IASLC 17th World Conference on Lung Cancer

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1 Developed in association with the European Thoracic Oncology Platform IASLC 17th World Conference on Lung Cancer December 4 7, 2016 Vienna, Austria Supported by Eli Lilly and Company. Eli Lilly and Company has not influenced the content of this publication

2 Letter from Prof Rolf Stahel Dear Colleagues It is my pleasure to present this ETOP slide set which has been designed to highlight and summarise key findings in thoracic cancers from the major congresses in This slide set specifically focuses on the IASLC 17th World Conference on Lung Cancer 2016 and is available in 4 languages English, French, Japanese and Chinese. The area of clinical research in oncology is a challenging and ever changing environment. Within this environment we all value access to scientific data and research which helps to educate and inspire further advancements in our roles as scientists, clinicians and educators. I hope you find this review of the latest developments in thoracic cancers of benefit to you in your practice. If you would like to share your thoughts with us we would welcome your comments. Please send any correspondence to etop@etop.eu-org. I would like to thank our ETOP members Drs Solange Peters and Martin Reck for their roles as Editors for prioritising abstracts and reviewing slide content. The slide set you see before you would not be possible without their commitment and hard work. And finally, we are also very grateful to Lilly Oncology for their financial, administerial and logistical support in the realisation of this complex yet rewarding activity. Yours sincerely, Rolf Stahel President, ETOP Foundation Council

3 ETOP Medical Oncology Slide Deck Editors 2016 Focus: Advanced NSCLC (not radically treatable stage III & stage IV) and related biomarker data Dr Solange Peters Multidisciplinary Oncology Center, Lausanne Cancer Center, Lausanne, Switzerland Focus: Early and locally advanced NSCLC (stage I III) and related biomarker data / other malignancies Dr Martin Reck Department of Thoracic Oncology, Hospital Grosshansdorf, Grosshansdorf, Germany

4 Contents Biomarkers and screening Early stage and locally advanced NSCLC Stages I, II and III Advanced NSCLC Not radically treatable stage III and stage IV 1 st line Later lines Other malignancies SCLC and mesothelioma Rare tumours

5 Biomarkers and screening

6 OA04.03: Preliminary Results of a Low Cost Intervention to Improve Tobacco Cessation Practices within a Large University Health System Hamby MK, et al Study objective Review of the initiation of a systematic multi-step program to improve tobacco practices from assessing tobacco use to prescribing pharmacotherapy, and referral to tobacco cessation counsellors Methods This quality initiative had four aims: Train key personnel at selected clinics in a Tobacco Treatment Specialist course Develop an assessment tool to monitor the completeness of tobacco history (current/former/never), recording of pack-years, quit dates*, use of FDAapproved tobacco cessation pharmacotherapy, and referrals for either tobacco cessation or formal lung cancer screening Provide monthly feedback to clinic directors using automated data collection Monitor the activities over time *Former smokers only Hamby et al. J Thorac Oncol 2016; 11(suppl): abstr OA04.03

7 OA04.03: Preliminary Results of a Low Cost Intervention to Improve Tobacco Cessation Practices within a Large University Health System Hamby MK, et al Key results 20 sites were invited to participate and individuals from 14 sites completed Tobacco Treatment Specialist training Before training Initial assessment of tobacco use (current/former/never) was high (>99%) Pack-years were recorded on average less than 40% of the time Quit dates for former smokers were recorded less than 30% of the time After training and ongoing feedback to clinical directors over 9 months Significant initial increase in accurate recording of pack-years and quit dates Significant increase in number of referrals to tobacco counseling Gradual increase in number of referrals for lung cancer screening from an average of 30 per month to an average of over 70 per month No increase in the rate of prescription of tobacco pharmacotherapy Conclusions This quality improvement initiative led to a modest improvement in overall practices, but the trend was not sustained It highlighted areas where additional improvements are required Hamby et al. J Thorac Oncol 2016; 11(suppl): abstr OA04.03

