be synergistic. We examined the cohort of patients (pts) with metastatic NSCLC, with no prior therapy for advanced disease, from this multicentre phase Ib trial. The primary objective was to establish the recommend phase II doses of durvalumab (Du) ± tremelimumab (Tr) in combination with platinum-doublet chemotherapy. Secondary objectives included assessing safety, tolerability, and antitumour activity of the 4-drug combination.

Method:
Pts were treated with Du±Tr at one of 4 dose levels (DL) concomitantly with either pemetrexed (Pem) +cisplatin/carboplatin followed by maintenance Pem for nonsquamous histology or gemcitabine (Gem) +cisplatin/carboplatin for squamous tumours. At DL0 Du 15 mg/kg IV q3wks was added; 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), DL3 and DL4 added a fixed doses of Du 1125mg/Tr 56 mg and Du 1500 mg/ Tr 75 mg q3wk respectively. Du could continue until 1 year or unacceptable toxicity.

Result:
To date, 45 pts (median age=62 (range 36-78); 44% male, 100% ECOG PS≤1) have received 346 cycles in the Pem-platinum cohort while 9 pts (median age=64 (range 57-80); 78% male, 100% ECOG PS≤1) have been received 55 cycles in the Gem-platinum group. Most adverse events were ≤grade 2 and attributed to chemotherapy. Immunotherapy-related adverse events (irAEs) ≥ grade 3 were observed in 27% of patients and were more commonly reported with the addition of Tr. In the Pem-platinum cohort, diarrhea (n=5), fatigue (n=4) and elevated lipase (n=4) were the most come irAEs ≥ grade 3, while rash, pneumonitis and hypothyroidism occurred in 1 pt each after the introduction of Tr. In the Gem-platinum cohort, irAEs ≥ grade 3 were fatigue and rash (1 pt each at DL2b) and elevated lipase (1 pt at DL3). The objective response rate in 35 evaluable patients receiving Pem-platinum was 57.1% (95% CI=39.4, 73.7 ) and 37.5% (95% CI=8.5, 75.5) in the 8 evaluable patients receiving Gem-Platinum.

Conclusion:
The combination of Du±Tr can be safely administered with platinum-doublet chemotherapy with encouraging preliminary response data. Adding Tr may increase ≥ grade 3 irAE hence patient selection and early intervention is key to managing irAEs. *contributed equally

Background:
Chemotherapy may enhance immunotherapeutic effects by causing tumor antigen release, which primes the immune system to kill tumor cells. Early clinical data on nab-paclitaxel + carboplatin in combination with immune checkpoint inhibitors (ICI) demonstrated promising activity without compounding toxicities in patients with non-small cell lung cancer (NSCLC). ABOUND.2L+ evaluated nab-paclitaxel–based regimens in previously treated patients with advanced NSCLC. Here we report the efficacy and safety of nab-paclitaxel + durvalumab as second/third-line treatment.

Method:
Patients with advanced NSCLC were assigned to receive second/third-line (immunotherapy allowed in prior line, including platinum doublet combination) nab-paclitaxel 100 mg/m[2] on days 1 and 8 + durvalumab 1125 mg on day 15, in 21-day cycles, administered until unacceptable toxicity/progression per immune-related RECIST v1.1. Primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety.

Result:
Seventy-nine patients were enrolled. Median age was 63 years, 68% of patients were male, 23% had Eastern Cooperative Oncology Group performance status of 0, and 70% had nonsquamous NSCLC; 11% of patients received prior ICIs. Median PFS (Table) and OS were 4.5 (3.4-5.8) months and NE (7.3-NE). ORR was 27% (1 complete response) and DCR was 71%. Grade 3/4 treatment-emergent adverse events of special interest occurring in ≥ 5% of patients included neutropenia (6%) and dyspnea (5%); grade 3/4 peripheral neuropathy and anemia each occurred in 4% of patients. Median treatment duration was 24 weeks; median number of treatment cycles was 7. For nab-paclitaxel and durvalumab, median dose intensities were 59.05 mg/m[2]/week and 326.61 mg/week, respectively; median percentages of per-protocol dose were 88.58% and 87.10%.

Conclusion:
The combination of durvalumab with nab-paclitaxel demonstrated antitumor activity with manageable toxicity in the second/third-line setting. Further details will be presented. NCT02250326

Nab-P Durva	Median PFS (range), months
Overall (n = 79)	4.5 (3.4-5.8)
ICI pretreated (n = 9)[a] ICI naive (n = 69)[a]	6.9 (1.4-NE) 4.4 (3.0-5.7)
Squamous (n = 23)[a] Nonsquamous (n = 55)[a]	5.9 (3.0-7.8) 4.2 (2.9-5.7)
ICI, immune checkpoint inhibitor; NE, not estimable; PFS, progression-free survival. [a] Data pending for 1 patient.

Background:
Atezolizumab (anti–PD-L1) has demonstrated OS benefit over docetaxel in a randomized Phase II study, POPLAR, in patients with advanced NSCLC. This benefit has been confirmed in the randomized Phase III study OAK (Rittmeyer, 2017). The 3-year survival analysis of the POPLAR study presented here describes the longest survival follow-up reported to date of an all-comer randomized PD-L1/PD-1 immunotherapy trial in 2L+ NSCLC.

Method:
Patients were randomized 1:1 to receive atezolizumab (1200 mg) or docetaxel (75 mg/m[2]) IV q3w. Tumors were prospectively evaluated for tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression using the VENTANA SP142 IHC assay. Landmark OS was estimated using the Kaplan-Meier method. Data cutoff, April 7, 2017; minimum follow-up, 3 years.

Result:
The 2-year and 3-year survival with atezolizumab vs docetaxel were 32.2% vs 16.6% and 18.7% vs 10.0%, respectively. The long-term OS benefit of atezolizumab vs docetaxel was observed across histology and PD-L1 expression subgroups (Table). While the TC3 or IC3 subgroup derived the greatest OS benefit, the TC0 and IC0 subgroup also had improved long-term OS with atezolizumab vs docetaxel. The ITT ORR was 15% in both atezolizumab and docetaxel arms, but the median duration of response was 3 times longer with atezolizumab (22.3 months [95% CI: 11.6, 31.1] vs 7.2 months [95% CI: 5.8, 12.2] with docetaxel). Seven of the 11 docetaxel-arm 3-year survivors received subsequent non-protocol therapy with anti–PD-L1/PD-1 agents. Atezolizumab had a favorable safety profile compared with docetaxel that was consistent with previous reports.

Conclusion:
Atezolizumab demonstrates superior 2-year and 3-year OS benefit compared with docetaxel, and this benefit is observed across histology and PD-L1 expression subgroups (including TC0 and IC0). Atezolizumab is well tolerated, and responses are highly durable. These results are consistent with long-term OS results from OAK, presented separately.

Table. Landmark OS in the ITT, PD-L1 expression, and histology subgroups in POPLAR
Population (n, atezolizumab vs docetaxel)	2-year OS rate, %			3-year OS rate, %
	Atezolizumab	Docetaxel	P value[a]	Atezolizumab	Docetaxel	P value[a]
ITT (144 vs 143)	32.2%	16.6%	0.0027	18.7%	10.0%	0.0419
PD-L1 Expression Subgroups
TC3 or IC3 (24 vs 23)	41.7%	19.9%	0.1003	37.5%	14.9%	0.0724
TC2/3 or IC2/3 (50 vs 55)	36.1%	13.8%	0.0082	21.2%	9.9%	0.1166
TC1/2/3 or IC1/2/3 (93 vs 102)	36.0%	19.8%	0.0124	18.0%	11.0%	0.1759
TC0 and IC0 (51 vs 41)	25.0%	6.8%	0.0202	20.5%	6.8%	0.0693
Histology Subgroups
Non-squamous (95 vs 95)	32.2%	21.1%	0.0960	23.3%	12.4%	0.0585
Squamous (49 vs 48)	32.7%	7.8%	0.0020	9.4%	5.2%	0.4603
[a ]For descriptive purpose only. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC2/3 or IC2/3 = PD-L1 ≥ 5% TC or IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT01903993.

Abstract not provided

Background:
Bavituximab targets exposed phosphatidylserine (PS) in the tumor microenvironment, resulting in repolarization of myeloid suppressor cells/M2 macrophages to M1, production of pro-inflammatory cytokines such as IFNγ and IL-12, dendritic cell maturation, and tumor specific cytotoxic T-cell activation. SUNRISE was a Phase III trial of docetaxel with bavituximab (D+B) or placebo (D+P) in patients with treated Stage IIIb/IV non-squamous NSCLC. Recent correlative analyses from SUNRISE suggest bavituximab is more active in PD-L1 negative, immune cold tumors and thus may complement PD-1/PD-L1 ICI.

Method:
This subgroup analysis included all patients who received subsequent ICI after discontinuing SUNRISE study drug. We calculated overall survival (OS) both from randomization and start of subsequent ICI.

Result:
Ninety-three of 597 randomized patients (16%) received ICI as next line of therapy after SUNRISE assigned treatment. Baseline characteristics were balanced between the treatment groups and consistent with the ITT population. From randomization, mOS was not reached (95% confidence interval [CI], 15.2-NA) in D+B (N=46) and 12.6 months (95% CI, 10.4-17.8) in D+P (N=47) (hazard ratio [HR], 0.46; P=0.006) (Figure). From start of ICI, mOS was not reached (95% CI, 10.2-NA) in D+B and 6.2 months (95% CI, 3.9-8.7) in D+P (HR, 0.42; P=0.002). The mPFS was 6.0 months (95% CI, 3.5-6.5) in D+B and 4.4 months (95% CI, 2.6-6.3) in D+P (HR, 1.00; P=0.991). ORR was 20% vs. 13% (Odds ratio 0.6; P=0.41) for D+B and D+P, respectively. The safety profile was similar between groups and no immune related (IR) toxicities (colitis, pneumonitis, hypothyroidism) were reported.

Conclusion:
Within the limits of a subgroup analysis, a significant improvement in OS was observed for patients previously treated with D+B. Furthermore, bavituximab has not been associated with IR toxicities and might serve as a useful drug in combination with ICI for the treatment of immune cold tumors. Figure 1

Background:
Nivolumab monotherapy has shown survival benefit in patients (pts) with different tumors, including melanoma, lung cancer, renal cell carcinoma, head and neck cancer and Hodgkin lymphoma. Controlled clinical trial setting differs from what experienced by pts and physicians in routine clinical practice. Here, we report efficacy and safety results of nivolumab in pts with non-squamous non-small cell lung cancer (Non-Sq-NSCLC) treated in the Expanded Access Programme in Italy.

Method:
Nivolumab was available upon physician request for pts aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV non-Squamous NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks to a maximum of 24 months. Pts included in the analysis had received at least one dose of nivolumab and were monitored for adverse events (AE) using Common Terminology Criteria for Adverse Events.

Result:
Overall, 1588 pts were enrolled in the EAP across 168 Italian centers. Baseline characteristics of pts were representative of Non-Sq-NSCLC population, in the advanced disease setting. As of March 2017, median overall survival (OS) was 11 months (10.0-12.0), with a median follow-up of 7.8 months (1-21.9) and a median of 7 doses (1-46). The best overall response rate (BORR) was 18%, including 10 pts (<1%) with complete response and 280 pts (17.6%) with partial response. Stable disease has been defined for 414 pts (26.0%) and totally 274 (17.2%) patients were treated beyond progression. Response rates and survival were comparable among pts regardless age (< and ≥ 75 years), presence of brain metastasis and number of prior therapies. Overall, among 1588 pts, 1254 discontinued treatment for any reason, with only 93 (7%) pts who discontinued treatment due to adverse events, in line with what observed in previous studies.

Conclusion:
To date, this is the largest clinical experience with nivolumab in a real-world setting and these EAP data are in line with what reported in the registrative phase 3 clinical trial. According to these results, nivolumab seems to be an effective and safe therapy for pre-treated patients with non-squamous NCSLC, supporting its use in current clinical practice.

Background:
Immunotherapy is revolutionising the way many cancer types are treated. The immunosenescence and the high heterogeneity of the elderly raises questions on the benefits with such treatments and real-world data is lacking.

Method:
ELDERS is a prospective, observational pilot study on the use of checkpoint inhibitors in patients with advanced/metastatic non-small cell lung cancer (NSCLC) or malignant melanoma. The study was designed with 2 arms, the elderly (≥ 70 years) and the non-elderly (45-69 years) with 2 co-primary endpoints, immune-related toxicity (irAE) profile and health-related quality of life (HRQoL) through the EORTC QLQ-C30. A comorbidity score (CIRS) was applied at baseline (score 0-56) and serial geriatric assessments were performed for stratification with a screening tool (G8) and further geriatric assessment as needed. A total of 110 patients of a planned 120 have been recruited. This interim analysis is of the NSCLC cohort with a minimum of 3 months on study/follow-up.

Result:
32 patients were included, with 96% treated with pembrolizumab (9% first-line) and 40.6% enrolled on the elderly arm. In both arms, 45% had a tumour PD-L1 expression of ≥50%. The elderly arm had more advanced disease with 69% staged M1b vs. 42.1% in younger arm (p=0.05). 69% of patients, in both arms, were performance status 0/1 at the start of treatment. The median CIRS total score was 12 for the elderly and 7 for the younger arm. 46% of elderly patients had an abnormal geriatric screening (G8≤14), requiring further assessments. With a median follow-up of 6 months, the objective response rate (ORR) was overall 19% with a median time to response of 8 weeks. The ORR was numerically higher in the elderly with 30.8% vs. 10.5% (p=0.09). 9.4% of patients on study had a grade 3/4 irAE, with no difference between study arms. Elderly patients had a numerically higher rate of admissions, 53.8% vs. 36.8% (p=0.18). No statistically significant correlation was identified between higher comorbidity score or abnormal geriatric assessment and the incidence of irAEs. No significant negative impact on the global HRQoL was detected in either arm during treatment with immunotherapy.

Conclusion:
Despite the small number of patients and the limited follow-up time, there is no signal in this interim analysis to indicate that elderly patients have less benefit or higher risk of irAE compared with younger patients, despite more comorbidities and geriatric syndromes. These results help to inform clinical practice in the absence of trials dedicated to the elderly population.

Abstract not provided

Background:
T follicular helper cells (Tfh) are an antigen-experienced CD4+ T cell subset that have been found to play crucial roles in the development of humoral immunity. In particular, their presence in the B cell-rich germinal centre of secondary and tertiary lymphoid tissue aids in B cell maturation through selection of B cells producing high-affinity antibodies. Tfh cells have known roles in autoimmune disease and B cell malignancies; however, their role in many solid tumours, including those of the lung, remains unclear.

Method:
We analyzed 83 paired tumour-normal lung adenocarcinoma samples from the BC Cancer Agency (BCCA) as well as 576 unpaired samples from The Cancer Genome Atlas (TCGA). Relative immune cell content was obtained from gene expression data using a linear support vector regression deconvolution approach (CIBERSORT). Spatial positioning of B and T cells within selected tumour sections was examined through IHC. The impact of Tfh infiltration on patient survival was analyzed using a Cox Proportional Hazard model.

Result:
T follicular helper cells are increased in tumour tissue, accompanied by global upregulation of Tfh markers PDL1 and CXCR5 in both the BCCA and TCGA cohorts. Histological analysis revealed localization of Tfh cells within tertiary lymphoid organs, with direct contact with B cells in the follicular zone observed. Importantly, Tfh recruitment appears to be an early event in tumour development and a function of neoantigen exposure, indicative of an active anti-tumour response rather than a result of chronic inflammation of the tumour microenvironment.

Conclusion:
T follicular helper cells are required for B cell maturation and subsequent antibody responses. As such, it is not surprising that Tfh infiltration in tumour-resident ectopic lymphoid structures correlates with patient survival in various cancer types. Given the importance of tumour-specific antibody responses in natural and therapeutic immunity, further investigation of Tfhs may show prognostic utility and be a marker of early-stage lung tumours.​

Background:
There is growing appreciation for the role of tumor-draining lymph nodes (TDLN) in the dynamic of immunoediting orchestrated by non-small cell lung cancers (NSCLC). By comparing T-cell subsets and gene expression in TDLN and non-draining lymph nodes (NDLN), we aim to determine whether there is tumor-regional variation in immunophenotype.

Method:
Patients undergoing endobronchial ultrasound-guided transbronchial needle aspiration for the diagnosis/staging of NSCLC were recruited. Aspirates were obtained from TDLN (N1/N2 nodes with increased fluorodeoxyglucose-F-18 (FDG) avidity and/or enlarged >1cm) and NDLN (non-enlarged/non-FDG-avid N2/N3 nodes) along with peripheral blood. Samples were stained with fluorophore-conjugated antibodies (CD4-FITC, CD8-V450, CD25-PECy7, CD127-APCR700, CD45RO-PECF594) and analyzed by flow cytometry. CD4+CD25- and CD8+ effector T-cells (Teff) were sorted. Gene expression profiling was performed on sorted Teff using the Nanostring™ platform to measure differential expression between TDLN and NDLNs.

Result:
We compared T-cell subpopulations in TDLN and paired NDLN from 16 subjects. There were significantly fewer CD4+ T-cells in TDLN vs NDLN (10.1% vs 28.9%, p=0.0039), with more Tregs (12.1% vs 7.3%, p=0.1563) suggesting a pattern of tumor-regional immunosuppression in the TDLN. This was more consistent when tumor histology was adenocarcinoma compared to squamous cell cancer with respect to both depletion of Teff and higher proportion of Tregs (Figure 1). A more immunosuppressive TDLN phenotype was also observed with high tumor PD-L1 expression (>50%), with 36% fewer CD4+ T-cells in TDLN relative to paired NDLN when PD-L1 expression was high relative to just 3.2% fewer CD4+ T-cells with low PD-L1 expression. Gene expression in Teff has preliminarily demonstrated upregulation of genes mediating T-cell exhaustion (CTLA-4, PD-1, TGF-β) and downregulation of co-stimulatory/recruitment factors (CD28, ICOS, ICAM2) in TDLN suggesting impaired activation of tumor-regional Teff. Figure 1



Conclusion:
Our findings suggest that TDLNs in patients with NSCLC display a tolerogenic phenotype, with more marked immunosuppression in the setting of adenocarcinoma and high tumor PD-L1 expression.

Background:
Using Tumor Growth Rate (TGR), HPD was identified in 9% of 131 advanced cancer pts, treated with IO in a single institution (Champiat et al. 2017). In this study, we explored HPD in a large, multicenter cohort of advanced NSCLC pts treated with IO.

Method:
We performed a retrospective analysis of consecutive NSCLC pts treated with IO, in 8 institutions, between November 2012 and April 2017. Eligibility criteria required, for each patient: 2 CT scans performed before starting IO and one during IO, an interval between two CT scans ≥2 weeks or 3 months (m) and presence of target lesions. CT scans were centrally assessed according to RECIST 1.1 criteria. We calculated TGR before IO (TGR pre-IO) and during IO (TGR IO); patients were defined HPD if they had progression disease (PD) at first evaluation during IO and a ≥ 2-fold increase in the TGR IO compared to TGR pre-IO. Median overall survival (mOS) was estimated using Kaplan-Meier method for the total population and HPD pts.

Result:
Among 419 eligible pts, 86 were excluded for inadequate intervals between CT scans. Among 333 evaluable pts, 63% were male, 46% ≥65 years, 43% smokers; 12% had PS ≥ 2, 65% adenocarcinoma, 45% ≥3 metastatic sites, 22% KRAS mutation, 4% EGFR mutation, 1% ALK rearrangement; 21% had PD-L1 positive status, 10% negative, 69% unknown, >90% received single agent PD-1 inhibitor in ≥ 2 line. Response rate (RR) to IO was 18%, median follow up was 12 m [10-14]. 33% of pts had TGR IO ≥1 (not regressing tumors), 25% had TGR IO ≥ 2-fold TGR pre-IO and 54 pts (16%) had HPD. 15 pts (4%) had confirmed pseudoprogression, 3 were initially qualified as HPD. Compared to not-HPD, HPD pts had more frequently ≥ 3 metastatic sites at baseline (59% vs 43% p=0,02) and more new lung lesions during IO (34% vs 17% p=0,007). PD-L1 negative status was more common among HPD pts but the association was borderline significant (53% vs 28% p=0,05). Age, clinical, molecular characteristics, RR to treatment before IO, baseline tumor burden, liver or brain new lesions during IO were not different according to HPD status. mOS was 13 m [10-17] in the total population, 5 m [3-8] in HPD pts.

Conclusion:
HPD occurred in 16% of advanced NSCLC pts treated with IO and was associated with plurimetastatic disease and appearance of new lung lesions. Further work is needed to characterize HPD prognostic value.

Abstract not provided

Background:
Circulating tumor DNA (ctDNA) has been shown beneficial in monitoring EGFR mutations in blood, especially for the detection of resistance mutations, like T790M in NSCLC patients. However, the role of BRAF (V600E) ctDNA for monitoring the patient’s response has not been studied yet. The aim of this study was to determine the clinical relevance of BRAF (V600E) ctDNA for monitoring the response to BRAF inhibitors in a prospective cohort of advanced NSCLC BRAF (V600E) patients.

Method:
We prospectively enrolled advanced NSCLC patients with BRAF (V600E) treated with BRAF +/- MEK inhibitors in our institution. A blood sample was collected at different time points, including at baseline, during treatment and at progressive disease. ctDNA BRAF analysis was performed using the Inivata InVision platform (enhanced tagged-amplicon next-generation sequencing (eTAM-Seq).