8 OA04.07: Clinical Characteristics of Lung Adenocarcinoma in the Young: Results from the Genomics of Young Lung Cancer Study Gitlitz BJ, et al Study objective To assess the genomics of young lung cancer (GYLC) by examining lifestyle risk factors using specific genomic alteration to better characterize lung cancer in the young Methods Beginning in July of 2014, patients diagnosed with a bronchogenic lung cancer <40 years of age were recruited to the GYLC study Data were collected through tumour and blood and a questionnaire to investigate environmental, lifestyle, early life exposures, reproductive and genetic risk factors in relation to mutation specific risk Analysis will compare frequency of specific exposures in young lung cancer cases by specific mutations (e.g., ALK vs. EGFR) Study aims to recruit 500 cases and 2,000 controls Gitlitz et al. J Thorac Oncol 2016; 11(suppl): abstr OA04.07

9 OA04.07: Clinical Characteristics of Lung Adenocarcinoma in the Young: Results from the Genomics of Young Lung Cancer Study Gitlitz BJ, et al Key results Demographics of the first 114 subjects: median age at diagnosis of 34 years (range 16 39); 44% male; 80% stage 4, 20% stage 1 3; 85% adenocarcinoma Among the patients with stage 4 adenocarcinoma, 77% showed driver mutations by ALK, EGFR or ROS1 and 16% had other mutations including HER2, RET, ATM, TP53, BRCA2 and KRAS Conclusions Preliminary results revealed a heavily enriched population for oncogenic drivers This study will enable a more comprehensive Epidemiology of Young Lung Cancer study to identify risk factors related to specific genomic alterations Gitlitz et al. J Thorac Oncol 2016; 11(suppl): abstr OA04.07

10 OA15.01: Limited Resection Trial for Pulmonary Sub-solid Nodules: Case Selection Based on High Resolution CT: Outcome at Median Follow-up of 105 Months Yoshida J, et al Study objective To confirm limited resection efficacy in patients with minimally invasive lung cancer as indicated by high-resolution computed tomography (HRCT) Methods 101 patients with a tumour 2 cm in diameter, diagnosed or suspected as a clinical T1N0M0 carcinoma in the lung periphery were enrolled Patients were required to have an HRCT scan indicating a sub-solid nodule with tumour disappearance ratio 0.5 Key results 99 patients were eligible for analysis; 11 Noguchi type A tumours, 54 type B tumours, 26 type C tumours, 1 type D tumour, 1 malignant lymphoma, 3 hyperplastic lesions and 3 inflammatory fibroses No patients died during the study; one patient developed postoperative pneumothorax and pneumonia, and one developed haemorrhagic gastric ulcer As of June 2016, median follow-up was 105 months (range ) with no recurrences Conclusion HRCT scans appear to predict non- or minimally-invasive sub-solid lung cancers with high reliability Yoshida et al. J Thorac Oncol 2016; 11(suppl): abstr OA15.01

11 OA20.01: Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients Kowanetz M, et al Study objective To examine the association between atezolizumab efficacy and tumour mutation burden (TMB) Methods Targeted genetic sequencing of pre-treatment tumour specimens using the FoundationOne panel of 315 cancer-related genes Patients with NSCLC had enrolled in one of three phase 2 atezolizumab monotherapy trials POPLAR: randomised second-line and beyond trial of atezolizumab vs. docetaxel BIRCH/FIR: single-arm, PD-L1-selected, first-/second-line and beyond trials of atezolizumab TMB was quantified using an updated algorithm Efficacy was assessed in groups defined by the 75th (high) and 50th (median) percentile of each study-specific TMB Kowanetz et al. J Thorac Oncol 2016; 11(suppl): abstr OA20.01

12 OA20.01: Tumor Mutation Burden (TMB) is Associated with Improved Efficacy of Atezolizumab in 1L and 2L+ NSCLC Patients Kowanetz M, et al Key results In first-line and second-line and beyond PD-L1-selected patients, atezolizumab benefit was increased in those with TMB cut-offs PFS First-line patients (PD-L1-selected) OS Second-line and beyond patients (PD-L1-selected) PFS OS TMB cut-off mut/mb n TMB cut-off Mut/MB n In favour of high TMB Hazard Ratio a In favour of low TMB Hazard Ratio a In favour of high TMB In favour of low TMB In favour of high TMB Hazard Ratio a In favour of low TMB Hazard Ratio a In favour In favour of high TMB of low TMB Conclusions In NSCLC, TMB was associated with improved atezolizumab outcomes The efficacy of docetaxel was not associated with TMB a Unadjusted and unstratified HRs for above vs. below TMB cut-offs Kowanetz et al. J Thorac Oncol 2016; 11(suppl): abstr OA20.01

13 OA20.02: Neoantigen Targeting in NSCLC Patients with Complete Response to Anti-PD-1 Immunotherapy Smith K, et al Study objective To investigate the mechanisms underlying response to anti-pd-1 therapy in NSCLC Methods Tumour sections from 2 patients with advanced NSCLC who had complete responses to nivolumab had whole exome sequencing and mutation-associated neoantigen (MANA) prediction performed Peptides representing MANAs were synthesised and tested against PBMC Reactive MANAs were assessed in binding and stability assays TCR sequencing was performed on reactive cell cultures and on DNA obtained from tumour resections to match TCR clones with those infiltrating the tumour PBMC, peripheral blood mononuclear cell Smith et al. J Thorac Oncol 2016; 11(suppl): abstr OA20.02

14 OA20.02: Neoantigen Targeting in NSCLC Patients with Complete Response to Anti-PD-1 Immunotherapy Smith K, et al Key results Patient 1 had 30 sequence alterations and patient 2 had 314 Despite the difference in mutational load, MANA reactivity was detected in peripheral blood of both patients >1 year after being declared cancer-free TCR clones of MANA-reactive peripheral T cells were detected in tumour resections and were expanded in MANA-stimulated T cell cultures Binding and stability assays confirmed that these MANAs bind to their cognate HLA with high affinity and stability Conclusions Quality of mutations may be more influential in immunogenicity than the overall quantity of mutations MANA reactivity may be the underlying mechanism by which T cells eliminate tumour following anti-pd-1 immunotherapy Smith et al. J Thorac Oncol 2016; 11(suppl): abstr OA20.02

15 MA15.02: Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade Mahadevan NR, et al Study objective To retrospectively analyse the relationship of lung carcinoma mutation burden, PD-L1 expression and immune infiltrates with clinical response in patients receiving immune checkpoint blockade Methods Tumour non-synonymous mutation data derived from clinical targeted next generation sequencing (309 genes) of lung carcinomas from 85 patients treated with immune checkpoint inhibitors was correlated with clinical outcomes including: durable clinical benefit (DCB; >6 months partial or stable response) and PFS Samples were considered PD-L1 positive if 1% of tumour cells and/or tumourinfiltrating immune cells stained PU. 1, CD3, and FOXP3 immunohistochemistry were manually quantified to highlight tumour-associated macrophages and non-regulatory and regulatory T cell populations Mahadevan et al. J Thorac Oncol 2016; 11(suppl): abstr MA15.02

16 PFS, % PFS, % MA15.02: Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade Mahadevan NR, et al Key results Mutation burden and smoking were associated with improved clinical outcome 100 TML 100 Smoking TML TML p< Smoker Never p< No. at risk TML TML Time, months No. at risk Smoker Never Conclusion Mutation burden and increased smoking, but not PD-L1 expression, are associated with improved clinical outcome Mahadevan et al. J Thorac Oncol 2016; 11(suppl): abstr MA Time, months