Result:
Between June 2016 and June 2017, 14 patients have been included. Eight patients (57%) were females, 9 (64%) non-smokers, with a median age of 63 years (35-70). All the patients had adenocarcinoma and BRAF (V600E) mutation in tissue analysis. Thirteen patients (93%) had stage IV at diagnosis, 7 patients (50%) with bone, 6 (43%) pleural and 4 (29%) lung metastasis. The median of lines of treatment received was 2 (1-4). Thirteen patients (93%) received BRAF + MEK inhibitor and 1 patient (14%) BRAF inhibitor, with an objective response rate of 64% (1 complete, 8 partial response) and disease control rate of 86%. BRAF mutation detection was tested under treatment in 12 patients (86%). Longitudinal analysis was performed from the serial sampling in 6 patients to date: 4 patients (67%) were ctDNA positive for BRAF (V600E) at time of progression, with a range of allelic frequency of 0.11-6.16%. BRAF mutation was not detectable in patients with objective response (2/6, 33%) at time of sample collection(s). Additional BRAF (V600E) NSCLC patient samples are being analyzed.

Conclusion:
Liquid biopsy for monitoring BRAF (V600E) using ctDNA appears to be feasible and useful in advanced NSCLC patients. Updated longitudinal results for the complete patient cohort will be presented at the meeting.

Background:
To improve treatment selection and outcomes for patients with early stage non-small cell lung cancer (NSCLC) the development of an effective biomarker to diagnose and characterise the tumour and to detect residual disease after curative-intent treatment is crucial. Circulating tumour DNA (ctDNA) is a promising means to detect and track tumours non-invasively, as the genomic alterations in plasma are representative of the tumour’s clonal populations and their levels correlate with the burden of disease. Furthermore, ctDNA has shown promise for detecting minimal residual disease after treatment in several cancer types. This could help in the selection of patients that, after surgery or radical radiotherapy, will benefit from subsequent treatment. Nonetheless, more sensitive techniques are needed to enable the detection and study of ctDNA at very low concentrations in settings such as these.

Method:
The LUCID study (early stages of non-small cell LUng cancer - CIrculating tumour DNA) was designed to prospectively collect plasma samples from patients with early-stage NSCLC before and after treatment with surgery or radiotherapy (±chemotherapy), and during a minimum follow up of 3 years after diagnosis, in order to explore the clinical utility of ctDNA. For high sensitivity detection of ctDNA, TAilored Panel Sequencing (TAPAS) was developed: exome sequencing of tumour tissue enables the creation of patient-specific panels to analyse in parallel, large numbers of mutations with high sequencing depth. Plasma samples are being analysed using this approach to assess the levels of ctDNA at diagnosis and after radical treatment.

Result:
100 patients were recruited to the study. Longitudinal plasma sample collection and analysis are on-going. Preliminary analysis of the tumour tissue and pre-surgical plasma samples from 19 surgical patients show that most patients with early-stage NSCLC have detectable ctDNA. Analysis of additional samples will be presented.

Conclusion:
Preliminary data from LUCID suggest that the methods we have developed have high sensitivity and will allow detection of ctDNA at rates higher than previously reported. These methods will enable the study of ctDNA in early-stage cancers. We are also exploring the utility of these techniques for detection of minimal residual disease after radical treatment, as a potential tool to guide adjuvant or subsequent post-radiotherapy treatment.

Background:
EGFR mutations in plasma circulating free tumor-derived DNA (ctDNA) as a predictor of EGFR TKI efficacy in patients with NSCLC requires validation in prospective studies. The large, prospective Phase II, single-arm, multicenter BENEFIT study (CTONG1405; NCT02282267) validated the efficacy of first-line gefitinib in EGFR mutation-positive NSCLC detected in plasma ctDNA using droplet digital PCR (ddPCR).

Method:
Patients with stage IV lung adenocarcinoma and plasma ctDNA EGFR-sensitizing mutations (exon 19 del or exon 21 L858R; by ddPCR) received first-line gefitinib (250 mg once-daily) until progressive disease (PD). Blood samples were collected every 8 weeks for dynamic EGFR analysis until PD. Primary endpoint was ORR. Secondary endpoints included PFS, DCR (Week 8), and analysis of baseline ctDNA samples by next-generation sequencing (NGS).

Result:
From December 2014-January 2016, 426 patients from 15 Chinese centers were screened: 391 had matched tissue and blood samples; 188 had ctDNA EGFR mutation-positive NSCLC and received gefitinib; and 183 had ≥1 post-baseline tumor assessment and plasma samples every 8 weeks until PD. At data cutoff (January 31, 2017), 152 patients had progressed. ORR was 72.1% (95% CI 65.0%,78.5%); DCR (Week 8) was 92.3% (95% CI 87.5%,95.8%); and median PFS was 9.5 months (95% CI 9.07,11.04). PFS was significantly shorter in the subgroup with baseline ctDNA de novo T790M mutations (5.0%, n=9) versus the EGFR-sensitizing mutations subgroup (5.6 vs 9.6 months, HR=2.60; 95% CI 1.32,5.12, p=0.004). In patients with Week 8 on-treatment plasma samples (n=167), the subgroup who showed EGFR mutation clearance in ctDNA by ddPCR (88%, 147/167) had longer PFS compared with those who did not (11.0 vs 2.1 months, HR=7.28; 95% CI 4.35,12.18, p<0.0001). The median time to emergence of acquired T790M mutation in plasma was 7.6 months. The T790M-positive rate increased from Week 24 (15.7%) to Week 48 (32.6%), with a corresponding increase in PD rate (24.7% at Week 24, 56.9% at Week 48). Among 180 patients with baseline NGS data, 21 (11.7%) harbored aberrations in additional oncogenic drivers (MET, ERBB2, KRAS, BRAF, RET, or ROS1) and tumor suppressors (TP53, RB1, and PTEN). This subgroup had worse PFS versus those with EGFR-sensitizing mutations alone (3.9 vs 13.0 months, HR=2.83; 95% CI 1.65,4.87, p=0.00016).

Conclusion:
The BENEFIT study prospectively demonstrated that ctDNA-based EGFR mutation detection can be used to select patients for treatment with first-line gefitinib. Dynamic alterations in EGFR mutations could be used to predict efficacy and disease progression, ahead of radiological results.

Abstract not provided

Background:
Highly diverse somatic splice site alteration at MET exon 14 (METex14) result in exon skipping, which is supposed to be a therapeutic target in NSCLC. Here we report detection of METex14 alterations using targeted DNA- and RNA-based Next-Generation Sequencing (NGS) in pulmonary sarcomatoid carcinoma (PSC) with a high frequency of METex14 skipping.

Method:
Tumor specimens were collected from 77 Chinese PSC patients. DNA and RNA were subject to targeted NGS, allowing the detection of somatic splice site alterations and intragenic METex14 skipping respectively. Then, somatic mutations (mutation allele frequency ≥2%) that lead to METex14 skipping were recognized, and Fisher’s exact test was used to examine the association between METex14 skipping and clinical characteristics or other mutations. Two-sided P-values <0.05 were considered statistically significant. Moreover, RT-PCR and Sanger sequencing was also performed on the METex14-positive specimens.

Result:
We have detected genetic aberrations in 77 FFPE samples. For RNA-based NGS, METex14 skipping was identified in 16 (20.78%) of 77 patient cases. And 15 (93.75%) METex14-positive patients were detected somatic mutations by DNA-based NGS, including 12 (80%) cases with splice donor site mutations, 1 (6.67%) cases with splice acceptor site alterations, 1 (6.67%) case with a novel deletion (chr7: 116411868 - 116411883) at MET intron 13 region and 1 (6.67%) case with a novel deletion (chr7: 116412027 - 116412042) at MET exon14 region. In this study, 6 somatic mutations which induce METex14 skipping were firstly discovered. So far, RT-PCR and Sanger sequencing were performed on 3 specimens, including 1 sample with conflicting RNA- and DNA-based NGS results and 2 samples with unreported somatic deletions. According to the results of RT-PCR and Sanger, the unmatched sample was false negative on the basis of DNA-based NGS result. Interestingly, METex14 skipping was mutually exclusive with other recognized genomic alterations (such as mutations in KRAS, BRAF, EGFR, NRAS and PIK3CA), while no significant difference was found between METex14 skipping and single driver gene.

Conclusion:
Mutational events of MET leading to exon 14 skipping are frequent occurred in Chinese PSC patients. DNA-based NGS could discover new somatic mutations which results in METex14 skipping. However, RNA-based NGS could provide more accurate results than DNA-based NGS. METex14 skipping was mutually exclusive with other drivers, thus strongly highlighting its potential oncogenic role.

Background:
Clinical practice guidelines recommend genetic testing for advanced non-small cell lung cancer (aNSCLC) to guide 1[st]-line treatment. Small biopsies and low-tumor-content samples pose challenges to testing and reporting on an increasing number of relevant biomarkers. This study compared clinical aNSCLC biomarker testing to investigational use of the Oncomine™ Dx Target Test for different sample types.

Method:
A retrospective analysis was conducted using lung tissue testing data from a large, US-based commercial laboratory that offered single-gene tests (EGFR therascreen, ALK Vysis, BRAF cobas, and laboratory developed tests [LDT] for ROS1, HER2, BRAF, KRAS, MET, RET, and FGFR1) and a 173-gene next-generation sequencing (NGS) LDT panel (Illumina NextSeq 500). Clinical test orders received September 2015 – October 2016 were evaluated. This laboratory also conducted investigational testing on the Oncomine™ Dx Target Test (Ion Torrent PGM Dx) using archival tissue. Testing success rates and slide consumption were evaluated for core needle biopsies (CNBs; overall and by tumor content), fine needle aspirations (FNAs), and surgical resections.

Result:
Clinical testing orders were received on 1,029 CNBs, 144 FNAs, and 181 surgical resections. Among CNBs, 934 had tumor content data: 214 were 1-24% tumor; 720 were ≥25% tumor. Altogether, 3,571 single-gene tests and 198 NGS LDT panels were ordered. The Oncomine™ Dx Target Test was conducted on 169 archival samples: 69 CNBs (41 were 1-24% tumor; 28 were ≥25% tumor); 13 FNAs; 87 surgical resections.

Sample characteristics	Single-gene tests per clinical sample (N)*							173-gene NGS LDT (N)	Oncomine™ Dx Target Test (N)
	1	2	3	4	5	6	7
N samples	1,295	1,039	633	191	114	98	28	198	169
% samples able to successfully generate results for at least X tests, when ordered[†]
CNB[‡]	89.2% (988)	85.3% (788)	76.2% (495)	77.9% (154)	70.8% (96)	61.9% (84)	58.3% (24)	N/A[§]	75.4% (69)
• 1-24% tumor	95.7% (209)	87.1% (170)	70.0% (110)	70.8% (24)	62.5% (16)	60.0% (15)	N/A (4)		70.7% (41)
• ≥25% tumor	98.2% (685)	91.8% (570)	82.9% (362)	85.8% (120)	76.3% (76)	66.2% (65)	61.1% (18)		82.1% (28)
FNA	79.3% (140)	72.4% (116)	75.0% (60)	40.0% (10)	N/A (4)	N/A (4)	N/A (1)		69.2% (13)
Surgical resection	100% (167)	98.5% (135)	91.0% (78)	88.9% (27)	64.3% (14)	50.0% (10)	N/A (3)		98.9% (87)
Total number of slides used to initiate exactly X tests
CNB[‡]	2.6 (165)	4.1 (268)	5.5 (324)	8.7 (56)	8.5 (11)	11.8 (55)	16.8 (16)	16.5 (24)	1.0[¶]
• 1-24% tumor	2.7 (39)	4.8 (60)	5.9 (83)	9.5 (8)	9.0 (1)	12.3 (11)	18.3 (3)	18.7 (3)
• ≥25% tumor	2.6 (118)	3.9 (208)	5.4 (241)	8.7 (47)	8.4 (10)	11.7 (44)	16.5 (13)	16.1 (21)
FNA	2.4 (21)	4.3 (41)	6.1 (42)	9.8 (5)	N/A (0)	11.5 (2)	18.0 (1)	14.0 (2)
Surgical resection	1.8 (32)	4.5 (57)	5.4 (51)	9.5 (13)	11.0 (4)	16.3 (7)	14.0 (2)	8.2 (13)
* Excludes clinical samples on which the NGS LDT panel had been initiated. † Success rates were not evaluated if N<10. ‡ While all samples had tumor content >0%, exact percentages were missing for 94 CNBs, 28 FNAs, and 1 surgical resection. § Success rates not evaluated; nearly all NGS LDT panels were ordered on samples that also initiated single-gene tests, and tissue depletion prevented initiation of most of the ordered NGS LDT panels. ¶ All tests were conducted using 1 slide according to protocol.

Conclusion:
Among lung tissue samples submitted for clinical testing, 13.4% were surgical resections, 10.6% FNAs, and 76% CNBs. The Oncomine™ Dx Target Test had higher testing success rates using fewer slides than single-gene testing for ≥5 biomarkers on CNBs, ≥4 on FNAs, and ≥2 on surgical resections. These preliminary results suggest the Oncomine™ Dx Target Test may facilitate multiple-biomarker testing for more aNSCLC patients to support therapy decisions as more gene targets are identified.

Background:
Acquired epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) resistance is a major factor contributing to targeted therapy failure in EGFR mutant non-small cell lung cancer (NSCLC), among which T790M mutation accounts for 50-60%. Emerging evidence has shown that as mediators between cells, exosomes shed by drug resistant cancer cells have the ability to horizontally transfer drug resistant phenotype to drug sensitive cells, which has been described as an important mechanism of dissemination of drug resistance. However, whether exosomes derived from EGFR-TKIs resistant NSCLC cells harboring T790M mutation could transfer resistance to sensitive cells has not been understood and the potential mechanism also remains unknown.

Method:
Exosomes were isolated from supernatants of T790M mutant NSCLC cell line (H1975) and characterized by transmission electron microscopy, nanosight and western blot. Their potential roles in mediating gefitinib resistance in sensitive cell line (PC9) were investigated in vitro and in vivo. Cell viability and the effects of exosomes on downstream signaling pathways were analyzed by CCK-8 assays and western blot. The roles of exosomes in regulating gefitinib resistance in vivo were assessed by subcutaneous transplantation tumor model in athymic nude mice. Exosomes miRNA sequencing and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) were used for exploring the underlying mechanism.

Result:
Exosomes isolated from conditioned medium of NSCLC cell lines were cup-shaped membranous vesicles with a diameter of 30-100 nm and expressed the exosomal marker CD63. Exosomes derived from H1975 could transmit gefitinib resistance to PC9 (P＜0.01) in vitro while exosomes released from PC9 cell don’t have this effect. Treatment of PC9 with H1975-derived exosomes and the inhibitor of exosomes production (GW4869) could restore gefitinib response. In vivo, the tumor volume of xenograft model of PC9 cells treated with gefitinib plus H1975-derived exosomes was significantly larger than those mice treated with gefitinib alone (P＜0.05). Furthermore, H1975 xenografts could disseminate gefitinib resistance to PC9 xenografts in the same mice. This difference disappeared by the addition of GW4869. Mechanistically, intercellular transfer of microRNAs (miR-522-3p and miR-454-3p) by exosomes disseminated gefitinib resistance through activating PI3K/AKT and MEK/ERK signaling pathways

Conclusion:
Our findings demonstrate that EGFR-TKIs resistant cells could disseminate drug resistance to sensitive cells by intercellular transfer of exosome-transmitted microRNAs and then activating PI3K/AKT and MEK/ERK signaling pathways, which reveals a novel mechanism of acquired resistance to EGFR-TKIs in NSCLC.

Abstract not provided

Background:
After the introduction of third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in non-small cell lung cancer (NSCLC), the second tumor biopsy and EGFR mutation test to confirm T790M status is an established standard practice. But second biopsy is invasive, cost and time-consuming and occasionally impossible. We aimed to investigate the success rate of tissue rebiopsy and incidence of T790M mutation in tissue and plasma at the time of progression with earlier-generation EGFR TKIs in real world setting. Also, we studied the association between the efficacy of osimertinib and the status of tissue and/or plasma T790M mutation.

Method:
We analyzed patients who were screened and enrolled into ASTRIS trial in Yonsei Cancer Center (NCT02474355). Key inclusions were advanced/metastatic NSCLC with tissue and/or plasma T790M mutation and prior EGFR-TKI therapy. Tissue and plasma EGFR mutation tests were performed using PNAClamp[TM] and PANAMutyper[TM], respectively.

Result:
We screened 193 patients with NSCLC harboring EGFR-activating mutation who experienced disease progression upon earlier-generation EGFR TKIs during study period. The second biopsy including tissue and/or cytology was performed only in 60.1% of the patients (116/193) and the success rate was 86.2% (100/116). The reasons for not trying a biopsy were as follow: inaccessibility (n=25), poor PS (n=8), previously reported plasma T790M+ (n=8), and patients’ refusal (n=4). The parenchymal lung tissue (n=61) was most commonly targeted lesion and bronchoscopy was the most frequently used method (n=35). Six patients underwent video-assisted thoracoscopic surgery. Tumor T790M mutation was reported in only 25.9% of patients (50/193). Of 193 patients, 88 patients were enrolled into ASTRIS trial and 43 patients were registered based on the plasma test only. With a median follow-up of 25.1 weeks, the objective response rate (ORR), median progression-free survival (PFS), and duration of the response (DoR) were 44.3%, 32.7 weeks, and 27.0 weeks, respectively. Median overall survival (OS) was not reached. The ORR, median PFS and DoR of tumor T790M+ (n=45) vs. plasma T790M+ (n=54) were 57.8% vs. 35.2%, 45.0 vs. 20.4 weeks, and 26.3 vs. 25.9 weeks, respectively.

Conclusion:
With the increasing importance of tissue rebiopsy after EGFR-TKI failure, there is a growing interest to overcome the challenge of subsequent biopsy. Even though relatively lower ORR and shorter PFS in patients with plasma T790M+ compared with tissue T790M+, the plasma EGFR genotyping may be good alternative to the tissue biopsy in consideration of long DoR when treated with osimertinib and low yield rate of tissue T790M testing.

Background:
Epidermal growth factor receptor (EGFR) activation mutations occur in 10-50% of lung adenocarcinoma patients of Caucasian ethnicity and in 50% of Asian descent. Currently, EGFR tyrosine kinase inhibitors (TKIs) are first line therapy for stage IV non-small cell lung cancer (NSCLC) patients with EGFR mutations. Despite initial significant response to TKIs, most tumors develop resistance. The main mechanism of resistance detected in 50-60% of cases is a cytosine to thymine (C>T) single nucleotide transition mutation at position 2369. This leads to a threonine to methionine amino acid change at position 790 (i.e. T790M). Interestingly, a similar mechanism of C>T mutation is seen in imatinib treated CML and GIST tumors. Our data suggests that the C>T mutation is an acquired event secondary to 5-methylcytosine deamination with Activation Induced Cytosine Deamination enzyme (AICDA).

Method:
PC9 is a lung adenocarcinoma cell line known to have an EGFR del19 activation mutation and can acquire T790M mutation from T790M-negative clone. We utilized droplet digital PCR (ddPCR) to detect T790M mutations. In addition, qPCR was used to assess the expression of AICDA and NFκB pathway before and after TKI exposure.

Result:
Sub clones of PC9 cell line with no evidence of T790M mutation by ddPCR at baseline, were treated with EGFR TKI. After serially increasing the treatment dose, T790M mutation was detected by ddPCR associated with a significant increase in AICDA expression. Furthermore, using a UDG assay, we show that AICDA recognizes a CAC motif and can deaminate cytosine at position 2369. By mass spectrometry we established that 2369 cytosine is methylated. Deamination of 5-methylcytosine leads to thymine directly rather than uracil, explaining the C>T mutation. In addition, using ChIP assay and pharmacological inhibition we confirmed that NFκB binds AICDA promoter and induces its expression. Similarly, using a mouse xenograft model, EGFR TKI increases the expression of NFκB and AICDA; this is abrogated by concurrent use of an IKKα inhibitor. Knocking down AICDA by shRNA, decreases the rate of T790M development in PC9 cell lines after TKI exposure. Assessing AICDA expression in patients at baseline (n=4) and upon T790M mutation progression (n=4), there was a significant 20-fold increase in its expression.

Conclusion:
Our data suggest that upon exposure to EGFR TKI, AICDA is overexpressed through an NFκB dependent pathway, causing the deamination of 5-methylcytosine to thymine, manifesting as T790M mutation and leading to TKI resistance. This indicates that T790M is acquired and its development could be targeted.

Background:
Nivolumab is the first checkpoint inhibitor approved for the treatment of non-Squamous non small cell lung cancer (non-Sq-NSCLC). Although smoking habits are considered a relevant risk factor related to the onset of lung cancer, previous studies showed that current and former smokers patients (pts) treated with nivolumab may have a greater advantage in terms of clinical benefit than never smokers and EGFR mutated. Nevertheless, to date, no definitive conclusion may be drawn and no data are available from a real world setting. Here we report the data from Italian expanded access program (EAP) in the never smoker pts and EGFR mutated pts.