17 Early and locally advanced NSCLC Stages I, II and III

18 OA03.02: Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1 Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study Garassino MC, et al Study objective To evaluate atezolizumab monotherapy in PD-L1-selected advanced NSCLC patients results from Cohort 1 of the phase 2 BIRCH trial Key patient inclusion criteria Locally advanced or metastatic NSCLC Tumour PD-L1 expression by IHC (TC2/3 and/or IC2/3 No brain metastases R Cohort 1 (1L) No prior chemo Atezolizumab 1200 mg IV q3w (n=138) Cohort 2 (21L) 1 prior platinum chemo Atezolizumab 1200 mg IV q3w (n=271) PD Loss of clinical benefit ECOG PS 0 or 1 (n=667) Cohort 3 (3L+) 2 prior chemo (incl. 1 platinum) Atezolizumab 1200 mg IV q3w (n=254) Loss of clinical benefit Primary endpoint Secondary endpoints ORR (RECIST v1.1) PFS, DoR, OS, safety Garassino et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.02

19 Frequency, % OA03.02: Atezolizumab as 1L Therapy for Advanced NSCLC in PD-L1 Selected Patients: Updated ORR, PFS and OS Data from the BIRCH Study Garassino MC, et al Key results TC3 or IC3 TC2/3 or IC2/3 TC2 and IC2 49% 42% 34% 34% 25% 18% CR/PR SD Conclusion In patients with advanced NSCLC, atezolizumab showed promising efficacy and had a similar safety profile to previous atezolizumab studies TC3 or IC3 = TC 50% or IC 10% PD-L1 expressing cells; TC2 and IC2 = 5% but IC <10% and TC <50% PD-L1 expressing cells; TC2/3 or IC2/3 = TC or IC 5% PD-L1 expressing cells, respectively. Safety summary, n (%) n=138 Total patients with 1 AE 126 (91) Grade 5 2 (1) AEs led to dose interruption 39 (28) TRAEs 83 (60) Grade 5 0 TRAEs led to withdrawal 5 (4) SAEs 45 (33) TC3 or IC3 (n = 65) TC2/3 or IC2/3 (n = 138) TC2 and IC2 (n = 73) mos, months (95%CI) 26.9 (12.0, NE) 23.5 (18.1, NE) 23.5 (18.1, NE) 1-year OS rate, % (95%CI) 61.5 (49.0, 74.0) 66.4 (58.1, 74.6) 70.7 (59.8, 81.6) Garassino et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.02

20 PL03.03: Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) Papadimitrakopoulou V, et al Study objective To compare osimertinib to platinum-based doublet chemotherapy in patients with centrally-confirmed EGFR T790M-positive advanced NSCLC Key patient inclusion criteria Locally advanced or metastatic NSCLC Disease progression following first-line EGFR-TKI therapy EGFR T790M mutation WHO PS 0 1 Stable asymptomatic CNS metastases allowed (n=419) R 2:1 Stratification Osimertinib 80 mg/day (n=279) Ethnicity (Asian vs. non-asian) Pemetrexed 500 mg/m 2 + carboplatin AUC5 or cisplatin 75 mg/m 2 q3w* (n=140) PD Optional crossover to osimertinib PD Primary endpoint PFS by investigator assessment *Optional maintenance pemetrexed Patients could receive study treatment beyond PD, as long as they experience clinical benefit Secondary endpoints OS, ORR, DoR, DCR, BICR-assessed PFS Papadimitrakopoulou et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.03

21 Probability of progression-free survival PL03.03: Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) Papadimitrakopoulou V, et al Key results PFS by investigator assessment mpfs, months (95%CI) HR (95%CI) 10.1 (8.3, 12.3) 0.30 (0.23, 0.41) 4.4 (4.2, 5.6) p<0.001 No. at risk Time, months Osimertinib Platinumpemetrexed PFS by BICR was consistent with investigator-based analysis: HR 0.28 (95%CI 0.20, 0.38); p<0.001 PFS benefit with osimertinib was observed across all subgroups including: ethnicity, sex, EGFR-TKI sensitising mutation status and CNS metastases Papadimitrakopoulou et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.03

22 PL03.03: Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) Papadimitrakopoulou V, et al Key results (cont.) Osimertinib (n=279) Platinum-pemetrexed (n=140) ORR, % (95%CI) 71 (65, 76) 31 (24, 40) Odds ratio (95%CI); p-value 5.39 (3.47, 8.48); <0.001 CR, n (%) 4 (1) 2 (1) PR, n (%) 193 (69) 42 (30) SD 6 weeks, n (%) 63 (23) 60 (43) PD, n (%) 18 (6) 26 (19) NE, n (%) 1 (<1) 10 (7) Median DoR, months (95%CI) 9.7 (8.3, 11.6) 4.1 (3.0, 5.6) Papadimitrakopoulou et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.03