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

Result:
Overall, of 1588 patients with non-Sq-NSCLC, smoking history was available for 1430 pts and 305 (21%) were never smokers and, among 1455 pts evaluable for EGFR mutation, 102 (7%) were positive. In the never smoker group, EGFR status was available for 287 pts, with 51 (18%) who harbored an activating EGFR mutation. Among never smokers, with a median follow-up (FU) of 7.0 months (0.1-20.3) and a median of 7 doses (1-38), the best objective response rate (BORR), the disease control rate (DCR) and the median overall survival (OS) were 9%, 42% and 10.0 months (8.1-11.9), respectively. Among all EGFR positive pts, with a median FU of 5.5 months (0.1-21.2) and a median of 6 doses (1-40), the BORR, DCR and median OS were 9%, 30% and 8.3 months (2.2-14.4), respectively. In the never smoker group, EGFR positive pts had 2% ORR, 26% DCR and 5.6 months (3.4-7.8) of median OS. However, it should be considered that these pts had poorer prognostic factors (ECOG performance status, brain metastasis) at baseline.

Conclusion:
These preliminary results represent the first real-life data regarding the efficacy of nivolumab in special subpopulations, including never smokers and EGFR positive pts. These results warrants further studies to evaluate the possible therapeutic options in these pts, also taking into account available alternatives and safety profile.

Abstract not provided

Background:
T790M mutation of EGFR exon 20 is observed in approximately 50% of the non-small cell lung cancer (NSCLC) patients progressed on EGFR tyrosine kinase inhibitors (TKIs). Based on a preclinical study demonstrating that pharmacologic JAK1 inhibition increased the anti-tumor activity of afatinib in T790M-positive NSCLC cell lines, we conducted a phase Ib study to evaluate the safety and efficacy of the combination of afatinib and ruxolitinib, a selective JAK inhibitor, in NSCLC patients who had progressed on EGFR-TKIs.

Method:
We used the classical 3+3 design for dose-escalation cohort (DAC). Patients with histologically diagnosed, EGFR mutant stage IV NSCLC and documented disease progression on EGFR-TKIs were considered eligible. Afatinib was administered alone once daily from day 1 through day 8 (run-in period), then ruxolitinib was orally administered twice daily concomitantly with afatinib until progression. The primary endpoint was to determine RP2D and DLT. If DLT was not observed in 9 patients at the cohort of the highest level, we planned to decide RP2D and enroll 6 additional patients in the dose-expansion cohort (DEC).

Result:
As of June 14, 2017, 21 patients (12 with exon19 deletion, 9 with exon21 L858R) were enrolled in DAC, 8 of which had T790M mutations. All patients were previously treated with erlotinib (n=6) or gefitinib (n=15), and previously received a median of 2 (range, 1-4) lines of chemotherapy. Because no DLT was observed in the 9 patients at the highest dose level (afatinib 50 mg once daily plus ruxolitinib 25 mg twice daily), 6 patients with T790M mutation were enrolled in the DEC. Frequent AEs included paronychia (G1 in 11 cases, G2 in 2 cases), diarrhea (G1 in 14 cases, G2 in 2 cases, and G3 in 2 cases), acneiform rash (G1 in 13 cases), and oral mucositis (G1 in 7 cases, G2 in 3 cases). SAEs were reported in 6 patients, which were not related to the investigational products. Partial responses were observed in 7 patients (25.9%) with disease control rate (CR+PR+SD) of 96.3%. Median PFS was 5.7 months (95% CI, 4.2-7.2) and 3 patients remain on study.

Conclusion:
The combination of afatinib with ruxolitinib was well tolerated with clinical benefit of disease control in NSCLC with acquired resistance to EGFR-TKIs (NCT02145637).

Background:
S49076 is a potent ATP-competitive TKI that targets MET, AXL and FGFR1/2/3 at clinically relevant doses. Preclinical data showed that combination of S49076 with 1[st] generation EGFR-TKI can overcome acquired resistance to EGFR inhibition in a NSCLC EGFR-mutated MET-amplified cell model. Here we report interim phase I data from NSCLC patients treated with S49076 in combination with gefitinib to overcome acquired non-EGFR-T790M-mediated resistance to EGFR TKI (1[st]/2[nd] generation).

Method:
This is a phase I dose-finding study of S49076 combination with a standard dose of gefitinib using a modified Bayesian Continual Reassessment Method with S49076 doses of 500 and 600mg. Both agents are administered orally once daily. The primary objective is to determine the safety profile of the combination and the recommended phase 2 dose (RP2D) based on safety assessments. Patients are selected according to tumor status; they carried an activating-EGFR mutation without secondary T790M mutation and with at least one of the following dysregulations: MET IHC3+, MET FISH 2+/3+, or AXL IHC 2+/3+.

Result:
In June 2017, molecular screening was performed in 48 EGFR/T790M-negative tumor samples to assess MET and AXL dysregulation. 17/48 met the molecular eligibility criteria: 12/17 with MET overexpression/amplification; 4/17 with both MET overexpression/amplification and AXL overexpression; and 1/17 with AXL overexpression. As regards S49076 dose levels, 4 patients were included at 500 mg and 4 at 600 mg. Five patients discontinued treatment: 4 disease progression and 1 consent withdrawal. The most frequent related AEs (≥2 patients) were asthenia (n=5), diarrhea, nausea and paronychia (n=4 each), ASAT/ALAT increase, anemia, and yellow skin (n=3 each), peripheral edema, stomatitis, blood creatinine increase, vomiting, hypoalbuminemia, and decreased appetite (n=2 each); most were grade 1-2. A DLT occurred in 1 patient at 600mg (grade 3 stomatitis). The other severe related AEs included grade 3 ALAT increase, asthenia, and neutrophil count decrease. Concomitant intake of gefitinib did not appear to modify the S49076 PK profile as compared to previous data. The best overall response rate were partial response (PR, 1/8), stable disease (SD, 6/8), and progressive disease (1/8), including 3 patients with PR/SD ≥6 months.

Conclusion:
According to preliminary data, the frequency of MET and AXL dysregulations is consistent with the literature. Combination of S49076 and gefitinib is well tolerated and safety data are consistent with the overall safety profile of each drug. The phase II part of this study will start once the RP2D is defined to evaluate the anti-tumour activity of the combination.

Background:
Resistance invariably develops in EGFR-mutated NSCLC treated with EGFR tyrosine kinase inhibitors (TKI). In approximately 50% of cases, resistance is mediated by the EGFR T790M mutation; however, multiple other mechanisms of resistance have also been described, including case reports of acquired kinase fusions (PMIDs: 26187428, 28089157).

Method:
Hybrid-capture based genomic profiling (FoundationOne® or FoundationACT™) was performed prospectively on DNA isolated from tissue-based FFPE samples or blood-based circulating tumor (ctDNA) samples from NSCLC patients.

Result:
From a dataset of 3,014 unique EGFR-mutated (exon 19 deletion, L858R, G719X, L861Q, or S768I) TKI naïve or relapsed NSCLCs we identified 28 (0.9%) cases with co-occurring likely activating kinase rearrangements (BRAF [12], FGFR3 [5], RET [5], ALK [4], NTRK1 [1], EGFR [1]), including 24 confirmed fusions. Treatment histories were available for 21/28 cases, and prior evidence of EGFR mutation and treatment with an EGFR TKI was evident in 21/21 (100%) cases. In 25/28 cases no other known mechanisms of acquired resistance co-occurred with the primary EGFR mutation and the kinase fusion. The 3 cases with co-occurring known resistance mechanisms (T790M or MET amplification) were those with BRAF rearrangements for which no fusion partner was identified. Additionally, our dataset included 10 paired pre- and post-EGFR TKI treatment samples where the latter sample showed an acquired kinase fusion (4 FGFR3-TACC3, 2 EML4-ALK, 2 CCDC6-RET, 1 AGK-BRAF, 1 TPM3-NTRK1) in addition to the primary EGFR alteration. Notably, in 3/10 paired cases (2 FGFR3 and 1 BRAF) the fusion was acquired in the setting of dropout of an existing T790M mutation.

Conclusion:
Acquired kinase fusions are rare yet recurrent mechanisms of acquired resistance in EGFR-driven NSCLCs, and may be enriched in the setting of resistance to T790M-specific inhibitors. Genomic profiling capable of detecting all classes of genomic alterations, including base substitutions, indels, copy number alterations, and fusions, is warranted at the time of progression on EGFR TKIs, and often provides rationale for treatment in such cases.

Abstract not provided

Background:
The T790M mutation in the epidermal growth factor receptor (EGFR) gene altering the kinase domain is the most common mechanism of resistance to first or second-generation EGFR tyrosine kinase inhibitors (TKIs). Osimertinib is currently approved for treatment of metastatic EGFR T790M mutation positive non-small cell lung cancer (NSCLC). However, resistance to osimertinib is an emerging issue. Evaluation of the genomic profiles of patients with EGFR T790M mutated NSCLC treated with osimertinib is necessary to gain an understanding of the potential resistance mechanisms.

Method:
Between January 2014 and June 2017, we retrospectively reviewed DNA profiling data from blood and/or tissue (FoundationONE/ACT, Guardant 360, TruSight panel and/or Pyrosequencing) from patients with advanced NSCLC to identify those with an EGFR T790M mutation. For patients harboring the EGFR T790M mutation, electronic health records were reviewed to identify the clinical variables , outcomes and genotyping at the time of progression on osimertinib. Survival analysis was done using the Kaplan-Meier method (SPSS version 23).

Result:
We identified a total of 433 NSCLC patients who underwent genotypic profiling; EGFR T790M mutation was present in 29 (6.7%) patients. All patients received EGFR-TKIs prior to testing. Patient demographics included: Caucasian (76%), female (76%), adenocarcinoma (100%), never-smokers (52%) with a median age of 65 years and 3 median prior lines of treatment. At the time of identification of the T790M mutations, 27 (93%) patients retained their EGFR exon 19 deletion or exon 21 mutations and 24 (82%) patients received osimertinib. The median overall survival was 4.9 ± 3 months in patients not on osimertinib, and was not reachable in patients on osimertinib in the current follow up period. 7 of the 24 patients had repeat genotyping at the time of progression on osimertinib which revealed presence of acquired secondary mutations including EGFR C797S (43%, N=3), EGFR C797G (14%, N=1), amplifications in EGFR (43%, N=3), ERBB2 (HER2, 28%, N=2) and cell cycle genes (CD-K4, CCND1, CCND2, 28%, N=2), MAPK/ERK pathway alteration (KRAS amplification and Q61R mutation, 28%, N=2), PI3K/AKT/mTOR pathway alteration (ATK3 and PIK3C2B amplification, 14%, N=1) and RET fusion (NCOA4-RET, 14%, N=1).

Conclusion:
There is limited data regarding the mechanisms of resistance to osimertinib. In addition to the acquired mutations in C797S, our study identified several potential pathways for developing resistance to osimertinib including emergence of acquired amplification in EGFR and ERBB2, as well as MAP Kinase and PI3K/AKT pathway aberrations. Updated data will be presented at the meeting.

Background:
Acquired resistance to therapy occurs with both first- and newer-generation epidermal growth factor receptor (EGFR) inhibitors. One strategy to delay the emergence of resistance is to use the most active/least toxic inhibitor and replace the traditional daily dosing with a biologically-rational dosing approach. Osimertinib is a covalent mutation-specific EGFR tyrosine kinase inhibitor (TKI) with activity against common EGFR plus EGFR-T790M mutations and less activity against the wild-type receptor. This drug is poised to become a 1[st] line EGFR TKI for treatment-naïve EGFR mutated lung adenocarcinomas. Therefore, it is an ideal candidate to devise rationale dosing schemes to maximize its efficacy and minimize tumor adaptation.

Method:
We explored pulse dosing of osimertinib, to delay the emergence of acquired resistance. We applied population dynamics mathematical modeling to this question, using key parameters (“birth rate” and “death rate”), established through cellular assays. These parameters are presumed to be dose-dependent. First, we experimentally determined the “birth-rates” of PC9 lung cancer cells, PC9 cells bearing the T790M resistance mutation, and PC9 cells that were resistant to osimertinib, with increasing concentrations of osimertinib (0 - 10μM, total of eight doses at half log intervals) using cell viability assays (MTS assay). Next, we determined cellular “death-rates” using annexin V/propidium iodide (PI) fluorescence-activated cell sorting (FACS). We then applied those parameters to our population dynamics model and simulated various treatment conditions with different dosing strategies, to identify the most effective regimens at delaying or preventing the emergence of resistance to osimertinib.

Result:
Using our mathematical model, we predicted that high-dose weekly treatment of osimertinib with a low maintenance dose led to minimal cell proliferation in comparison to daily dosing. Following this in silico prediction of the superiority of pulse dose treatment, we experimentally compared the frequency of emergence of resistance with different treatment dosing regimens, using a long-term cell culture system. Indeed, weekly administration of 5uM osimertinib to PC9 cells, followed by a maintenance dose of 0.25uM, suppressed the emergence of resistance for up to 5-7 weeks in culture.

Conclusion:
We have established a population dynamics mathematical model to predict optimal dosing regimens for osimertinib in treatment-naïve EGFR mutated lung cancers. The model was experimentally validated using a long-term culture system. Future validation in additional preclinical models (cell lines, xenografts and genetically engineered mice) can lead to rationale development of pulse-maintenance clinical trials of osimertinib and eventually establish a novel paradigm for clinical use of EGFR TKIs.

Background:
Osimertinib was granted conditional marketing authorization from the EMA and accelerated approval by the FDA based on single-arm trial (SAT) data. Subsequent full FDA approval was supported by the RCT AURA3 (NCT02151981) and based on superior progression-free survival (PFS) of osimertinib versus platinum-based doublet chemotherapy (PDC) for patients with epidermal growth factor receptor (EGFRm) T790M-positive non-small-cell lung cancer (NSCLC). Accelerated and conditional approval coupled with a large treatment effect led to increased treatment switching post-progression from the control arm to the intervention arm in the RCT as clinicians and patients demanded the new treatment. This will confound analysis of overall survival (OS) benefit in the RCT. Adjusted indirect comparison from other sources can offer a robust analysis of OS without confounding owing to treatment switching and difference in subsequent therapies post-progression.

Method:
Recent SAT data (data cut-off, 1 November 2016) for osimertinib were provided by the AURA (NCT01802632) and AURA2 (NCT02094261) studies (N=405). Data for PDC were provided for a subgroup of the control arm of an RCT, IMPRESS (NCT01544179), which comprised patients with centrally confirmed EGFRm T790M-positive NSCLC whose prior treatment with an EGFRm TKI had failed and were subsequently treated with PDC (N=61). A propensity score (PS) approach was used to adjust for differences in baseline demographics and disease characteristics. Baseline characteristics of both groups were compared using statistical tests.

Result:
Following estimation of PS for each patient and adjustment for heterogeneity across the groups by matching, 288 patients from the osimertinib group and 53 patients from the PDC group were retained for analysis. Osimertinib demonstrated a statistically significant improvement in median PFS of 10.9 months versus 5.3 months for PDC (HR 0.28, 95% CI 0.19 to 0.41, P<0.0001), which was consistent with the gain in PFS from the RCT AURA3 (10.1 months versus 4.4 months; HR 0.30, 95% CI 0.23 to 0.41, P<0.001), and a statistically significant improvement in OS (HR 0.41, 95% CI 0.27 to 0.62, P<0.0001). Median OS for osimertinib was not reached and was 14.1 months for PDC.

Conclusion:
The indirect comparison estimated a statistically significant improvement in PFS and OS with osimertinib compared with PDC. The PFS benefit was consistent with that of the confirmatory RCT. The combined evidence from RCT data and indirect comparisons described may bridge the potential gap and confounding in evidence for OS produced by subsequent treatments after first progression in the RCT.

Abstract not provided

Background:
EGFR TKI therapy has improved lung adenocarcinoma patients’ prognosis tremendously, but almost all of the patients inevitably develop acquired resistance, and EGFR T790M mutation is the major contributors. T790M restores the EGFR tyrosine kinase domain affinity to ATP, and therefore gefitinib is displaced from the binding pocket, and the ‘driving’ signal for proliferation is switched on again. Previous work has shown that after TKI therapy, lung adenocarcinoma patients kept the sensitive mutation and acquired resistance mutation simultaneously by sequencing methods or in vitro cell line experiments. Whether the two different type mutations are in the same cell group or in two different cell groups is unknown. None of them has observed what was happening in the tumor cells after TKI therapy.

Method:
RNA in situ hybridization methods was employed to examined EGFR T790M and L858R mutation in lung adenocarcinoma cancer tissues which was obtained before and after TKI therapy. EGFR expression was examined by immunohistochemistry. EGFR mutation were detected by ARMS PCR methods.

Result:
Twenty five patients were enrolled in this study which were divided into 3 groups. Group 1: 5 patients who had concurrent primary T790M and sensitive EGFR mutation. Group 2: 14 patients who acquired T790M mutation after receiving TKI therapy. Among them, 6 patients had biopsy tissues before and after TKI therapy. 8 patients only own tissues after TKI therapy. Group 3: 6 patients who had sensitive EGFR mutation and received TKI therapy, but re-biopsy tissues didn’t had EGFR T790M. We found that the results of RNA ISH and ARMS PCR methods was identical in the majority of the examined tissues. Only one repeated biopsy tissue didn’t identify EGFR T790M after TKI therapy by PCR in group 3, while the RNA ISH method detected T790M in this tissue which contain only 150 tumor cells. In the serial cut slides, we observed that T790M and L858R mutations were in the same cell group, not only in the primary resistance cases, but also in the acquired resistance cases. For the two cases which had tissues available after receiving third generation TKI therapy, we observed that T790M disappeared in the repeated biopsy specimen, leaving the sensitive mutation which existed from the beginning.

Conclusion:
In the primary and acquired resistance tissues, EGFR sensitive mutation and T790M co-exist in the same cell groups. EGFR sensitive mutation is a trunk and drive mutation, while T790M is a passenger mutation during the treatment process by TKI therapy.

Background:
Circulating tumor DNA (ctDNA) has emerged as a specific and sensitive blood based biomarker for detection of several mutations in non–small cell lung cancer (NSCLC). Other clinical applications for ctDNA include molecular assessment of patients at diagnosis and serial (real-time) monitoring of biomarker status or the development of resistance mutations.

Method:
Eighty patients with advanced NSCLC who either (Group 1) had a new diagnosis or (Group 2) had developed acquired resistance to an EGFR kinase inhibitor were analyzed with highly sensitive Biocept, Inc. TargetSelector[TM] Real Time PCR based plasma assays genotyping for the detection of EGFR mutations L858R, Del19 and T790M. In addition, group 1 was analyzed for KRAS, BRAF, ROS1 and ALK and circulating tumor cells (CTCs) before and after TKI treatment.

Result:
Our results showed concordance rates of EGFR, KRAS and ALK mutations for up to 90% between the tissue and blood samples in newly diagnosed patients (Group 1). Paired analysis of mutations status monitoring in this group (P= 0.016) showed that the pattern of mutant ctDNA and CTCs changed in response to systemic therapy in 83% of the cases (Partial response or disease progression; R2=0.808). Plasma ctDNA analysis of multiple mutations showed that 40% of patients had at least one more mutation besides the one detected in tissue biopsy; 28% of EGFR tissue positive patients also had a KRAS mutation. In addition, 75% of KRAS positive patients had a BRAF mutation. These results demonstrate that plasma ctDNA analysis may even detect mutations missed by standard tissue genotyping due to tissue heterogeneity. Plasma EGFR T790M mutation was analyzed in patients with clinical progression to TKI inhibitors. Considering the RECIST criteria, 58% of progressive disease, 10% of stable disease and 16% of partial response patients were positive for T790M. According to metastatic disease type (locoregional, oligometastatic, polimetastatic), the T790M mutation was found on 64.3% of polimetastatic patients, 30.8% of oligometastatic patients and 17.6% of loco-regional patients.

Conclusion:
TargetSelector[TM] ctDNA assay is capable of rapidly detecting EGFR, KRAS and ALK mutations and is highly concordant with mutations present in tumor tissue with the robustness needed for real world testing to identify patients who progress on first line TKI therapy as well as for real-time monitoring of patients’ clinical status. Our findings highlight the importance of the RECIST criteria to define the progressive disease and determine the right moment to test for T790M mutation regardless the metastatic disease type.

Background:
Pre-treatment EGFR T790M mutation is more likely to coexist with L858R mutation than with exon 19 deletions (19del) in NSCLC. However, EGFR-TKIs might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19del and L858R by assembling all existed data.

Method:
Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma).

Result:
A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19del than in L858R mutated patients (53% vs. 36%; OR 1.87; p=0.00). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19del and L858R respectively (OR 0.59; p<0.01). The increase of T790M rate was 2.79-fold in 19del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy.

Conclusion:
Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19del than in L858R among EGFR-TKI resistant acquired patients. The difference in T790M alteration between 19del and L858R encourages development of specific resistance mechanism detection or treatment strategies.

Abstract not provided

Abstract:
Superior sulcus tumors (SSTs), involving structures at the thoracic inlet, have posed a challenging problem for surgeons, radiation oncologists and medical oncologists alike, ever since they were first described[1)]. Pre-operative radiotherapy had long been the community standard in the management of SSTs. However, both the complete resection rate (approximately 50%) and long-term survival (approximately 30%) rate had remained poor and unchanged over 40 years, since the first treatment strategy was reported in the 1960’s. Local control had remained the main problem, adversely affecting the quality of life as well as the survival of the patients[2)]. Encouraged by the promising data of concurrent chemoradiotherapy for mediastinal node-positive N2 NSCLC, two prospective studies applied this modality as preoperative therapy for patients with SSTs; one from the US (led by the Southwest Oncology Group SWOG9416-Intergroup Trial 0160[3)]), and the other from Japan (by the Japan Clinical Oncology Group, JCOG 9806[4)]). In both trials, patients with SSTs received two cycles of cisplain-based chemotherapy (etoposide-cisplatin in US, mitomycin-vindesine-cisplatin in Japan), concurrently given with thoracic radiotherapy 45Gy/27fr. Then they underwent surgical resection. Boost radiotherapy was given to unresected/imcompletely resected tumors. In spite of minor differences, the results of the two trials were strikingly similar (Table). The intensive trimodality approach was found to be feasible in both reports, with a reasonably low toxic death rate of 4%. The resection rate, which had remained unchanged at about 50% for almost 40 years with conventional preoperative radiotherapy, was approximately 70% in both studies. Particularly noteworthy was the reproducibility of the favorable survival data, with a 5-year OS of 44% in the US trial and 56% in the Japanese trial, which were clearly superior to the historical value of 30%. Although T factor (T3 vs. T4) was not a significant prognostic factor in the US trial, T3 patients did far better than T4 in the Japanese study (Figure), reflecting lower resection rate (78% vs. 40%).Figure 1 A shift in the trend of clinical problems also became clear. The relapse patterns changed from predominantly locoregional to mainly distant recurrences in cases with complete resection, and a significant number of such patients suffered from metastasis in the brain as the initial site of relapse. In the JCOG study, 7-year follow-up data[5)] revealed that 21 (41%) of the 51 patients who underwent R0 resection relapsed; initial site of relapse included locoregional only in 1, distant metastasis only in 14 (5 were “brain only”), and both in 6. In contrast, out of the 24 patients who failed to get R0 resection, 18 got tumor recurrence, with 13 locoregional relapses. In order to improve the outcome, SWOG subsequently launched another trial, S0220, with docetaxel consolidation after the induction therapy[6)]. However, the overall survival was no better than the initial two reports, with the 3-year OS of 61%. The relapse pattern remained predominantly distant. Preoperative chemoradiotherapy was compared to conventional pre-operative radiotherapy in the Massachusetts General Hospital. In their retrospective analysis, Wright et al[7)] did show that pre-op chemoradiotherapy was better that pre-op radiotherapy, with 4-year OS of 84% vs. 49%. In their single-institute trial (#92-038) at the MD Anderson Cancer Center, Gomez et al reported[8)] the results of initial surgery followed by chemoradiotherapy in “resectable” SST. The result was comparable with those of the multi-institutional studies (Table), which included many “marginally resectable” tumors. Given the potential selection biases, the evidence would favor pre-operative chemoradiotherapy strategy.

Trial	JCOG9806	SWOG9416	MDA92-028
Patient accrual	76/ 3.6 years	116/ 4.3 years	32/ 13 years
No. institutions	19	NR (5 groups)	1
Chemotherapy	Pre-op	Pre- & post-op	Post-op
Chemotherapy	MVP	EP	EP
Radiotherapy	Pre-op	Pre-op	Post-op
Radiotherapy	45Gy/25fr	45Gy/25fr	60Gy/50fr
%T4 disease	26%	29%	22% (pathological)
Radiological ORR	61%	42%	N/A
Resection rate	75%	80%	100%
Complete resection rate	68%	76%	72%
Pathological CR rate	16%	29%	N/A
Toxic death rate	4%	4.5%	0
OS at 3-years	62%	NR	NR
OS at 5-years	56%	44%	50%
OS at 7-years	52%	41%	50%

In summary, preoperative chemoradiotherapy is the current standard of care for patients with SSTs. Several critical questions remain unsolved, however, including effective suppression of micrometastases in cases with R0 resection, prevention of brain metastases, and management of N2 SSTs, which were excluded from the hitherto reported trials. References 1) N Engl J Med 337: 1370-1376, 1997 2) J Thorac Cardiovasc Surg 119: 1147-1153, 2000 3) J Clin Oncol 25: 313-318, 2007 4) J Clin Oncol 26: 644-649, 2007 5) Proc Am Soc Clin Oncol 28 suppl: 2010, (abstr 7025) 6) Ann Thorac Surg. 98: 402–410, 2014 7) Ann Thorac Surg 73:1541-4, 2002 8) Cancer 118: 444-51, 2012

Abstract:
Pancoast tumors or superior pulmonary sulcus tumors (SSTs) are a rare subgroup of non-small cell lung carcinomas and occur in about 3-5% in patients with lung cancer. It is one of the most challenging thoracic malignancy to treat because of their proximity to vital structure in the thoracic inlet. In the last two decades improvements in appropriate preoperative staging, in multimodality treatment and development of new operative techniques have resulted in more curative treatment and better long-term results. However, in the preoperative assessment the role of positron emission tomography (PET) and magnetic resonance imaging (MRI) has not been studied specifically in SSTs, also imaging methods to access pathological response after induction treatment is not clearly defined. Furthermore, management of STSs with invasion of spine or subclavian vessels remains controversial. Invasion of these structures was traditionally considered as a contraindication to surgery because of technical difficulties and poor long-term results. Also, patients with SST and N2 or N3 disease had an extremely poor prognosis due to loco regional recurrences, so that due to previous recommendations, this group of patients should not be treated surgically except in a protocol setting. The surgical approach (anterior/posterior/combined) varies dependent on tumor spread and although lobectomy is recommended as the standard type of pulmonary resection, many authors reported no significant different survival rates after sublobar operations. Finally, brain metastases remain the most common form of distant relapse, the use of prophylactic cranial irradiation is not generally accepted. Clinical diagnosis and appropriate staging has to be conducted. SSTs are well accessible by transthoracic fine-needle aspiration. MRI is the modality of choice for imaging structures of the thoracic inlet, including the brachial plexus, subclavian vessels, spine and neural foramina. It shows local extent of the disease and is important for preoperative planning. EBUS-TBNA and PET is recommended for evaluation of mediastinal disease and distant metastasis before starting the induction treatment, mediastinoscopy is indicated to access pathological nodal response before surgery. A prospective phase II trial (SWOG INT 0160) showed that induction treatment with preoperative two cycles chemotherapy and concurrent radiotherapy with 45 Gy followed by surgery resulted in better tumor response and local control, higher rates of R0 resections and improved long-term overall survival, by low perioperative morbidity and mortality. Today, induction chemo radiotherapy followed by surgery has been established as standard treatment regimen for SSTs. Although vertebral body invasion and subclavian artery involvement are declared as negative prognostic factors, improvement in surgical techniques and cooperation of different surgical specialists, resulted in promising results for these difficult group of patients. Several authors described surgical techniques for tumor resection involving the transverse process only, or the intervertebral foramina, requiring hemivertebrectomies with spinal fixation, or the vertebral body, requiring total vertebral body resection with spinal fixation. In highly selected patients these extensive resections could be performed with acceptable morbidity and mortality in specialized centers with interdisciplinary teams of thoracic and spine surgeons. The en bloc resection technique provided acceptable recurrent rate (local 15%, distant 45%) and good long-term survival (25%-30% at 5-years). The introduction of the anterior approach made the resection of SSTs with subclavian artery involvement easier. After resection, the subclavian artery was reconstructed either with a ring supported polytetrafluoroethylene (PTFE) graft or direct by end-to-end anastomosis. Some authors reported about resection along the subadventitial plane to obtain tumor free margins or the use of autologous grafting. Five-year survival rates range between 25% and 32%. Extrapolating from the favorable results in other lung cancers, investigators have also considered induction chemoradiation for SSTs with mediastinal lymph node involvement (N2 disease), a group of patients previously considered hopeless. It is noteworthy that in two studies, no difference in median and overall survival was found between positive or negative pretreatment mediastinal N2 disease. Although these data should be interpreted with caution because they are liable to selection, they show that surgery is feasible with an acceptable outcome. Another important issue is that some authors found that ipsilateral supraclavicular lymph node is a local lymph node, so that patients with SSTs and N3 status (ipsilateral supraclavicular node involvement) showed a better prognosis than patients with N2 status (ipsilateral mediastinal node involvement). This have been confirmed in two larges and a few small series and underlines that ipsilateral supraclavicular N3 involvement could represent only local extension and may have a prognostic importance near to that of N1 disease. The influence of the type of lung resection, lobectomy versus sublobar resection, on the survival rates remains controversial. Lobectomy was associated with better survival compared with patients with wedge resections, but these data came predominantly from the pre-induction era with trimodality treatment. One important question is the necessity of lobectomy in patients with SSTs and pathological complete response (pCR). Some authors reported no significant different survival rates after sublobar operations in pCR patients and a higher incidence of wedge resection was found using the anterior approach only. Infiltration of the thoracic inlet increases the technical complexity of surgery, requiring extended resections and demanding reconstructive procedures. Completeness of resection represents one of the main factors influencing the long- term outcome of patients, pointed out in all publications about SSTs. Brain metastases remain one of the most common forms of relapse, prophylactic cranial irradiation (PCI) may be useful addition to preoperative chemoradiotherapy. Improvements in the combined preoperative treatment and surgical approach have significantly influenced local control and survival rates of SSTs. Further refinement of these techniques, also the addition of other chemotherapy agents or biologic agents as angiogenetic inhibitors or tyrosine kinase inhibitors could give some new perspectives in the treatment of SSTs. Further studies are needed to examine the effect of PCI on the survival after relapses in the brain. I declare no conflicts of interest.

Abstract:
Complete en bloc resection is the corner stone of the treatment of solid tumors. Those located in the superior sulcus (SS) or thoracic inlet are known to have bad reputation because their resection represents a real technical challenge. The complexity of such surgery is due to the congestion of a very tight space (SS) by major neurovascular structures as well as to the proximity of the esophagus, the trachea and the spine. The preoperative work-up, in order to assess the involvement of such structures by SS tumors, may include, further to the routine bronchoscopy and cervico thoracic CT scan, an MRI to rule out spinal extension, venous angiography, subclavian arteriography or esophagoscopy. Many surgical approaches to remove SS tumors and many anatomical classifications have been reported during the last 6 decades. The goal of the surgical approach is to allow a wide and safe exposure of the SS, complete en-bloc resection of the tumor and all the involved structures and a potential arterial or spinal resection and reconstruction. The main goal of an anatomical classification is to facilitate the choice of the most appropriate surgical approach according to the extension of the tumor. After an anatomical description of the SS, we will review all the surgical approaches described in the literature to remove benign or malignant tumors developed in the SS. The emergence of new surgical techniques during the last 2 decades, such video-assisted and robotics surgeries had modify the surgical approaches in thoracic surgery. We will describe all the surgical approaches currently available to resect SS tumors with their advantages and their limits. Based on our experience we will describe a simplified anatomical classification of SS tumors. After identification of all contra-indications to SS tumor resection, we will describe the surgical approaches we use currently allowing when needed arterial and spinal resections and reconstructions.

Abstract:
In 2003, an IASLC Consensus Report recommended that ‘superior sulcus tumors (Pancoast tumors, T3 or T4) should preferentially undergo trimodality treatment, including chemoradiation and surgery’ [Eberhardt WE, Lung Cancer 2003]. This recommendation was based on the early results of the phase II Intergroup Trial 0160) trial, findings which have been subsequently updated [Rusch VW, J Clin Oncol 2007]. Results of two other prospective phase II trials, namely the JCOG 9806 and the SWOG-Intergroup Trial S0220, support the use of the trimodality approach in superior sulcus tumors [Kunitoh H, J Clin Oncol 2008; Kernstine KH, Ann Thorac Surg 2014]. Between 30-40% of patients with a locally-advanced NSCLC can develop local disease recurrence following full-dose chemoradiation [Baker S, Radiat Oncol 2016]. As the impact of a local recurrence for patients with superior sulcus tumors can be great, the role of surgery remains relevant for this site. Recent ESMO guidelines have identified this patient subgroup as having an increased risk of an incomplete resection [Eberhardt WE, Ann Oncol 2015], and consequently, the role of concurrent CT-RT as an induction scheme is considered standard at centers with the available surgical expertise. This overview will address radiation-related topics such as dose and fractionation schemes, treatment fields, newer radiation delivery techniques (MRI-guided radiotherapy, protons), salvage radiotherapy for small volume recurrences, and the treatment of second primary lung tumors.

Abstract:
Superior sulcus tumors have been long defined as a distinct clinical entity. Symptoms including Horner’s syndrome and other neurologic findings as well as severe shoulder pain and SVC syndrome characterize this disease. Early on, the use of preoperative therapy was recognized as potentially useful. Over time, initial chemoradiotherapy followed by surgery has emerged as standard of care for patients with T3 or T4 lesions and N0 or N1 disease. 3-year survival rates of approximately 60% have been reported for surgically resectable patients with advanced disease. More recently, the addition of consolidation chemotherapy following subsequent surgery was evaluated, but its exact contributions to increasing survival remain unclear. The majority of patients will progress, usually with systemic disease and a large fraction of patients develop brain metastases. Patients with unresectable disease receive concurrent chemoradiotherapy as definitive therapy. Here, commonly used regimens such as the combination of cisplatin/etoposide, carboplatin/paclitaxel, and cisplatin/pemetrexed are utilized. However, more effective therapies are needed and special emphasis on increasing the systemic antitumor activity against micrometastatic disease will be required. The use of targeted therapies such as erlotinib or crizotinib for EGFR mutated or ALK fusion-related adenocarcinomas is currently under investigation. Of high recent interest is the possible addition of immune oncology agents such as the PD-1 or PD-L1 inhibitors. A recent report on the use of the PDL1 inhibitor durvalumab after completion of concurrent chemoradiotherapy in patients with unresectable stage IIIB disease has been reported as meeting its primary endpoint. It is likely that this and other studies will be relevant for superior sulcus tumors as well. Currently ongoing trials of increasing progression-free survival and their scientific basis will be reviewed.

Abstract not provided

Abstract not provided

Abstract not provided

Abstract:
The Philippines is an archipelago composed of more than 7000 islands and is considered one of the emerging economies in Asia. Hence, it is not a surprise that although there is a huge improvement seen in the country, providing sustainable healthcare, even though it is in the list of the government’s priorities, is still a major problem. Cancer, as reported by the Philippine’s Department of Health (DOH) is the third leading cause of mortality behind Infectious and Cardiovascular Diseases. The top malignancy cases reported by the DOH involve the Breast, Lung, Prostate, Cervical and Colorectal. Incidence rates are highest in more developed countries due to early detection of the disease therefore in areas like the Philippines, which lacks access to early diagnosis and treatment, mortality rates remain high. One reason surmised besides lack of financial back up is the geography of the country. With more than 7107 and rising islands, health care delivery is more challenging due to most towns, especially in the southern parts of the country, are difficult to go to or inaccessible by land, air and/or sea. However, in spite of lack thereof, the Department of Health – Philippine Cancer Control Program established in 1990, with Administrative Order 89-A, continue to work hard to bridge the gap. Its mission is to reduce cancer morbidity and mortality in the country operating in a systematic and organized approach utilizing primary and secondary prevention at the community level and tertiary prevention in the different regions of the country through hospitals and community levels. By means of the 6 pillars namely, Epidemiology & Research; Public Information & Health Education; Prevention & Early Detection; Treatment; Training; and Pain Relief (focusing on subprograms involving breast, lung and cervical cancer control, cancer pain relief), a healthcare system that is sustainable was hoped to be established. There are numerous projects formulated using the 6 pillars however due to lack of financial support, stricter implementations of guidelines and slow government approvals into law, mortality from cancer continues to rise. Nonetheless, the program as well as medical societies such as the Philippine Society of Medical Oncology, Philippine Cancer Society, Philippine Society of Oncology, Philippine College of Surgeons and so on, remain confident and continue to work towards the goal. Programs, such as the Philippine Medicines Policy of 2011 employed strategies that would provide free medicines in the hope to address priority diseases such as TB, HIV, Malaria and Cancer. The Philippine Health Insurance Corporation in 2012 provided Benefit Packages in the aim of giving assistance to marginalized sectors of society afflicted with certain malignancies and promote patient empowerment to become active participants in healthcare decision-making by being informed and educated about their illness and adhering to treatment plans. Republic Act 10606 (The Universal Health Care Act of 2013), ensures that all Filipinos, especially the poorest of the poor, will receive health insurance coverage from the Philippine Health Insurance Corporation. The National Center for Disease Prevention and Control-Degenerative Disease Office (2014), developed clinical pathway guidelines for selected non-communicable diseases including cancer in the hope to manage these cases systematically in the country. All these policies and laws are meant to provide a sustainable healthcare in the Philippines but unless properly implemented, followed and financed, the realization of these dreams will remain elusive. There is nevertheless a glimmer of hope with the newly signed law last July 23, 2017, the Executive Order 26, known as the National Tobacco Ban which prohibits smoking in all public places and utility vehicles nationwide. If implemented properly, it would significantly decrease lung cancer incidence and mortality in the country.

Abstract not provided

Abstract:
Brain metastases (BMs) concern more than 10-15% of patients with stage IV NSCLC at baseline and more than 40% during the disease course. The wider use of MRI and improvement of extra-cranial systemic disease control contribute to increase the BMs incidence. The issue of BMs is critical in the management of NSCLC patients in the perspective of the neurological consequences of brain lesions. BMs occurrence is synonymous of a poor outcome in NSCLC but reflects in fact many different situations. Establishing a therapeutic strategy needs first to assess their prognosis; the most appropriate scale is the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers including as prognostic factors EGFR mutations and ALK rearrangement in addition to age, number of BMs, extra-cranial disease and Karnofsky status, with a median survival varying from 3.0 months for the worse subgroup (GPA 0.5-1) to 46.8 months for patients with oncogene addiction and good prognostic factors (GPA 3.5-4). The second step is to evaluate the indications, efficacy and side effects of available therapeutic "weapons". Corticosteroids are active against cerebral edema and improve symptoms. Whole brain radiotherapy (WBRT) has been for decades the treatment "reflex" of BMs but the emergence of stereotactic radiosurgery (SRS) or radiotherapy (SRT) and the issue of neurocognitive complications led to deferral or omission of WBRT in an increasing number of patients. WBRT remains indicated in patients with symptomatic, large (≥3 cm) and numerous BM. However, palliative WBRT did not provide any benefit in terms of survival, quality of life and QUALYs compared to supportive care alone in the Quartz trial; the subgroup analysis suggests a benefit only in patients with better prognostic factors. Neuroprotective strategies as sparing hippocampi during WBRT are currently evaluated. SRS defined by invasive contention with sub-millimeter accuracy or noninvasive SRT with millimeter accuracy are indicated in case of 1 to 3 BMs (but now up to 10 lesions) with a diameter <3 cm, alone or as a boost on the top of WBRT. SRS/SRT alone avoids neurocognitive toxicity of WBRT and provides a similar OS to that of surgical resection when using SRS/SRT for patients with operable lesions. Radionecrosis is observed in 10-17% of patients treated with SRS/SRT, making difficult the distinction with a tumor relapse. In spite of reduction in local and distant brain failures or in death from neurological causes, adjuvant WBRT after SRS/SRT does not improve overall survival and has a detrimental effect on neurocognitive functions and quality of life. Surgical resection of BMs achieves survival and functional benefit in addition to WBRT. Surgery is indicated in case of a symptomatic lesion, larger than 2 cm, with a mass effect, allowing fast improvement of symptoms. The invasive edge of BMs explains the high local recurrence rate after resection and the need for adjuvant radiotherapy. WBRT is progressively less used in favor of SRS/SRT despite a better intracranial control rate because of a higher rate of cognitive deterioration. Systemic treatment remains critical for extracranial systemic control of the disease. Brain-blood barrier limits the brain penetration of systemic agents, especially with efflux transporters as P-gp, for which many TKIs and cytotoxic agents are substrates. BMs usually cause brain-blood barrier disruption with heterogeneous drug penetration. Cytotoxic chemotherapy provides similar response rates in BMs to those of extracranial disease. Anti-PD-1 antibodies seem to be active in the brain but available data are scarce. First and second-generation EGFR TKIs have a low brain penetration but sufficient to obtain response rates similar to those achieved for systemic disease; duration of response might be inferior. Osimertinib has a better CNS penetration. For ALK+ disease, crizotinib is a P-gp substrate with a low blood/CSF concentration ratio and brain is the most frequent site of progression. Next-generation ALK TKIs have a better CNS diffusion; alectinib largely decreases the cumulative incidence of BMs compared to crizotinib. Concurrent administration of TKIs with brain radiotherapy is controversial and is not recommended outside of a clinical trial. Defining an optimal multidisciplinary strategy needs to take into account many parameters, including number, location and size of brain metastases, leptomeningeal lesions, neurological symptoms, risk factors for neurocognitive alteration, extracranial metastases and their control, primary lung tumor control, and identification of a targetable oncogenic addiction. In absence of a targetable genomic alteration, BMs at baseline can benefit from systemic treatment alone in selected patients with no neurological symptoms, small intracranial tumor burden, low risk of impending neurologic issues, on the condition that they are closely monitored; brain radiotherapy can be safely deferred to intracranial progression. Symptomatic BMs require local treatment, by favoring SRS/SRT rather than WBRT; adjuvant WBRT is not recommended but further close monitoring is mandatory to detect new intra-cranial lesions. Surgery is preferred for large lesions, posterior fossa location or diagnosis; adjuvant SRS/SRT is mandatory to avoid local recurrences. WBRT remains indicated for multiple symptomatic lesions not eligible for SRS/SRT except in poor PS patients. In case of EGFR mutations, asymptomatic patients with BMs are treated with first or second-generation EGFR TKIs but must be closely watched with repeated brain imaging. A recent retrospective study suggests that front-line SRS/SRT might improve overall survival as CNS remains a sanctuary site in oncogene-addicted disease. Symptomatic patients are locally treated, favoring SRS/SRT requiring only a short interruption of systemic treatment. For patients with ALK+ disease, the advent of alectinib as standard front-line treatment should change the management approach to BMs: the low incidence of BMs should allow spacing brain monitoring while the high intra-cranial response rate should permit to delay local treatment. For ALK+ patients developing BMs on ALK TKI, local treatment with SRS/SRT or surgery if necessary is the first option; switching to another TKI with a better brain penetration is another option for patients candidates to WBRT. The longer life expectancy of ALK+ patients leads to defer as far as possible the use of WBRT. However, improvement of intracranial control should be considered in patients at preferential risk of dying from intracranial progression, independently on mutational status.