23 PL03.03: Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) Papadimitrakopoulou V, et al Key results (cont.) AEs, n (%) Osimertinib (n=279) Platinumpemetrexed (n=140) Conclusion Any AE 273 (98) 135 (99) Any AE grade 3 63 (23) 64 (47) Any AE leading to death 4 (1) 1 (1) Any serious AE 50 (18) 35 (26) Any AE leading to discontinuation 19 (7) 14 (10) Osimertinib demonstrated superiority in patients with EGFR T790M-positive NSCLC, with lower rates of grade 3 AEs compared with platinum-pemetrexed Papadimitrakopoulou et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.03

24 OA12.02: Excellent Survival Achieved by Stereotactic Body Radiotherapy for Medically Operable and Young (< 75 Years) Patients with Stage I Lung Cancer Onishi H, et al Study objective To collect results of stereotactic body radiotherapy (SBRT) for operable and young (<75 years old) patients with stage I NSCLC from multiple Japanese institutions Methods A retrospective analysis of 252 patients who were <75 years old with stage I NSCLC treated with curative intent by SBRT in 20 institutions of the Japanese Radiological Society Key results OS at 2 years was 86.6% and at 5 years was 78.9% Radiation pneumonitis of grade 3 was noted in 0.8% of all patients By a univariate analysis, female gender, adenocarcinoma, no emphysema and no pulmonary interstitial change were better prognostic factors for OS Conclusions In a large Japanese database, SBRT for the medically operable and young (<75 years old) with stage I NSCLC was excellent OS rate was comparable to survival that would have been expected with surgery Onishi et al. J Thorac Oncol 2016; 11(suppl): abstr OA12.02

25 OA15.02: Survival Outcomes in Sublobar Resection for Clinical T1N0M0 Non- Small Cell Lung Cancer: Wedge Resection or Segmentectomy Kobayashi AK, et al Study objective A retrospective analyses of patients from 26 institutions in Japan, to determine the optimal surgical procedure for early stage lung cancer in patients who had undergone limited resection for c-t1n0m0 NSCLC Methods Nodules were retrospectively scored based on CT findings: low risk group = tumour size <2 cm and ground glass appearance (GGA) dominant; medium risk group = tumour >2 cm and GGA dominant or tumour <2 cm and solid dominant; high risk group = tumour >2 cm and solid dominant 731 patients were matched 1:1 according to surgical procedure (segmentectomy and wedge resection) Key results OS for segmentectomy vs. wedge resection in the low risk group was 90.2% vs. 94.7% (p=0.0351), in the medium risk group 93.6% vs. 80.4% (p<0.001) and in the high risk group 79.1% vs. 69.2% (p=0.109) DFS for segmentectomy vs. wedge resection in the low risk group was 90.2% vs. 92.7% (p=0.0645), in the medium risk group 94.1% vs. 75.3% (p<0.001) and in the high risk group 87.0% vs. 58.1% (p=0.581) Conclusions There was no difference in survival between the surgical procedures in low risk patients In the medium risk group prognosis was better with segmentectomy than sublobular resection Sublobular resection should be avoided for patients in the high risk group Kobayashi et al. J Thorac Oncol 2016; 11(suppl): abstr OA15.02