Abstract:
The management of brain metastases remains a challenging issue due to the detrimental impact on the patient quality of life and the wide range of clinical situations. The question is not a local treatment or WBRT but when and how to use the different modalities for each patient. Survival, an endpoint often used, is probably not the best way to evaluate the local efficacy: most patients will died from progressive extracranial disease. The brain tumor control (local or freedom from new brain metastases) is a better way to assess the impact of WBRT or SBRT. Another major problem is the great heterogeneity of the primary tumors and clinical situations. First, we should remember that most patients are not candidate for a local treatment (SBRT or surgery (S)) due to the number of lesions, locations, performance status, meningeal infiltration…and WBRT remains the standard treatment if a brain irradiation is needed. For patients with an “oligo metastatic disease”, many studies have clearly showed the superiority of a form of local treatment (S or SBRT) compared to WBRT at least in term of progression or control at the primary brain site (table1)(1-5). Another issue is to control the disease within the brain: new brain metastases are very common. WBRT has been tested either after S or SBRT to prevent the development of those new lesions: indeed adding WBRT let to a better brain tumor control but this did not translate in any major survival benefit. One major drawback of WBRT is its possible toxicity: the impact on the quality of life, the neurocognitive toxicity, the fatigue and the hair loss. In the EORTC trial, WBRT had a transitory negative impact on the physical or cognitive functioning and more fatigue in the early period of observation compared to the group of patients in the observation arm (6.). A current approach is to follow the patient after SBRT and in case of relapse to propose a salvage treatment which may be a new course of SBRT or even WBRT. Another question was to improve the local control after S adding SBRT. Postoperative SBRT has been proposed and several retrospective studies have shown the feasibility results. Two recently published randomized trials have compared postoperative SBRT to either WBRT or observation. The two main conclusions were less cognitive deterioration with SBRT compared to WBRT( 15% vs 48%) and less local relapse at the primary site compared to no treatment (at 1 year 43% vs 72%) but no difference in overall survival (4,5). An intriguing observation was the better local control at one year after postoperative WBRT compared to SBRT (4). Is there a group of patients benefiting from WBRT? In a new analysis of the Aoyama trial, patients with NSCLC were divided according to a graded prognostic assessment: a statistically significant benefit was observed only in the favorable group with a 6 months gain in median survival (7). A similar observation was reported in the RTOG trial testing the role of adding SBRT to WBRT with a median survival of 14 vs 21 months (8). Is it possible to reduce WBRT toxicity? The hippocampus region play an important role in the preservation of the neurocognitive functions: techniques have been developed to spare the hippocampus region keeping the dose below 7 Gy with a better quality of life and a very low risk of new brain metastases occurring in this spared regions (9). This approach should be tested in large scale phase III trial. Last but not least, the timing of the treatment should be individualized based on the patient needs, and in asymptomatic patients, SBRT may be safely postponed if a systemic treatment is to be administered.

Authors	Treatment	Evaluation Time	Local Control	Brain Tumor Control
Aoyama Kocher Andrews Brown Mahajan	SBRT SBRT+WBRT Surgery Surg+WBRT SBRT SBRT+WBRT WBRT WBRT+SBRT Surg+WBRT Surg +SBRT Surg SURG.SBRT	1 Y 2 Y 1Y 1Y 1 Y	72% 88% 41% 73% 69% 81% 60% 74% 78% 55% 45% 72%	23% 53% 58% 77% 52% 67% 51% 62% 69% 32% 33% 43%

· Estimated from figures References 1.Aoyama H., Tago M., Shirato H. for the Japanese Radiation Oncology study Group 99-1 (JROSG 99-1) investigators Stereotactic radiosurgery with or without whole-brain radiotherapy for brain metastases. Secondary analysis of the JROSG-99 randomized clinical trial JAM Oncol. 2015; 1: 457-464 2.Kocher M., Soffietti R., Abacioglu U., et al Adjuvant whole-brain radiotherapy versus observation after surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J.Clin.Oncol. 2011; 29:131-141 3.Andrews D.W., Scott C.B., Sperduto D.W. et al Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: Phase III results of the RTOG 9508 randomised trial Lancet 2004; 363:1665-72 4.Brown PD, Ballman KV, Cerhan JH,et al Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial.Lancet Oncol. 2017 Jul 4. pii: S1470-2045(17)30441-2. doi: 10.1016/S1470-2045(17)30441-2. [Epub ahead of print] 5.Mahajan A, Ahmed S, McAleer MF, et al Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial. Lancet Oncol. 2017 Jul 4. pii: S1470-2045(17)30414-X. doi: 10.1016/S1470-2045(17)30414-X. [Epub ahead of print) 6.Soffietti R., Kocher M., Abacioglu U., et al A European Organiszation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation after surgical resection of one to three cerebral metastases: quality of life results J.Clin.Oncol. 2011; 31:65-72 7.Aoyama H., Tago M., Shirato H. et al Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial JAMA 2006; 295: 2483-91 8.Sperduto P.W., Shanley R., Luo X., et al Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation verus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int.J.Radiat.Biol.Phys. 2014; 90: 526-531 9.Gondi V., Hermann B.P., Mehta M.P., Tome W.A. Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int. J. Radiat. Oncol. Biol. Phys. 2012 ; 83 : 487–93

Abstract not provided

Abstract:
The optimal management of patients with CNS metastases from lung cancer should be a multidisciplinary approach which encompasses supportive therapy, local CNS-directed therapies including surgery, stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT), and most importantly systemic therapy. In the case of patients with small cell lung cancer (SCLC), both the primary tumour and systemic metastases are generally chemosensitive, at least initially. Most studies suggested that brain metastases are as sensitive to systemic chemotherapy as extracranial disease. The concept of the brain as a pharmacologic sanctuary site for established metastases is in contrast with clinical observations of frequent responses in brain metastases to systemic chemotherapy. Response rates (RRs) of brain metastases from SCLC to systemic chemotherapy in treatment naive patients have been reported to range from 27% to 85%. RRs in previously treated patients with brain metastases range from 22% to 50% and are comparable to the RRs with second-line chemotherapy observed in extracranial disease. A meta-analysis of five studies with a single chemotherapy for pretreated patients showed RRs ranging from 33% to 43%.[1] Adding WBRT to chemotherapy increases the RR of the brain metastases, but does not appear to improve survival as shown in a phase III trial by the European Organization for Research and Treatment of Cancer.[2] For patients with advanced non-small cell lung cancer (NSCLC) without molecular drivers, chemotherapy is the mainstay of treatment. Although NSCLC is less responsive to systemic chemotherapy than SCLC, results of combining platinum compounds and third generation agents are substantially better than with earlier regimens. Platinum-based doublets are the cornerstone treatment in the first-line setting for metastatic NSCLC.[3] There is a presumed lack of effectiveness of systemic chemotherapy in CNS metastases from NSCLC because of the belief that chemotherapeutic drugs cannot cross the blood-brain barrier (BBB).[4] However, there is increasing evidence that the integrity of the BBB is impaired and disrupted in the presence of macroscopic CNS metastases. Despite a low penetration of the CNS, chemotherapy drugs have demonstrated encouraging activity against CNS metastases from NSCLC. A number of phase II studies reported RRs to cisplatin-based combination chemotherapy regimens ranging from 35% to 50%. Several clinical trials with upfront platinum-based chemotherapy have shown intracranial RRs ranging from 23% to 50% which correlated with and almost comparable to systemic RRs.[5 ]These data suggest that the intrinsic sensitivity of the tumour to the cytotoxic drug is more important in predicting response to the chemotherapeutic drug than the theoretical expected ability of the drug to penetrate the BBB. There are few randomised phase III trials of advanced or metastatic NSCLC evaluating different kinds of treatment in patients with brain metastases because generally, such patients have been excluded from clinical trials because of poor prognosis. Despite a penetration of CNS of less than 5%, pemetrexed demonstrated a consistent activity against brain metastases from NSCLC. One of the first evidence of pemetrexed activity against brain metastases came from a retrospective Italian study by Bearz and colleagues on 39 NSCLC patients with CNS metastases treated with pemetrexed as second or third line.[6] Although the patients were unselected for histology, the study reported an intracranial RR of 30.8%, with clinical benefit obtained in 69% of patients. All patients who had an overall response (i.e., partial response and stable disease) to pemetrexed had a benefit over cerebral metastases as well with partial response in 11 patients (28.2%) and stable disease in 21 (53.8%), with a clinical benefit rate of 82% for CNS metastases and an overall survival (OS) of 10 months. The addition of platinum compounds to pemetrexed slightly improved the outcome as shown in subsequent studies. In a phase II trial on 43 chemotherapy naïve NSCLC with brain metastases (93% with non-squamous histology) treated with pemetrexed and cisplatin for six cycles, the intracranial RR was 41.9%.[7] A comparable intracranial RR of 40% was observed when pemetrexed was combined with carboplatin in an observational study on 30 patients with adenocarcinoma and brain metastases.[8] These clinical trials showed that platinum-based regimens are active against brain metastases from NSCLC and high RRs can be achieved with pemetrexed-containing regimens in patients with non-squamous NSCLC. A post-hoc analysis of a large prospective observational European study on 1,564 patients with newly diagnosed advanced NSCLC receiving first-line platinum-based regimens showed that in the subgroup of 263 patients with brain metastases the median OS was 7.2 months which ranged from 5.6 months for patients treated with cisplatin/gemcitabine up to 9.3 months for those treated with platinum/pemetrexed.[9] In conclusion, systemic chemotherapy is an important part of the multidisciplinary managment of CNS metastases. Patients with small asymptomatic brain metastases from SCLC and NSCLC should be treated with the most active platinum-based combination chemotherapy upfront. Radiation therapy and other CNS-directed treatment may be deferred until the effects of the systemic chemotherapy on the CNS metastases can be determined. References 1. Grossi F, Scolaro T, Tixi L, et al. The role of systemic chemotherapy in the treatment of brain metastases from small-cell lung cancer. Crit Rev Oncol Hematol 2001; 37:61-7. 2. Postmus PE, Haaxma-Reiche H, Smit EF, et al. Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 2000; 18:3400. 3. Du L, Morgensztern D. Chemotherapy for Advanced- Stage Non-Small Cell Lung Cancer. Cancer J 2015;21:366-70. 4. Schuette W. Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer 2004; 45:S253-7. 5. Zimmermann S, Dziadziuszko R, Peters S. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev 2014; 40:716-22. 6. Bearz A, Garassino I, Tiseo M, et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung Cancer 2010; 68:264-8. 7. Barlesi F, Gervais R, Lena H, et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann Oncol 2011; 22:2466-70 8. Bailon O, Chouahnia K, Augier A, et al. Upfront association of carboplatin plus pemetrexed in patients with brain metastases of lung adenocarcinoma. Neuro Oncol 2012; 14:491-5. 9. Moro-Sibilot D, Smit E, de Castro Carpeño J, et al. Non-small Non-small cell lung cancer patients with brain metastases treated with first-line platinum-doublet chemotherapy: Analysis from the European FRAME study. Lung Cancer 2015; 90:427-32.

Abstract:
Central nervous system (CNS) metastases including brain metastasis (BM) and leptomeningeal metastasis (LM) are associated with poor prognosis in non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutations were initially reported in 2004 and currently defined the most prevalent actionable genomically classified subgroup of NSCLC, which account for 40% of Asian patients and 10-15% of White or African American patients. Patients with EGFR mutant NSCLC may have a higher incidence of CNS metastases due to prolonged survival with targeted agents and the increased quality of CNS imaging. More than 50% of NSCLC patients with EGFR mutation develop CNS metastases during their lifetime (1). The median overall survival (OS) for patients with BM is around 16 months (2) and 4.5-11 months for those with LM (3). Whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or surgery is widely used for BM, whereas no standard therapy is available for LM. Moreover, the benefit of radiotherapy is limited due to toxicities and long term sequelae. Brain is a privileged site, sheltered from the systemic circulation by the blood-brain-barrier (BBB), which is highly specialized structure with tight junctions created by the interaction between astrocytes, pericytes and endothelium. In addition, numerous efflux transporters (e.g. P-glycoprotein) have been identified, leading to prevent many traditional drugs from the circulation into the brain parenchyma. Although the permeation of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib across the BBB has been reported, the cerebrospinal fluid (CSF) concentrations of TKIs at standard doses comprise only small fraction of the plasma concentration indicating the limited ability to permeate into the CSF (4). Several small series of phase II studies reported that EGFR TKIs, gefitinib, erlotinib or afatinib show CNS response rate of 55 to 89%, median PFS of 5.8 to 14.5 months and median OS of 15.9 to 22.9 months in patients with brain metastases. Recently, new generation EGFR TKI, AZD 3759 which is designed to effectively penetrate BBB demonstrated profound anti-tumor activity in preclinical models. Phase I study showed the free plasma concentration of AZD 3759 was approximately at the same range as that in CSF and yielded K~p,uu~,~CSF~ values of 1.18 and 1.00 for 200mg and 300mg, respectively. Tumor responses were observed in 83% and 72% of the patients with CNS and extracranial disease respectively in EGFR TKI naïve NSCLC (5). Osimertinib, a third generation EGFR TKI designed to target both activating EGFR mutation and T790M but sparing wild type EGFR, distributed into mouse brain to a greater extent than gefitinib (brain/plasma ratio 3.4 for osimertinib vs 0.21 for gefitinib). Osimertinib showed significant brain exposure and tumor shrinkage in preclinical brain metastases model. In 50 of 411 evaluable for CNS response in pooled AURA phase II study, osimertinib showed 53% of response rate and the median CNS PFS has not been reached (6). Confirmatory phase III study comparing osimertinib with platinum-doublets in T790M positive patients demonstrated significant improvement of PFS regardless of CNS metastases suggesting this agent has benefit in patients with CNS metastases. Recently released press showed that first-line osimertinib comparing with gefitinib/erlotinib (FLAURA) met the primary endpoint of PFS. It would be interesting to evaluate whether upfront use of osimertinib in EGFR mutant NSCLC can delay CNS metastases. Given the relatively high response rate in brain metastasis with EGFR TKI, the upfront use of EGFR TKI can delay other local therapies such as WBRT, SRS or surgery, leading to reduced side effects related to local therapy. However, the retrospective multi-institutional analysis demonstrated that the use of upfront EGFR TKI and deferral of radiotherapy is associated with inferior OS in patients with EGFR mutant NSCLC who developed brain metastases (7). Based on the potential synergistic effects of the combination of EGFR TKIs and radiotherapy due to opening of BBB by radiotherapy, several prospective trials were conducted. A phase II study of erlotinib combined with WBRT in 40 patients with NSCLC achieved 86% of response rate, 11.8 months of overall survival, whereas 19.1 months in patients with EGFR mutation (8). The Radiation Therapy Oncology Group conducted a phase II trial of WBRT and SRS alone or with either temozolomide or erlotinib for NSCLC patients with one to three brain metastases (EGFR mutation status was not tested). This study was closed early due to slow accrual and three arms did not show any differences in terms of efficacy. However, grade 3 to 5 toxicities were 41-49% in two concurrent drug combination arms. Thus, prospective randomized trial of SRS followed by EGFR TKI vs EGFR TKI followed by SRS at CNS progression is needed. Leptomeningeal disease (LM) is a fatal manifestation and its incidence is increasing in EGFR mutant NSCLC up to 10%. The prognosis remains very poor despite systemic treatment, intrathecal chemotherapy, radiotherapy and even molecular targeted therapy. Although EGFR TKIs have shown promising efficacy in the treatment of LM, especially with high dose or pulsatile dosing, the duration of efficacy is still limited with lack of survival improvement (9). Compared to gefitinib, erlotinib showed higher CSF concentrations (28.7 vs 3.7 ng/ml) and retrospective analysis showed promising activity with erlotinib in LM. It is not clear whether combination of intrathecal chemotherapy or WBRT can be applied to EGFR mutant NSCLC patients. Given the significantly higher penetration across the BBB (K~p,uu,brain ~=0.86) of AZD 3759, AZD3759 showed 28% of response rate (5/18) in TKI pretreated LM patients and 75% (3/4) in TKI naïve patients suggesting promising efficacy. The mean osimertinib concentration in CSF was 7.5nM in the T790M unselected cohort and AZD 9291 at 160mg once daily demonstrated encouraging activity with 43% of LM disease response and manageable tolerability (10). Both agents are currently being investigated in a larger cohort of patients with brain metastasis and leptomeningeal disease. Another challenge of conducting clinical trial in patients with LM is lack of standardized response evaluation method. Combinational measurements including neurological sign, CNS imaging and CSF cytology have been proposed, but further validation is warranted. In conclusion, CNS metastases in EGFR mutant NSCLC are increasing. Although EGFR TKI has been reported to improve clinical outcome, isolated or pre-dominant progression of CNS metastases remains a major issue in patients on EGFR inhibitors due to relative low penetration to BBB. New generation EGFR TKIs with better BBB penetration might have an impact on therapeutic strategies. Further studies are required to evaluate the optimal sequence of EGFR TKI therapy and radiotherapy. References Rangachari D, , et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 2015; 88: 108-11. Fan Y, Xu X, Xie C. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data. Onco Targets Ther 2014; 7: 2075-84. Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small-cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer 2012; 77: 134-9. Togashi Y, Masago K, Masuda S, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70: 399-405, 2012. Ahn MJ, Kim DW, Kim TM, et al. Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM)., ASCO Meeting Abstracts. 34 (2016) 9003. Goss G, Tsai CM, Shepherd F, et al. CNS Response to osimertinib in patients with T790M-positive advanced NSCLC: Pooled data from two phase II trials. J Thorac Oncol Vol. 12 No. 1S (MA16.11)x William J. Magnuson, Nataniel H. Lester-Coll, et al. Management of brain metastases in tyrosine kinase inhibitor–naïve epidermal growth factor receptor–mutant non–small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol 35:1070-1077.James Chih-Hsin Yang Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 31: 895-902, 2013. Yu HA, Sima CS, Reales D, et al. A phase I study of twice weekly pulse dose and daily low dose erlotinib as initial treatment for patients (pts) with EGFR-mutant lung cancers. J Clin Oncol33(Suppl 15s): 426s, 2015. Yang J.C.-H, Kim DW, Kim, SW, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study., ASCO Meeting Abstracts. 34 (2016) 9002.Search for articles by this authorAffiliations Cancer Research Center, National Taiwan University, Taipei/Taiwan

Abstract:
Despite fast growing information of tumor molecular biology, the increase in the therapeutic portfolio, and a significant improvement in diagnostic radiology, treatment of advanced NSCLC in 2017 remains palliative with still no curative perspective for the vast majority of patients. Therefore, the main treatment goals include the change from an acute into a chronic disease, extending survival times as well as improving or just maintaining quality of life. In order to assure an optimal palliation the majority of patients with advanced NSCLC – considering the high age and concomitant comorbidities - frequently may require modifications of the treatment standard. Furthermore, it can also not be ignored that recently approved novel agents and innovative diagnostic technology represent a growing burden of financial toxicity leading to regional differences in the availability of modern therapy and in the access to molecular testing and modern imaging. Nonetheless, treatment algorithms for advanced NSCLC have over the last decade gradually gained in complexity by incorporating a number of diagnostic and therapeutic achievements allowing personalization, individualization, and precision of therapy. Not only patient factors such as performance status (PS), comorbidity, and patients’ treatment expectation must lead to treatment differentiation and modification but also disease characteristics such as tumor stage, tumor load, histological type (squamous vs non–squamous) and the molecular profile of the tumor (mutant vs wild type) influence the process in reaching the goal of optimal sustainable palliation. Other critical elements in realizing personalized therapy and precision medicine within the process of optimal palliation consist in a rational selection of anti-cancer agents (predictive factors, mode of action, toxicity profile) and their appropriate application (single agent, concomitant combinations, drug sequencing) as well as other novel therapeutic actions such as interventional radiology, modern radio therapy, and minimal surgery. Optimal therapeutic management for sustainable palliation should definitely be based on clinically reliable evidence presented by frequently updated treatment recommendations: Today’s treatment algorithm for advanced NSCLC is challenged by a number of newer agents, such as tyrosine kinase inhibitors, monoclonal antibodies, checkpoint inhibitors (Table 1),

2nd-line	Docetaxel, Pemetrexed, EGFR-TKI	1st-line	Bevacizumab - non-squamous NSCLC
|	Ramucirumab / Doc - NSCLC	|	Bevacizumab/Erl. – EGFRm NSCLC
|	Nintedanib / Doc - non-squamous	|	Pemetrexed - non-squamous NSCLC
|	Nivolumab - NSCLC	|	Pemetrexed, Erlotinib - maintenance
|	Osimertinib - EGFRmT790M	|	Gefitinib, Erlotinib, Afatinib - EGFRm
|	Crizotinib, Ceritinib – ALK	|	Necitumumab - squamous NSCLC
|	Alectinib - ALK	|	Crizotinib - ALK/ROS
|	Pembrolizumab – PD-L1-low	|	Ceritinib – ALK
|	Atezolizumab - NSCLC	|	Alectinib -ALK
		|	Pembrolizumab - PD-L1-high

Table 1 and the incorporation of new treatment strategies such as continuation or switch maintenance therapy (Figure 1).Figure 1 Figure 1 For advanced NSCLC (Figure 2) it is generally accepted that platinum based doubled chemotherapy remains the backbone for the majority of our patients with good PS and this combination therapy should be modified according to feasibility and tolerability, comorbidity, patients’ age over 70 years, PS. Figure 2 Figure 2 For wild type non-squamous NSCLC there is pemetrexed which has been shown to be favorable over older cytotoxic agents if combined with platinum based components. In addition, pemetrexed has also sufficiently demonstrated that if it is continued in case non-progression under four cycles of standard platinum based doublet chemotherapy not containing pemetrexed (switch maintenance) or containing pemetrexed (continuation maintenance) prolongs survival. Another agent, the small molecule and EGFR-tyrosine kinase inhibitor erlotinib also prolongs survival if used in the switch maintenance setting but its benefit depends on the quality of response to the chemotherapy and is restricted to patients which have experienced disease stabilization only. The VEGFR-targeting antibody, bevacizumab, if added to platinum based doublet therapy, specifically to carboplatin/paclitaxel significantly improves response rate, duration of response, progression free survival, as well as overall survival in eligible patients. Human immune checkpoint inhibitor-antibodies inhibiting the PD-1 receptor or PD-1 ligand have recently been integrated into the treatment algorithms of wild type NSCLC. Pembrolizumab is currently the only checkpoint inhibitor approved and recommended for first line therapy in patients with a PD-L1 expression level ≥ 50 % and with negative or unknown EGFR/ALC/ROS1 testing. In wild type squamous NSCLC the given treatment options are still limited and platinum based therapy (no pemetrexed, no bevacizumab) remains the recommended treatment standard. Nonetheless, just recently the EGFR-targeting monoclonal antibody necitumumab has shown to significantly improve survival if combined with the standard doublet regimen cisplatin/gemcitabine in comparison to cisplatin/gemcitabine only and therefore, has just recently approved. Maintenance therapy in squamous tumors with docetaxel or erlotinib (switch) or gemcitabine (continuation) may be justified in some patients even here the statistical evidence is weak. For about 10-30% of NSCLC (in Europe < 15%) non-squamous tumors expressing specific molecular features first-line treatment by genotype has been established. Tumors with sensitizing EGFR mutations have been exposed by gefitinib, erlotinib, and afatinib and have shown to prolong progression free survival over standard platinum based doublet standard therapy. In tumors bearing ALK-/ROS1-gene-rearrangements crizotinib and ceritinib have also shown to prolong progression free survival if compared to platinum based / pemetrexed doublet chemotherapy. Therefore, EGFR-TKI therapy (erlotinib, gefitinib, afatinib) should be prescribed for patient with tumors bearing sensitizing EGFR-mutations and for patients with tumors bearing ALK-/ROS1-gene-rearrangements ALK-/ROS1-targeted therapy (crizotinib, ceritinib) 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). Last but not least, second-/subsequent-line therapy is another strong element contributing to sustainable palliation in patients with advanced NSCLC. For tumor without driver mutations agents available before 2014 include docetaxel, pemetrexed (for non-squamous cell tumors only) and erlotinib. In recent years the two antiangiogenic agents nintetanib and ramucirumab (both in combination with docetaxel) and three immune checkpoint inhibitors (nivolumab, pembrolizumab, azetolizumab) have been added to the armentarium to treat patients with advanced non-mutated NSCLC who have progressed on or after first-line therapy (Figure 2). In mutated NSCLC several therapeutic options for second-/subsequent line-therapies are recommended depending on the type of progression and the molecular profile of the tumor. Osimertinib has been just recently approved for EGFRm/790M expressing tumors. For ALK-positive tumors ceritinib, alectinib, and crizotinib can be prescribed. In general, selection of agents for second-/subsequent-line therapies is based on whether the drugs have been used earlier, or toxicity or patients view. References are available by the author.

Abstract:
Lung cancer is the leading cause of death in the world. Approximately 85% of patients are diagnosed with advanced disease, associated with high morbidity and mortality. Lung cancer is associated with a higher burden of symptoms compared to other cancers. Patients may experience symptoms from disease such as cough, dyspnea, anorexia, malaise, pain and anxiety. Lung cancer patients often report symptom clusters (2 or more symptoms occurring simultaneously). Patients may also experience symptoms secondary to immediate and chronic side effects of treatment. Treatments for lung cancer include surgery, radiation therapy, chemotherapy, targeted therapy and immunotherapy. Patients may receive a combination of these therapies either concurrently or sequentially. Each therapy is associated with a unique adverse symptom profile. Collectively these symptoms negatively impact clinical outcomes. High symptom burden is associated with poorer clinical outcomes such as survival and health related quality of life (HRQOL). HRQOL is the evaluation of the patients own life situation from their perspective. HRQOL may also be referred to as patient reported outcomes (PROS) and the measurement referred to as patient reported outcome measures (PROMs). HRQOL is subjective and multidimensional. HRQOL measures include physical, psychological, cognitive, social and life roles. Quality of life may be negatively influenced by risk factors such as co-morbid medical conditions, poor nutritional status, emotional distress, sleep disturbances, poor pulmonary function, poor financial resources, poor social support and past family history. Poor nutritional status, including malnutrition, sarcopenia and cachexia, is associated with poor quality of life, poor response to treatment and decreased survival. Emotional distress, anxiety and depression, is linked to lower HRQOL, increased symptom burden and poorer prognosis. Previous experience with family cancer and perceived risk of cancer, specifically among women, is associated with poorer reported HRQOL. Caregivers of patients with poorer HRQOL have a greater caregiver burden. This in turn negatively impacts the patients HRQOL further. Maximizing quality of life is an essential component of lung cancer management. Pre-diagnosis HRQOL and HRQOL at diagnosis are a strong prognostic factor for survival in lung cancer. HRQOL measurements are useful to evaluate treatment efficacy. HRQOL is an important clinical outcome measure to consider as newer treatments and improved therapeutics are providing the opportunity for long term survival for some patients. It is especially important in cases when therapy is unlikely to be curative, as patients often report that HRQOL is more important than short term survival benefits. Several instruments have been developed to assess HRQOL (Table 1). Some of the tools are generic, some specific to cancer and others that specifically focus on lung cancer. Most of the instruments are questionnaires. Several tools developed demonstrate correlation with performance status, symptoms and survival. Studies suggest that disease specific instruments may enhance outcome measures and be more useful in predicting outcomes. The tools specific to lung cancer include: The Lung Cancer Symptom Scale (LCSS), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTIC-QLQ), Functional Assessment of Cancer Therapy-Lung (FACT-L) and the Short Form Health Survey (SF). The City of Hope Quality of Life Family Care Giver Tool (COH-QOL-FCG) focusses specifically on the quality of life impacted by the family care giver. Table 1

Tool	Questions	Context Areas
The Lung Cancer Symptoms Scale (LCSS)	15	Patient and observer (healthcare professional) forms. Measures physical and functional dimensions
EORTC-QLQ C30	30	Cancer symptoms, physical symptoms, 5 functional areas (physical, role, cognitive, emotional, social), overall financial impact.
EORTC-QLQ-LC 13	13	Developed as supplement to the QLQ-C30 above. 13 items assess lung cancer symptoms, treatment related side effects (chemotherapy specific) and pain
Functional Assessment of Cancer Therapy-Lung (FACT-L)	37	Combination of the FACT-generic 27 questions on general QOL (physical, social and family, emotional, functional well-being and relationship with physician), and 10 items on lung cancer specific symptoms.
Short Form Health Survey (SF-36)	36	General health (physical function, role physical function, bodily pain, general health perception, vitality, social functioning, role emotional, mental health) with 2 summary scales measuring physical and mental component scales.
City of Hope Quality of Life Family Care Giver Tool (COH-QOL-FCG)	37	Measures physical, psychological, social and spiritual

There are some inherent limitations of the instruments. The scales have been developed by health care providers who may have different biases on what defines HRQOL. Therefore, there are likely metrics that are missing from the measures obtained. Accurate and consistent data collection may be influenced by fluctuations in the patients’ health status and symptom burden, making it difficult for them to complete questionnaires. If instruments are completed by a caregiver or healthcare provider, performance status may be used as a proxy for overall HRQOL. While performance status is correlated with HRQOL, it does not include all parameters. Operational barriers may be time demands on the health care provider, space limitations or technology breakdown when using online access. Other barriers may be the influences of language, culture, religion, age and educational level. Health care providers should continue to explore other strategies for capturing HRQOL data. The overall goal of health care providers is to improve the lives of patients. Better HRQOL is associated with better performance status, less frequent symptoms, lower anxiety, and improved response to treatment. Therefore, health care providers should continue to develop strategies that enhance HRQOL. HRQOL assessment provides an opportunity to assess for symptoms and potentially modifiable risk factors that negatively impact HRQOL and long term outcomes. This provides the bases for designing interventions that enhance HRQOL. Ongoing efforts include: refining surgical procedures, radiation techniques, selection of systemic therapeutics (chemotherapy, targeted therapy and immunotherapy) and combinations, with on maintaining efficacy with improved HRQOL outcomes. Focused interventions on modifiable factors may include: aggressive symptom management, structured supportive and palliative care, structured distress screening, resilience building, nutritional support, physical therapy and activity, family caregiver support. Consideration of HRQOL is an integral responsibility of all members of the healthcare team. References Borges, E.L., Franceschini, J., Costa, L.H.D., Gernandes, A.L.G., Jamnik, S. & Santoro, I.L. (2017). Family caregiver burden: the burden of caring for lung cancer patients according to stage and patient quality of life. J. Bras Pneumol. 43 (1): 18-23. Bye, A., Sjøblom, B., Wentzel-Larsen, T., Grønberg, B.H., Baracos, V.E……Jordhøy, M. (2017). Muscle mass and association to quality fo life in non-small cell lung cancer patients. Journal of Cachexia, Sarcopenia and Muscle. May 10. doi: 10.1002/jcsm.12206. [Epub ahead of print] Chabowksi, M, Polanski, J, Mazur, G, Janczak, D. & Rosinczuk, J. (2017). Sociodemographic and clinical determinants of quality of life of patients with non-small cell lung cancer. Advs Exp Medicine, Biology-Neuroscience & Respiration. Jun 2. doi: 10.1007/5584_2017_36. [Epub ahead of print] Delibegovic, A., Sinanovic, O., Galic, G., Sabic, A. & Sabic, D. (2016). The influence of palliative care on quality of life in patients with lung cancer. Mater Sociomed. 28 (6): 420-423. Eser, S., Göksel, T., Erbaycu, A.E., Baydur, H., Başank, B….Eser, E. (2016). Comparison of generic and lung cancer-specific quality of life instruments for predictive ability of survival in patients with advanced lung cancer. Springer Plus.5: 1833. Lou, V.W.Q., Chen, E.J., Jian, H., Zhou, Z., Zhu, J, Li, G. & He, Y. (2017). Respiratory symptoms, sleep, and quality of life in lung cancer. Journal of Pain and Symptom Management. 53 (2): 250-256. Morrison, E.J., Novotny, P.J., Sloan, J.A, Yang, P., Patten, C.A., Ruddy, K.J. & Clark, M.M. (2017). Emotional problems, quality of life, and symptom burden in patients with lung cancer. Clinical Lung Cancer. Mar 2. pii: S1525-7304(17)30051-7. doi: 10.1016/j.cllc.2017.02.008. [Epub ahead of print] Pinheiro, L.C., Zagar, T.M. 7 Reeve, B.B. (2017). The prognostic value of pre-diagnosis health related quality of life on survival: a prospective cohort study of older Americans with lung cancer. Qual Life Res. 26: 1703-1712. Polanski, J, Jankowska-Polanska, B., Rosinczuk, J., Chabowski, M & Szymanska-Chabowska A. (2016). Quality of life of patients with lung cancer. Onco Targets Ther. 9:1023-8.

Abstract:
In the lung cancer field, several studies have described the relationship between prognosis and quality of life (QoL), with most reports (Table 1), concluding a QoL evaluation of patients with advanced lung cancer before the start of chemotherapy could predict a patient’s prognosis. Such reports described common features: a poor prognosis for investigated patients whose disease was at an advanced stage and/or who were elderly, and the use of cytotoxic agents or irradiation, with poor efficacy. Molecular targeted drugs for epidermal growth factor receptor (EGFR) mutations and the anaplastic lymphoma kinase (ALK) fusion gene have recently been used in clinical practice. Such agents have led to dramatic improvements in patients with driver mutations. Indeed, we witnessed a “Lazarus response” during the NEJ001 study [1], which investigated the efficacy of an EGFR–tyrosine kinase inhibitor (TKI), gefitinib, for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations with a poor performance status (PS): The PS improvement rate was 79% (p<0.00005); in particular, 68% of 22 patients improved from ≥PS 3 at baseline to ≥PS 1. And median survival time of the EGFR-mutated patients was 17.8 months, while that of the patients without EGFR mutations was 3.5 months. Unfortunately, following the introduction of “precision medicine” for lung cancer, few reports have described the relationship between prognosis and QoL. Herein, we describe NSCLC patients with an EGFR mutation treated with gefitinib or chemotherapy as first-line treatment in a randomized phase III study, termed NEJ002 [2]. The patients’ QoL was assessed prior to treatment and, thereafter, weekly by the Care Notebook [3]. The relationship between prognosis and QoL data, employed before and 4 weeks after the initiation of treatment, was analyzed by univariate and multivariate Cox regression. QoL data from 148 patients (72 in the gefitinib arm and 76 in the chemotherapy arm) were analyzed. Multivariate Cox regression showed that only a fatigue score on the Care Notebook assessed 4 weeks after the start of gefitinib could predict a patient’s prognosis. Other QoL scores, including those before starting not only gefitinib but also chemotherapy, did not affect survival. Estimating Prognosis - How Accurate Can We Be as the QoL Researcher? We hypothesize answers fall into two patterns: In the case of employing agents with a poor efficacy, such as cytotoxic agents, the QoL score before treatment should be evaluated as done previously. However, when treating with a very effective agent, the QoL score under treatment should be employed because any improvement in prognosis and QoL is strongly dependent on the efficacy of the agent. The next theme is “Estimating Prognosis of the Patient - How Accurate Can We Be as the Attending Physician? Unfortunately, we do not have rigid evidence for employing QoL assessments. Measuring QoL can have clinical benefits as well as research benefits. These include fostering patient–provider communication, helping clinicians and patients to identify problems and set priorities, and to assess therapy, palliative care, and rehabilitation. However, in my experience of validating the Japanese version of the EORTC QLQ-C30 [4], the answering rate for PS 0–2 patients was over 99% (225/228), but the corresponding rates for PS 3 and PS 4 patients were 81% (38/47) and 13% (9/69), respectively. Furthermore, multiple regression analyses showed that Symptom scale (coefficient: 0.188, p=0.001) and Emotional functioning (coefficient: 0.156, p=0.004) significantly related to Global QoL functioning in patients with PS 0-2; however, Symptom scale alone (coefficient: 0.220, p=0.042) significantly correlated to it in those with PS 3-4. Thus, when the patient concentrates on his/her symptoms and/or fails to respond a QoL questionnaire due to poor PS, a known adverse prognostic factor in advanced cancers, the attending doctor could recognize the patient’s short survival. Two studies have succeeded in showing the prolongation of patients’ survival under palliative care. Jennifer et al. [5] randomly assigned patients with newly diagnosed metastatic NSCLC to receive either early palliative care integrated with standard oncologic care or standard oncologic care alone. The FACT-L scale, including the lung cancer subscale (LCS) and Trial Outcome Index (TOI), measured at 12 weeks revealed that patients assigned to early palliative care had a better QoL than did patients assigned to standard care (p = 0.03). In addition, median survival was longer among patients receiving early palliative care (11.6 months vs. 8.9 months, p = 0.02). Basch et al. highlightened the importance of monitoring symptoms at ASCO 2017 [6]. Patients receiving routine outpatient chemotherapy for metastatic solid tumors, including lung cancer, were randomly assigned to self-report 12 common symptoms via tablet computers (“PRO intervention”), or to usual care. Median overall survival in the PRO intervention arm was 5 months longer than the control arm (31.2 vs. 26.0 months, HR, 0.832, p = 0.03). These two studies indicate that symptomatic QoL monitoring is critical for clinical practice and for predicting prognosis. Table 1 Studies on relationship between baseline QoL score and survival in advanced NSCLC patients

Reference	Therapy type	Number of patients	Questionnaire	Prognostic, baseline scale/item
Herndon et al. Cancer 1999, 85:333-340.	Cisplatin/vinblastine	206	EORTC QLQ-C30	Pain
Langendijk et al. Radiother Oncol 2000,55:19-25.	External irradiation (>/=60 Gy)	198	EORTC QLQ-C30	Global QOL
Moinpour et al. Qual Life Res 2002,11:115-26.	Cisplatin+vinorelbine or Carboplatin+paclitaxel.	222	FACT-L	Total FACT-L score
Eton et al. J Clin Oncol 2003, 21:1536-1543.	Cisplatin+etoposide or Cisplatin+paclitaxel	573	FACT-L + TOI	Physical well-being and TOI
Maione et al. J Clin Oncol 2005, 23:6865-6872.	Vinorelbine+gemcitabine, Vinorelbine alone, or Gemcitabine alone	566	EORTC QOL-C30	Global QOL
Sundstrøm S, et al, J Thorac Oncol. 2006;1(8):816-24.	Palliative radiotherapy	301	EORTC QOL-C30	Appetite loss
Efficace et al. Ann Oncol 2006, 17:1698-1704.	Paclitaxel+cisplatin Gemcitabine+cisplatin Paclitaxel+gemcitabine	391	EORTC QLQ-C30 + QLQ-LC13	Pain, and dysphagia

[1] Inoue A, et al. First-line gefitinib for patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations without indication for chemotherapy. J Clin Oncol. 2009;27(9):1394-400. [2] Maemondo M, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362(25):2380-8. [3] Kobayashi K, et al. Validation of the care notebook for measuring physical, mental and life well-being of patients with cancer. Qual Life Res. 2005;14(4):1035-43. [4] Kobayashi, K, et al. A cross-validation of the European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30) for Japanese with lung cancer Eur J Cancer 1998;34:810-815. [5] Temel JS, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733-42. [6] Basch EM, et al. Overall survival results of a randomized trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. (Abstract LBA2) presented in ASCO2017.

Abstract not provided

Abstract:
The incidence rate of lung cancer has declined in males and increased in females in Korea (Jung et al., 2017). In the United States, lung cancer incidence rates began declining in the mid-1980s in men and in the mid-2000s in women because of reductions in smoking prevalence that began decades earlier. Contemporary differences in lung cancer incidence patterns between men and women reflect historical differences in tobacco use (Siegel, Miller, & Jemal, 2016). Women took up smoking in large numbers decades later than men, first initiated smoking at older ages, and were slower to quit, including recent upturns in smoking prevalence in some birth cohorts (Giovino, 2002; Jemal, Ma, Rosenberg, Siegel, & Anderson, 2012). In the United States, the 3 most commonly diagnosed cancers are breast, lung and bronchus, and colorectum, representing one-half of all cases for women (Siegel et al., 2016). The purpose of this study is to analyze the correlation among mood state, distress, symptom experience, inner strength, and quality of life(QoL) in female patients with lung cancer. Also, this study includes descriptive research regarding the influence factors on QoL in them. A total of 206 research subjects who diagnosed with primary lung cancer at a cancer hospital in Gyeonggi, Korea were examined from 1 July 2016 to 31 October 2016. Several instruments were used for research methods: K-POMS-B for mood state, NCCN Distress Thermometer for distress, NCC for understanding aspect of distress, MDASI-LC for symptom experience, ISQ for inner strength, and FACT-G for QoL. Data of this study was analyzed by using SPSS Ver. 23.0 for Windows. The general and diseased characteristics of patients were analyzed through descriptive statistics, frequency, percentage, average, and standard deviation. Independent t-test and One-way ANOVA were used to examine differences according to their characteristics. Bonferroni correction, Pearson correlation coefficient, and hierarchical multiple regression for impact factors of QoL were also used. For reliability, Cronbach’s α was calculated. The results of this study are as fellows; 1. The mean score of the mood disorder was 20.74, symptom experience was 2.88, symptom degree was 2.76, disturbance of daily life was 3.01. The mean score of the inner strength was 97.98. Among sub-categories, the mean score of the searching for meaning on disease was 18.53, fellowship was 27.0, self-determination was 25.2, activity and rest was 27.1. The total mean score of QoL was 66.69, physical stability was 19.13, social stability was 18.04, emotional stability was 16.19, function status was 13.32. The highest result was in physical stability, whereas function status gained the lowest result. The mean score of distress was 4.19, sleep disorder was 3.2, insomnia affecting daily life was 2.45, anxiety symptom was 2.79, anxiety symptom affecting daily life was 2.25, depression was 1.92, depression affecting daily life was 1.68. In categories asking the needs of medical care, it was measured that insomnia was 38.5%, anxiety was 41,7%, depression was 19.9%. 2. The factors affecting in QoL were occupation, expectation of treatment outcome, activity ability, inner strength, symptom experience (the severity of symptom, the severity of disturbance of daily life), and mood state. 3. Higher scores in symptom experience, distress, and mood disorder categories have lower quality of life than those with higher scores of inner strength. 4. As a result of hierarchical analysis, these suggested that occupation status, expectation of treatment outcome (life extension), activity ability, inner strength, and symptom experience (the severity of symptom, the severity of disturbance of daily life) can be beneficial variables of QoL. The model was explained 70.7% of the total variance of quality of life. Cancer as a chronic illness places new demands on patients and families to manage their own care, and it challenges old paradigms that oncology's work is done after treatment. Therefore, to improve the quality of life in women survivors with lung cancer, we need to apply nursing interventions strengthening inner strength, activity ability, performance status, and symptom control.

Background:
Large-scale genomic characterization of large-cell neuroendocrine carcinoma (LCNEC) has revealed several putative oncogenic drivers. There are, however, little data to suggest that these alterations have clinical relevance.

Method:
We performed comprehensive genomic profiling of 68 stage IV LCNECs of the lung (including next-generation sequencing) and analyzed differences in the clinical characteristics of two major LCNECs subtypes: KRAS mutation and PIK3CA mutation. In order to better understand the divergence that might exist between brain metastases and their lung primaries, we performed whole-exome sequencing of paired lung primaries and brain metastases from four lung LCNEC patients.

Result:
Patients with PIK3CA mutation tumors had aggressive disease marked by worse survival (median OS 7.9 vs. 18.6 mo, P = 0.002), higher metastatic burden (> 3 organs 15.2% vs. 4.7%, P = 0.029), and greater incidence of brain metastases (19.0% vs.2.3% in others, P = 0.001). Whole-exome and RNA sequencing on paired brain metastases and primary LCNECs of the lung revealed that LCNEC primaries that gave rise to brain metastases harbored PIK3CA mutation. Significant tumor growth inhibition with GDC0941 was observed exclusively in the LCNEC patient-derived xenograft model that harbored PIK3CA mutation.

Conclusion:
PIK3CA mutation defines a distinct disease phenotype characterized by brain metastasis in LCNEC of the lung. The result may be relevant for targeted therapy and prophylaxis of NSCLC brain metastases.

Background:
Rovalpituzumab tesirine is a promising first-in-class DLL3-targeted antibody-drug conjugate for the treatment of HGNECs. In clinical practice, biopsies are often rendered for diagnoses of HGNECs before treatment. We tested DLL3 in paired biopsy and surgical specimens, aiming to assess the reliability of the scoring system in biopsy specimens and the correlation with HGNEC clinical characteristics and prognoses.

Method:
A total of 378 patients with de novo HGNECs, including 43 LCNECs and 335 SCLCs, were recruited between 2006 and 2015. All 43 LCNECs and 42 of 335 SCLCs had paired biopsy and surgical excision specimens, and the remaining 293 SCLCs had only biopsies. Immunohistochemical evaluation of DLL3 expression was performed using anti-DLL3 antibody (Abcam, ab103102) and was determined using immunohistochemical H score (HS).

Result:
No significant differences of DLL3 expression levels were observed in paired biopsy and excision specimens of LCNECs and SCLCs (Figure B-C). Discordant DLL3 results (high, HS > 150 vs low, HS ≤ 150) in paired specimens were observed in none of LCNECs and 2 of 42 SCLCs. DLL3 levels were significantly higher (p = 0.015) in all SCLCs (n = 335, median HS 200, IQR 100-300) than in LCNECs (n = 43, HS 160, IQR 100-200; Figure D). SCLCs with high DLL3 levels were more frequently male (p = 0.037), smokers (p = 0.019), and TTF-1 positive (p = 0.005) than SCLCs with low DLL3. SCLCs with low DLL3 experienced a superior overall survival compared with SCLCs with high DLL3, with the difference, however, not reaching statistical significance (p = 0.077; Figure F). Figure 1



Conclusion:
Biopsy specimen is a reliable material for evaluating DLL3 expression, which is equivalent to surgical specimen in a large percentage of HGNECs. High DLL3 level in SCLCs demonstrate a correlation with smoking history, TTF1 (neuroendocrine differentiation) and a trend of poor survival.

Background:
Small cell lung cancer (SCLC) shows an aggressive course with early metastases to distant organs. The main treatment regimen for SCLC patients involves platinum based chemotherapy (cisplatin or carboplatin) and etoposide. Genetic alternations, as single-nucleotide polymorphisms (SNPs) in TOP2A (topoisomerase II alpha) and in ERCC1 (endonuclease non-catalytic subunit) genes, were tested as a prognostic and predictive factors in patients with non-small cell lung cancer (NSCLC) treated with chemotherapy. However, there is limited data about clinical relevance of these genetic alternations in SCLC. Therefore, we undertook the present retrospective study to determine the influence of SNPs in TOP2A (rs34300454; rs13695; rs11540720) and ERCC1 (rs11615; rs3212986) genes on efficiency and toxicity of chemotherapy with platinum and etoposide in patients with SCLC.

Method:
The studied group included 103 Caucasian SCLC patients (65 male, 38 female, median age 65 ± 7,5 years). We collected detailed clinical-demographical data including: smoking history, environmental/occupational exposure to carcinogens, performance status, disease stage, and the presence of distant metastases. The response to the treatment was carefully monitored according to RECIST criteria, as well as side effects as anemia, neutropenia or weight loss were noted. For SNPs genotyping, we used DNA isolated from peripheral blood leukocytes using Qiamp DNA Mini Kit (Qiagen, Germany) and TaqMan hydrolyzing probes (Applied Biosystem, USA) in real-time PCR technique on Eco Illumina (Illumina, USA) device.

Result:
Patients with C/C genotype in rs13695 of TOP2A gene had significantly lower risk of neutropenia during chemotherapy than C/T heterozygous patients (p=0,01894; χ²=5.51; OR=2,676; 95% CI=1,165-6,143). Patients harbouring homozygous C/C genotype in rs3212986 of ERCC1 gene had significantly higher risk of anaemia during chemotherapy than heterozygous C/A patients (p=0,04531; χ²=4,01; OR=0,417; 95% CI=0,175-0,991). Furthermore, homozygous A/A genotype in rs11615 of ERCC1 gene was associated with significant prolongation of overall survival (12 vs. 9 months) compared to heterozygous G/A genotype of this gene (p=0,0120; χ²=6,3063; HR=1,657; 95% CI=1,0710-2,5633).

Conclusion:
SNPs in ERCC1 and TOP2 genes are associated with the toxicities and overall survival of SCLC patients treated with platinum and etoposide based chemotherapy.

Abstract not provided

Background:
Small cell lung cancer (SCLC) accounts for 15-30% of newly diagnosed lung cancers. Although chemotherapy and radiation play a vital role in the initial management of limited-stage SCLC, rates of combined modality utilization in the United States have not been comprehensively studied. As such, the National Cancer Database (NCDB) is a valuable resource to understand patterns of care for limited-stage SCLC, as it captures the majority of newly diagnosed thoracic malignancies in the United States.

Method:
All cases of IASLC defined limited-stage SCLC in the United States National Cancer Database (NCDB) were identified from 2004 to 2013. Rates of chemotherapy and radiation utilization were determined along with key factors associated with their use. Kaplan-Meier analysis and multivariable analysis were used to determine factors independently associated with overall survival.

Result:
From 2004 to 2013, there were 70,247 cases with analyzable data in the NCDB that met IASLC criteria for limited-stage SCLC. Of these cases, 40% did not receive radiation and 20% received neither chemotherapy nor radiation. For the irradiated group, the mean radiation dose was 52.8 Gy with a 16.2 Gy interquartile range. On multivariable analysis, being uninsured (OR 0.75, 95% CI 0.67-0.85, p < 0.001), Medicaid (OR 0.79, 95% CI 0.72-0.87, p < 0.001), and Medicare (OR 0.86, 95% CI 0.82-0.91, p < 0.001) were independently associated with a lower likelihood of radiation delivery in comparison to private/managed care insurance (after adjusting for age, tumor stage, and co-morbidity score). The irradiated group had significantly better median survival than the non-radiated group (33 vs. 17 months, p < 0.001). Radiation (HR 0.62, 95% CI 0.6-0.63, p < 0.001) and chemotherapy (HR 0.55, 95% CI 0.54-0.57, p < 0.001) delivery were both independently associated with better survival on multivariable analysis. Adjusted analysis showed that non-academic programs (HR > 1, p < 0.001) and non-private/managed care insurance (HR > 1, p < 0.001) was independently associated with a survival detriment.

Conclusion:
This is the most comprehensive study currently available describing the utilization of combined modality therapy in the initial management of limited-stage SCLC in the United States. A remarkable number of patients received neither radiation nor chemotherapy as part of their initial oncologic treatment. Insurance status was a key determinant of radiation and chemotherapy delivery even after adjusting for potentially confounding factors. Our findings highlight substantial barriers to quality care delivery and challenges in accrual seen for cooperative group clinical trials for limited-stage SCLC.

Background:
Veliparib, a potent inhibitor of Poly (ADP) ribose polymerase (PARP) enzyme potentiates standard chemotherapy against small cell lung cancer (SCLC) in preclinical studies. The combination of veliparib (V) with cisplatin/etoposide (CE) doublet as first-line therapy of extensive stage SCLC (ES-SCLC) showed significant signal of efficacy with adjusted PFS HR: 0.63 1-sided p=0.01. There was strata by treatment interaction indicating different efficacy benefit in patient subsets (adjusted treatment HR comparing CE+V: CE: 0.34; 80% CI: 0.22 - 0.51; 1-sided p<0.001 for male patients with high tumor burden versus adjusted HR: 0.81 80% CI: 0.60 - 1.09; 1-sided p=0.18 for other patients subsets). We explored clinical and tissue-based biomarkers as predictors of benefit from this treatment strategy.

Method:
Post-hoc analysis of clinical data was conducted to identify clinical differences in patients who derived significant benefit from the experimental therapy. Clinical differences were compared between patients in the control and experimental arms within the patient stratum with significant clinical benefit. Similarly, comparison was performed between the strata. Archival tissue samples collected from patients with ES-SCLC enrolled and treated on E2511 study was employed for biomarker analysis using immunohistochemistry to assessSLFN11 and DNA-PK expression. The study has 88% power to detect a PFS hazard ratio of 0.5 comparing biomarker positive to negative patients using a one-sided 0.025 level logrank test.

Result:
There was an imbalance between control and experimental arms in the Male/abnormal LDH stratum (in strata) with respect to Age: p=0.006; malignant pleural effusion: p=0.095 and T stage: p=0.02. Median PFS was 5.1 mos on CE (95% CI 4.1-6.1) vs. 6.2 mos on CE+V (95% CI 5.9-8.8); HR=0.32, p=0.002 (unadjusted); median OS on CE was 8.8 mos (95% CI 6.6-11.1) vs. 9.5 mos on CE+V (95% CI 7.8-12.8); HR=0.76, p=0.39. Mutivariable analysis controlling for these imbalances still showed a benefit of veliparib (HR=0.26, p=0.001). Comparison of “in strata” group (N=46) to the “not in strata” group (N=82) showed significant imbalance in pleural effusion (p=0.058); elevated AST (p=0.0099) and bilirubin (p=0.0447). Median PFS was identical at 5.9 mos for both groups while median OS was 10.7 mos (95% CI 8.9-13.2) for “not in strata” subsests vs. 8.8 mos (95% CI 7.8-10.8) for “in strata” with a HR of 1.57 (p=0.027) comparing “in strata” to “not in strata”. Outcome differences based on SLFN11 and DNA-PK expression will be presented at the meeting.

Conclusion:
PFS benefit of PARP inhibitor therapy in extensive stage SCLC patients with elevated LDH and male gender was not associated with any other clinical characteristics.

Background:
We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLD).

Method:
This study is a randomized, placebo-controlled, phase II study that enrolled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum combination therapy. Eligible patients were randomly assigned (1:1 ratio) to either placebo or pazopanib 800 mg per day until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS).

Result:
Ninety-seven patients were enrolled and randomly assigned; 2 patients did not receive study drugs. In total, 95 patients received maintenance therapy (pazopanib, n = 48; placebo, n = 47) and were included into the analyses. Grade 3 toxicities for pazopanib maintenance included thrombocytopenia (10.4%, including 1 case with grade 4 toxicity), liver enzyme elevation (10.4%), fatigue (6.3%), and hypertension (6.3%). Median PFS was 3.7 months for pazopanib maintenance and 1.8 months for placebo (Hazard ratio [HR] 0.44, 95% CI: 0.29 – 0.69, p < 0.0001). Median PFS longer than 6 months were achieved by 9 patients (18.8%) in pazopanib arm and 2 (4.3%) in placebo. Median overall survival for the pazopanib and placebo arms were 10.6 months and 12.9 months, respectively (HR 1.14, 95% CI: 0.74 – 1.76, p = 0.54).

Conclusion:
Though this study met the primary endpoint of PFS, it failed to translate into improvement of overall survival with pazopanib maintenance. Given the unneglectable toxicity profiles, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.

Abstract not provided

Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in T790M-positive lung cancer. Acquired resistance to osimertinib is driven by EGFR C797S in ~20-30% of cases. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) can be used to identify resistance mechanisms. The allelic configuration (cis vs. trans) of C797S with respect to T790M has therapeutic implications, but the relative frequency of each and other co-occurring genomic alterations are not well defined in clinical samples.

Method:
We queried the Guardant Health database for lung adenocarcinoma patients and an EGFR C797S mutation. All patients had comprehensive ctDNA testing using the Guardant360 NGS assay between June 2015 and June 2017. Cis/trans configuration for T790M and C797S was determined using Integrated Genomics Viewer software.

Result:
We identified 50 unique patients with a total of 66 samples which were C797S positive. All had a co-existent EGFR activating mutation (del19 74%, L858R 24%, other 2%). 60/66 (91%) C797S+ samples were also T790M+. In the 6 samples with C797S but without T790M in ctDNA, 4 were from patients who were T790M+ on a prior Guardant360 assay, 1 never had T790M in blood or tissue and developed C797S while on 1[st]-line afatinib, and 1 had no further clinical details available. T790M and C797S were on the same allele (cis configuration) in 44/46 evaluable patients (98%); 1 (2%) was in trans. One sample had two different C797S mutations, one cis and one trans to T790M. 13 C797S+/T790M+ samples (22%) had multiple C797X mutations detected and 12 samples carried other mutations in or adjacent to the EGFR ATP-binding pocket (e.g. L792, F795, G796, etc). The most common non-EGFR mutations co-occurring with C797S were BRAF amplification/mutation (20%), MET amplification (17%), PIK3CA mutation/amplification (15%), CCNE1 amplification 14% and MYC amplification (14%).

Conclusion:
Understanding EGFR TKI resistance mechanisms is critical to developing more effective therapies. ctDNA offers a non-invasive method to characterize the resistance landscape. Our data suggests C797S most commonly occurs with T790M in cis (98%), a state associated with resistance to all currently available EGFR TKIs. The trans configuration, which may respond to combined 1[st]/3[rd]-gen EGFR TKIs, is rare (2%). Moreover, C797S is frequently detected along with other resistance mechanisms in ctDNA, underscoring the heterogeneity of resistant cancers. New treatments targeting C797S/T790M are needed, as is a deeper understanding of therapeutic targeting of heterogeneity in resistant cancers.

Background:
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) active in EGFR-mutant NSCLC with resistance to prior TKI. Improved understanding of the clinical and molecular characteristics of acquired resistance to osimertinib is needed.

Method:
We initially studied resistance biopsies and plasma specimens from an institutional cohort of 119 patients treated with osimertinib for T790M-positive NSCLC with resistance to prior TKI. For validation, we studied plasma from 157 patients treated with osimertinib on the AURA trial (NCT01802632).

Result:
45 of 119 patients underwent a resistance biopsy and 33 had resistance tumor genotyping available. 11 patients maintained T790M at resistance: 7 acquired EGFR C797S, 1 had a PIK3CA mutation. 22 patients had loss of T790M at resistance: 14 harbored a competing resistance mechanism, including histologic transformation to SCLC, MET amplification, mutations in BRAF, PIK3CA, or KRAS, or fusions in RET or FGFR. Median time to treatment failure (TTF) on osimertinib was 3 months in patients with loss of T790M and 15 months in patients with maintained T790M. In the validation cohort, 110 of 157 patients had detectable tumor DNA in plasma and were eligible for analysis. 58 patients (53%) maintained T790M at resistance; 24 (22%) also acquired a C797S mutation. 52 patients (47%) had loss of T790M at resistance and no C797S. Median TTF was shorter in patients with loss of T790M than in those with maintained T790M at resistance (5.7 vs 12.5 months). 50 patients had both pre- and post-osimertinib plasma genotyping. Studying the relative allelic fraction (AF) of T790M compared to driver EGFR mutation, patients with T790M loss had only slightly lower relative T790M AF pretreatment (29% vs. 38% median, p = 0.06). The ability of plasma response to predict subsequent resistance was studied in 19 patients from the initial cohort with baseline and follow-up plasma genotyping after 1-3 weeks on osimertinib. Studying the difference between the relative change in plasma levels of T790M and the EGFR driver, patients with T790M loss at time of resistance consistently had a greater T790M response than driver response (median difference 16%), suggesting incomplete suppression of the driver due to competing resistance mechanisms.

Conclusion:
In patients with acquired resistance to osimertinib, repeat testing for T790M could offer key insights into disease biology. Patients with early resistance on osimertinib are at risk of T790M loss with emergence of a complex variety of competing resistance mechanisms, and represent intuitive candidates for combination approaches such as combined EGFR & MET inhibition.

Background:
MET amplification is a well described mechanism of acquired resistance to EGFR inhibition in EGFR-mutant NSCLC, making combined MET/EGFR inhibition a compelling therapeutic approach. We previously reported tolerability of the oral, CNS active, third-generation EGFR-TKI osimertinib, which is selective for both EGFR-TKI sensitizing and EGFR T790M resistance mutations, combined with the highly selective MET-TKI savolitinib (volitinib, HMPL-504, AZD6094). Here we assess safety and preliminary activity of this combination in a cohort of patients (pts) with EGFR-mutant NSCLC and MET-positive acquired resistance in the multi-arm, Phase Ib TATTON study (NCT02143466).

Method:
Eligible pts were aged ≥18 years (WHO performance status 0/1) with locally advanced or metastatic EGFR-mutant NSCLC who progressed on at least one prior EGFR-TKI with centrally confirmed MET-amplification (fluorescence in-situ hybridisation, MET gene copy ≥5 or MET/CEP7 ratio ≥2). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. Primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumour activity and pharmacokinetics.

Result:
As of data-cut off (15 April 2017), 45 pts with centrally confirmed MET-amplification (FISH) were enrolled and received treatment, including 25 pts previously treated with a third-generation EGFR-TKI and 20 without prior third-generation EGFR-TKI treatment (T790M negative n=13; T790M positive n=7). At baseline, median age was 58 years (range 38–76), 24 (53%) were female, 36 (80%) were Asian. The most frequent adverse events (AEs) were nausea (n=21, 47%), decreased appetite (n=15, 33%), fatigue (n=13, 29%) vomiting (n=13, 29%), rash (n=11, 24%), myalgia (n=8, 18%), pyrexia (n=7, 16%), ALT/AST increased (n=6, 13%), and WBC decreased (n=6, 13%), consistent with the known safety profiles. Serious AEs were reported in 15 (33%) pts; events reported in >1 patient were pneumonia, dyspnoea, acute kidney injury and pyrexia (all n=2). Four pts died due to AEs, none were considered related to study drugs. At data cut-off, confirmed partial responses were reported in 5/25 (20%) pts previously treated with a third-generation EGFR-TKI; 5/12 (42%) T790M negative pts without prior third-generation EGFR-TKI and 3/7 (43%) T790M positive pts without prior third-generation EGFR‑TKI. Twenty-eight (62%) pts are ongoing treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and osimertinib were consistent with historical data.

Conclusion:
These findings demonstrate promising safety, tolerability, and preliminary activity of osimertinib plus savolitinib and support further investigation of this combination for the treatment of pts with locally advanced or metastatic EGFR-mutant NSCLC and MET-amplification. Updated data will be presented.

Abstract not provided

Background:
While previous reports have established MET and HER2 amplification as two mechanisms of non-T790M driven EGFR TKI resistance in EGFR mutant NSCLC, resistance occurs in the absence of these modifications in a significant number of patients. Therefore, there exists an unmet need to define additional mechanisms of resistance to EGFR TKIs. We hypothesized that targeted next-generation sequencing could detect additional targetable activating mutations in paired tumor samples from patients with acquired resistance to first or second generation EGFR TKIs.

Method:
We conducted an analysis of clinical and molecular data prospectively collected from 285 EGFR-mutant NSCLC patients enrolled into the MD Anderson Lung Cancer GEMINI database. Of 157 patients treated with first-line therapy (erlotinib, gefitinib, or afatinib), we identified 75 patients with TKI-acquired resistance with matched pre/post-TKI tumor samples. Matched tumor samples were analyzed with targeted gene sequencing. Recurrent alterations were defined as an alteration occurring more than 2 times. Recurrent acquired mutations were expressed in Ba/F3 and EGFR mutant (T790M+/-) NSCLC cells. Mutation expressing Ba/F3 cell lines were assayed for IL-3 independence, and mutation expressing NSCLC cell were screened against combination targeted TKIs.

Result:
EGFR mutant NSCLC patients treated with first-line therapy had a median PFS of 14 months; and, of the patients with pre/post-TKI tumor molecular data, 47% of patients were T790M negative. There were 30 recurrent acquired alterations identified in 13 different genes. Genes included ARAF, BRAF, EGFR, FGFR, GNAS, JAK2, MCL1, PDGFRα, PIK3CA, RAF1, RB1, SMAD4, and TP53. Of the alterations identified, most occurred in 1 of 4 targetable genes: BRAF (N=3), FGFR (N=5), PDGFRα (N=3), or PIK3CA (N=2). Both previously reported and novel mutations were identified, and preliminary screening of mutant expressing Ba/F3 cell lines found that of the mutations tested (BRAF WT & G469H, FGFR2 A371G, PDGFRα WT & L682F, and PIK3Ca E545K) all grew independent of IL-3. HCC827 and H1975 cell lines expressing acquired mutations in BRAF, FGFR, PDGFRα, or PIK3CA were more sensitive to combination targeted therapy compared to EGFR TKIs or mutation specific TKIs alone unlike control cell lines, supporting the possibility that targeting these mutations would be of therapeutic benefit.

Conclusion:
Analysis of patient data identified 30 recurrent genomic alterations in 13 different genes including novel alterations in BRAF, EGFR, FGFR, PDGFRα, RB1, and SMAD4, many of which were found to be activating mutations. Our analysis identified potentially targetable mutations of BRAF, FGFR, PDGFRα, and PIK3CA which merits further pre-clinical and clinical investigation.

Background:
EGFR-tyrosine kinase inhibitor (TKI) treatment failure has been attributed to innate and/or acquired MET-amplification in patients with advanced EGFR-mutant NSCLC. Savolitinib (volitinib, HMPL-504, AZD6094), a highly selective small molecule MET-TKI, demonstrated greater efficacy combined with gefitinib than either compound alone in preclinical EGFR-mutant NSCLC models (D’Cruz et al. AACR, 2015).

Method:
This open-label, multi-centre, Phase Ib study (NCT02374645) assessed savolitinib plus gefitinib in patients enrolled in China with EGFR-mutant advanced NSCLC who progressed on prior EGFR-TKI. Primary objective was safety, tolerability, and identification of recommended Phase II dose (RP2D). Secondary objectives included preliminary anti-tumour activity (RECIST 1.1), pharmacokinetics, and ctDNA analysis for EGFR T790M mutation status. Eligible patients (≥18 years) had measurable disease, radiological disease progression on treatment, ECOG performance status 0/1, and adequate organ function. Patients had central evaluation of EGFR mutation (plasma based BEAMing digital PCR) and central screening for MET-amplification (MET/CEP7 ratio ≥2 or MET gene number ≥5, defined by tumour tissue FISH). Patients received gefitinib 250 mg once daily (QD) plus savolitinib 600 mg QD.

Result:
As of data-cut off (March 2017), 44 patients received study treatment. Median age was 61 years, 64% of patients were female; 6 patients were EGFR T790M positive and 5 were T790M negative (interim readout). The most common (≥20% patients) all causality adverse events (AEs), were vomiting (n=18, 41%), nausea (n=17, 39%), rash (n=16, 36%), increased ALT (n=14, 32%), increased AST (n=13, 30%), hypoalbuminaemia and gamma‑glutamyl transpeptidase increase (both n=11, 25%), and increased blood alkaline phosphatase (n=9, 21%). Grade ≥3 all causality AEs were reported in 14 (32%) patients; increased AST and increased ALT (both n=3, 7%) were most frequent. Three (7%) patients died due to an AE (respiratory failure [n=1], lung neoplasm [n=2]); none were considered treatment related. Anti-tumour activity was observed; confirmed partial responses were reported in 11/44 (25%) patients and a further 4 patients are awaiting confirmation of response (confirmed and unconfirmed response rate 15/44 [34%]). At the time of the scheduled 12 week study assessment, 20 (46%) patients remained on study treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and gefitinib were consistent with historical data.

Conclusion:
These encouraging findings warrant further assessment of savolitinib plus gefitinib for patients with EGFR-mutant, MET-amplified NSCLC who progressed on prior EGFR-TKI. The RP2D was confirmed as savolitinib 600 mg QD plus gefitinib 250 mg QD. This study is ongoing; updated safety and efficacy including anti-tumour activity by T790M status will be presented.

Background:
cMET activation is a valid mechanism of secondary TKI resistance in EGFR mutation-positive (EGFR-M+) NSCLC. However, its role in the treatment-naïve setting remains unclear. We sought to ascertain the prevalence and clinical impact of co-existing cMET copy number gain(CNG) in TKI-naïve early-stage and metastatic EGFR-M+ NSCLC.

Method:
Multi-region SNP array analysis (n=59 sectors) was performed on 13 early-stage resected EGFR-M+ NSCLC. cMET FISH was performed in a separate cohort of 206 metastatic treatment-naïve EGFR-M+ patients, all of whom were treated with first-line EGFR TKIs. We defined cMET-high as CNG≥5 copies, with an additional criteria of MET:CEP7 ratio >2.0 for amplification. Time-to-treatment failure(TTF) in patients cMET-high/low was estimated by Kaplan-Meier method and compared using log-rank test. A cell line from a cMET-high patient exhibiting primary TKI resistance was established.

Result:
Relative to median ploidy across sectors, 7/13(53.8%) early-stage EGFR-M+ tumors showed cMET CNG in at least one sector, with majority displaying(n=6/7) copy number intra-tumor heterogeneity. In the metastatic cohort, 55/206 patients (26.7%) were found to be cMET-high at diagnosis: 6(10.9%) had MET amplification, 49(89.1%) MET polysomy, with the following distribution: 5-6 copies(n=11), 6-8 copies(n=32), and >8 copies(n=12). We next evaluated clinical outcomes stratified by MET-high v low: median TTF was 14.7m(12.2–NE) vs 14.6m(12.7–16.5), p=0.985 respectively, with no significant difference in response rates(RR) to EGFR TKI (66.7%v73.7%; p=0.940). Further stratification by level of CNG did not reveal any differences in RR (5-6 copies:75.0%, 6-8 copies:63.0%, >8 copies:71.4%; p=0.868). In MET-high amplified group, only 2/6 (33.3%) had a partial response to EGFR TKI. In the cohort with suboptimal TKI response (PFS<6m, n=22), we did not observe significant enrichment for MET-high, relative to rest of the cohort (36.4%v25.5%, p=0.278). Finally, in 6 patients with progressive disease within 4 weeks of initiating EGFR TKI, 2/6(33.3%) were MET-high. In a cell line model derived from a MET-high patient (L858R, cMET:7.3 copies) genomic profiling of cell colonies revealed clonal cMET CNG and subclonal EGFR, with the patient demonstrating clinical response to crizotinib.

Conclusion:
Although up to 26% of TKI-naïve EGFR-M+ NSCLC harbor high cMET CNG by FISH, this occurs on the background of a highly variegated copy number landscape. cMET CNG alone does not significantly impact clinical outcomes to EGFR TKI, with the exception of one patient with a clonal cMET-driven tumor. Our data challenges the utility of arbitrary copy number thresholds to define clinically relevant MET pathway dysregulation and underscores the importance of targeting dominant truncal drivers.

Abstract not provided

Abstract:
Small cell lung cancer (SCLC) accounts for 15%–20% of all lung cancers, and the overwhelming majority (>95%) are associated with tobacco exposure. The incidence of all types of lung cancer, including SCLC, has been declining in the United States with the onset of tobacco smoking cessation programs, although this trend took nearly 20 years to become evident among men. Overall survival (OS) rates for patients with lung cancer have also increased by about 5% since the advent of low-dose spiral computed tomography (CT) scanning to detect early lung cancer. The prognosis for patients with SCLC continues to be poor but has improved with the advent of smoking cessation campaigns, more effective chemotherapy agents and radiation planning and delivery techniques, and the use of prophylactic cranial irradiation (PCI) for those who experience a complete response to therapy. Consolidation with chest radiotherapy has improved OS among patients with extensive-stage SCLC who achieved a complete response to chemotherapy. SCLC often presents as bulky symptomatic masses, and mediastinal involvement is common with or without pleural effusion and extrathoracic disease. Extrathoracic spread (i.e., extensive-stage disease) is also quite common, being present in 80%-85% of cases at diagnosis. Brain metastases are present in approximately 20% of patients at diagnosis; roughly half of these metastases are symptomatic and the other half are detected by imaging. Predictors of poor prognosis include poor performance status, older age, and being male. The pathologic subtypes of the disease (small cell carcinoma and combined small cell carcinoma) all carry a similarly poor prognosis. Current guidelines of the U.S. National Comprehensive Cancer Network recommend the use of positron emission tomography (PET), CT scanning, or fused PET/CT scanning of the chest, liver, adrenals, bone, and other areas of concern in the diagnosis and staging of SCLC (NCCN guideline-SCLC 2017) . Thoracic radiotherapy has also become important for improving OS among patients with SCLC who achieved a complete response to chemotherapy. In one prospectively randomized study of 498 patients with extensive-stage SCLC (WHO performance status score 0-2) who achieved complete response to chemotherapy, patients who received consolidation thoracic radiotherapy (30 Gy in 10 fractions) had significantly better 2-year OS rates than did those who did not receive thoracic radiotherapy (13% vs. 3%, P=0.004). Thoracic radiotherapy further improved thoracic-only failure rates (19.8% vs. 46% without, P=0.001) (Slotman B et al, Lancet Oncol 2015;385:36-42). However, many patients with extensive-stage SCLC do not respond to the standard etoposide/cisplatin chemotherapy (Figure 1). Those patients may need to receive molecular-targeted therapies or immunotherapy with the consolidating thoracic radiotherapy. Several histologic and immunohistochemical markers have been evaluated for diagnosing or monitoring treatment response in SCLC, including transcription thyroid factor-1 (positive in >85% of SCLC cases); cytokeratin 7; deletions in chromosome 3; Leu-7; chromogranin A; synaptophysin; myc amplification; and p53 mutations (present in ~75% of cases). Deletions in tumor-suppressor genes are also relatively common and include fragile histidine triad (FHIT) (80%); RAS effector homologue (RASSF1) (>90%); TP53 (>75%); retinoblastoma-1 (RB1) (>90%); and retinoic acid receptor-beta (72%). However, to date no biomarkers have been validated for use in diagnosing SCLC. Moreover, mutations that are often present in non-small cell lung cancer (such as epidermal growth factor receptor [EGFR] mutations and anaplastic lymphoma kinase [ALK]) are rare in SCLC. Several clinicopathologic features have been linked with worse prognosis, including poor performance status, significant weight loss, high lactate dehydrogenase levels, large numbers of metastatic sites, and the presence of paraneoplastic syndromes. Because SCLC has the among the highest rates of somatic driver mutations, and because more than 95% of patients with SCLC are former or current smokers, immunotherapy seems a reasonable approach, as high mutation burdens correlate with good response to chemoradiotherapy and sensitivity to immunomodulators (Peifer M et al., Nat Genet 2012;44(10):1104-10). At MD Anderson Cancer Center, an ongoing phase I/II study of patients with extensive-stage SCLC has been proposed to the NRG as a prospective randomized study (PI J Welsh) (Figure 2). Use of thoracic radiotherapy to consolidate a site at which SCLC is quite likely to recur is reasonable, given that recurrence considerably reduces quality of their life as well as OS. In summary, in most cases SCLC presents as extensive-stage disease, for which outcomes are very poor. Consolidation with thoracic radiotherapy for patients who achieve a complete response to chemotherapy can improve 2-year OS rates. However, less toxic and more effective systemic treatment is also required to derive the greatest benefit from consolidation thoracic radiotherapy. Figure 1(Figure 1) Figure 2(Figure 2)

Abstract not provided

Abstract:
Radiation therapy (RT) has an important role in both limited stage and extensive stage (M1) small cell lung cancer (SCLC), although more recent randomized trial results have led to increasing discussion and opposing views regarding the indications and type and degree of benefit conferred. This is one such debate, in which I am arguing in favour of recommending Prophylactic Cranial Irradiation (PCI) in extensive stage (ES) SCLC. There is no disagreement about the prevalence of brain metastases (BM) in SCLC. There is strong randomized trial evidence that delivery of modest doses of RT, such as 25 Gy in 10 fractions (fr) over 2 weeks, can reduce the incidence of BM. The simplistic explanation is that RT reduces the tumor cell burden and affects the ability of cancer cells to multiply, thus delaying or preventing the progression of microscopic intracranial metastases, and reducing the likelihood, that patient will develop symptomatic metastases – thus the term “prophylactic” brain RT. A meta-analysis [1 ]of previously conducted randomized clinical trials (RCTs) in patients with limited stage (LS) or ES SCLC with response to chemotherapy demonstrated not only a reduction in symptomatic BM (from 58% to 33% at 3 yrs) but also a survival benefit (15.3% to 20.7%). A large RCT [2] in LS SCLC confirmed that 25Gy/10 fr is the optimal dose fractionation, and described the potential negative neurocognitive and quality of life (QOL) impact of PCI [3]. Other studies [4 ]provided further data to inform patients regarding the potential risks and benefits of PCI. The EORTC group conducted a RCT in ES SCLC [5], randomizing 286 patients who had a response to 4-6 cycles of chemotherapy and had no clinical evidence of BM (but who did not have brain imaging to confirm absence of radiological metastases) to PCI vs observation. Their primary endpoint was time to symptomatic BM. A range of fractionation schedules was allowed; 62% of pts were treated with 20 Gy/5fr, 22% with 30 Gy/10-12 fr and only 4% with 25Gy/10 fr. There was a large reduction in symptomatic BM, 16.8% in the PCI group vs 41.3% in the control group (p < 0.001, hazard ratio (HR) 0.27 (95% confidence intervals (CI) 0.16-0.44). Disease-free survival (DFS) was significantly longer in the PCI group (median 14.7 weeks, vs 12 weeks, p = 0.02, HR 0.76 (95% CI 0.59-0.96), as was the overall survival (OS) (median 6.7 mo vs 5.4 mo, p = 0.003). This study let to the more widespread recommendation of PCI to patients with ES SCLC who have responded to chemotherapy. Practice guidelines on management of ES SCLC include PCI in their recommendations. A more recent Japanese RCT [6] randomized patients with ES SCLC who had a response to chemotherapy and no BM on MRI, to PCI (25 Gy/10 fr) vs observation. Follow up MRIs were mandated every 3 mo initially, then q6 mo. If patients were discovered to have radiological brain progression, whole brain RT was utilized regardless of whether they were symptomatic or not. Primary endpoint was OS. The study was closed after interim analysis, as the PCI group was not going to have a superior OS; 224 patients were enrolled in all. There was a reduction in BM in the PCI group, with the cumulative incidence at 6 mo15% vs 46% in the observation arm; at 12 months there was also a difference (33% and 59% respectively). PFS was identical, and there was no significant difference in OS (11.5 mo median OS in the PCI group vs 13.7, p = 0.094, HR 1.27 (95% CI 0.96-1.68)). The study concluded that PCI doesn’t result in longer OS and is thus “not essential for patients with ES SCLC (..) and a confirmed absence of BM, if patients will be followed by periodic MRIs”. Those are indeed very fair conclusions of their data, although it is interesting that some, perhaps many, especially in the medical oncology community, after hearing the presentation at ASCO 2015, seem to have concluded that PCI may be detrimental to survival (given the small and statistically non-significantly longer survival in the observation group). Comments have been made that in the era of staging/ restaging MRIs, there may be no benefit to PCI in ES SCLC, and that perhaps the EORTC study showed improved survival because patients may have had clinically undetected gross metastatic disease (ie not just microscopic disease). That is clearly an incorrect interpretation of the Japanese data, and an assumption that has no proof in terms of the EORTC study. Every study that looked at local control ie ability of PCI to eradicate metastatic disease showed a benefit to RT, whether assessed radiologically or clinically. The incidence of BM in the control arms of the EORTC and Japanese trials was similar, suggesting that patients staged with MRIs did not have a different risk of brain disease than patients staged clinically. Even if restaging MRIs are routinely available in many parts of the world, close surveillance with regular MRIs is not routinely done for ES SCLC; it should be noted that Japan has the highest ratio of MRI to population. A very large proportion of patients in the observation arm of the Japanese study (83%) had whole brain RT for BM – no wonder there was no survival difference as it was really a comparison of early vs late RT. Finally, the risk of systemic disease in ES SCLC is high, so that a treatment that clearly has an impact in reducing brain relapse would be expected to have a relatively small OS benefit. Thus, Japanese study provides valuable data that continue to support the role of PCI in ES SCLC, and emphasize the need for a more realistic and holistic view of the expected role and benefit of RT – ie reducing BM, prolonging survival in some, and aiming to provide good neurological functioning and QOL. Rather than trying to argue against PCI as a strategy, we should continue with attempts to reduce its toxicity, such as through hippocampal sparing techniques [7 ]and to identify groups of patients who are more or less likely to benefit in terms of survival [8], [9]. References: Auperin A, Arriagada R, Pignon JP, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. N Engl J Med. 341(7):476-84, 1999. Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomized clinical trial. Lancet. 10(5):467-74, 2009. Le Pechoux C, Laplanche A, Faivre-Finne C, et al. Clinical neurological outcome and quality of life among patients with limited small-cell cancer treated with two different doses of prophylactic cranial irradiation in intergroup phase III trail (PC I00-01, EORTC 22003-08004, RTOG 0212 and IFCT 99-01). Annals of Oncology 22: 1154-1163, 2011. Wolfson AH, Kyounghwa B, Ritsuko K, et al. Primary Analysis of a phase II randomized trial radiation therapy oncology group (RTOG) 0212: Impact of different total doses and schedules of prophylactic cranial irradiation of chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int. J. Radiation Oncology Biol. Phys Vol 81 (1): 77-84, 2011. Slotman B, Faivre-Finn C, Kramer G, et al. EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 357(7):664-72, 2007. Takahashi T, Takeharu Y, Takashi S, et al. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicenter, randomized, open-label, phase 3 trial. The Lancet Oncology, 18: 663-71, 2017. Gondi V, Paulus R, Bruner DW et al. Decline in tested and self-reported cognitive functioning following prophylactic cranial irradiation for lunc cancer: Pooled secondary analysis of RTOG randomized trials 0212 and 0214. Int J. Radiat Oncol Biol Phys. 86(4): 656-664, 2013. Rule WG, Foster NR, Meyers JP et al. Prophylactic cranial irradiation in elderly patients with small cell lung cancer: Findings from a North Central Cancer Treatment Group pooled analysis. Journal of Geriatric Oncology 6: 119-126, 2014. Farooqi AS, Holliday EB, Allen PK et al. Prophylactic cranial irradiation after definitive chemoradiotherapy for limited-stage small cell lung cancer: Do all patients benefit? Radiotherapy and Oncology 122: 307-312, 2017.

Abstract:
What does prophylactic cranial irradiation (PCI) prevent in ED-SCLC? - Why isn’t the presence of brain metastasis evaluated before performing PCI? Background: In a European trial, prophylactic cranial irradiation (PCI) was performed on patients with extensive-disease small cell lung cancer (ED- SCLC). As a result, PCI was reported to reduce the incidence of symptomatic brain metastasis and to prolong patient survival. However, their treatments were completely different from our routine medical care. For example, they did not perform tests to examine whether there was a metastatic brain tumor before assignment to the PCI group or observation group and, after assignment, symptoms alone were observed and no imaging test was performed. For this reason, in Japan, we corrected this inconsistency of protocol and repeated the trial to determine whether PCI contributes to prolonged survival. Participants and method: Included in the current trial were patients who underwent two or more cycles of platinum-based combination chemotherapy, had achieved at least stable disease (SD), and had no metastatic brain tumor on their MRI. They were randomly assigned to either the PCI group or observation group. Follow-up with brain, chest and abdominal diagnostic imaging tests was performed every three months in both groups. Results: In the first pre-specified interim analysis, it was found that there was no possibility of improving patient prognosis using PCI even if the trial were continued. An independent data monitoring committee therefore terminated the trial. At that time, 224 cases had already been enrolled, with 113 cases assigned to the PCI group and 111 cases to the observation group. Median survival period in the final analysis was 11.6 months for the PCI group and 13.7 months for the observation group (hazard ratio, 1.27; 95% CI, 0.96 to 1.68). There was no statistically significant difference between the groups, but PCI actually tended to make the prognosis somewhat worse or, at least, did not improve prognosis in patients with ED-SCLC.Discussion: The biggest difference between the two trials was whether follow-up assessments were conducted using symptoms or brain MRI. In the current trial, it is impossible to estimate the proportion of asymptomatic brain metastasis cases; however, in the European trial, asymptomatic brain metastasis cases were also included, which means that there were in fact two different subgroups in the PCI group: a subgroup of patients with asymptomatic brain metastasis undergoing therapeutic cranial irradiation and a subgroup of patients without brain metastasis undergoing true PCI. It seems that the survival difference between patients with asymptomatic brain metastasis in the PCI group and in the observation group caused the apparent improvement of survival period. On the other hand, it is conjectured that PCI generated a lot of toxic effects in the patients without brain metastasis and that their survival curve tended to be inferior. PCI is a treatment to prevent new brain metastasis. One year of PCI reduces the incidence of new brain metastasis in no more than 30% of cases. For patients with MRI showing no metastatic brain tumor, needless PCI can be avoided by performing regular brain imaging tests, without impairing survival.