26 OA15.03: Comparison of Prognosis between Lobectomy and Sublobar Resection for Clinical Stage I Non-Small Cell Lung Cancer with Interstitial Lung Disease Tsutani Y, et al Study objective To compare prognosis after lobectomy and sublobar resection in early NSCLC with interstitial lung disease Methods 107 patients with clinical stage I NSCLC with interstitial lung disease on high-resolution computed tomography who underwent complete resection were identified Key results 3-year OS was significantly worse for patients with usual interstitial pneumonia (UIP) or possible UIP pattern than those with inconsistent UIP pattern (64.5% vs. 82.1%; p=0.031) No significant difference existed in 3-year OS with lobectomy vs. sublobar resection for all patients with interstitial lung disease (67.1% vs. 81.9%; p=0.14), respectively In patients with inconsistent with UIP pattern, 3-year OS was similar in lobectomy vs. sublobar resection groups (81.1% vs. 83.6%; p=0.87), respectively However, in patients with UIP or possible UIP patterns 3-year OS was better for patients who underwent sublobar resection vs. lobectomy (81.0% vs. 50.5%; p=0.069), respectively Conclusion For clinical stage I NSCLC with interstitial lung disease, sublobar resection may be an alternative option especially for those with UIP or possible UIP patterns on HRCT Tsutani et al. J Thorac Oncol 2016; 11(suppl): abstr OA15.03

27 PL04a.02: OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses Gadgeel S, et al Study objective To conduct subgroup analyses of atezolizumab vs. docetaxel in patients with advanced NSCLC in the OAK study Key patient inclusion criteria Locally advanced or metastatic NSCLC 1 2 lines of prior chemotherapy Any PD-L1 status (n=850) R 1:1 Atezolizumab 1200 mg IV q3w (n=425) Stratification PD-L1 expression Histology Prior chemotherapy regimens Docetaxel 75 mg/m 2 q3w (n=425) PD/ loss of clinical benefit PD Primary endpoints OS in ITT population OS in PD-L1 1% TC or IC Secondary endpoints ORR, PFS, DoR, safety Gadgeel et al. J Thorac Oncol 2016; 11(suppl): abstr PL04a.02

28 PL04a.02: OAK, a Randomized Ph III Study of Atezolizumab vs Docetaxel in Patients with Advanced NSCLC: Results from Subgroup Analyses Gadgeel S, et al Key results CNS mets subgroup CNS mets OS HR PFS HR Tobacco use subgroup Never OS HR 0.71 PFS HR 1.3 No CNS mets Current/previous ITT ITT Hazard ratio Favours atezolizumab Favours docetaxel Hazard ratio Favours atezolizumab Favours docetaxel EGFR mutation subgroup Mutant Wild type ITT Conclusion OS HR Hazard ratio Favours atezolizumab Favours docetaxel PFS HR Age, n (%) <65 years years years ITT 453 (53%) 307 (36%) 88 (10%) 850 (100%) OS HR PFS HR Hazard ratio Favours atezolizumab Favours docetaxel Subgroup analysis of the OAK trial demonstrated efficacy for atezolizumab across a range of patient populations; PD-L1 expression, histology, age range, smoking status and brain metastases, but not with EGFR mutation Gadgeel et al. J Thorac Oncol 2016; 11(suppl): abstr PL04a.02

29 Advanced NSCLC Not radically treatable stage III and stage IV 1 st line

30 OA03.01: First-Line Nivolumab Monotherapy and Nivolumab plus Ipilimumab in Patients with Advanced NSCLC: Long-Term Outcomes from CheckMate 012 Gettinger S, et al Study objective To evaluate the efficacy and safety of first-line nivolumab with or without ipilimumab in patients with advanced NSCLC Methods Patients with advanced, chemotherapy naïve NSCLC (any histology; n=52) received nivolumab 3 mg/kg IV q2w alone ± ipilimumab 1 mg/kg q6/12w Key results Grade 3 4 TRAEs occurred in 19% of patients receiving nivolumab alone, 42% of those receiving nivolumab + ipilimumab 1 mg/kg q12w and 31% of those receiving nivolumab + ipilimumab 1 mg/kg q6w 1-year OS rate was 69% for nivolumab, 91% for nivolumab + ipilimumab 1 mg/kg q12w and 83% for nivolumab + ipilimumab 1 mg/kg q6w ORR 23% for nivolumab alone and 43% for nivolumab + ipilimumab ORR was higher in those with PD-L1 expression 50%, 50% for nivolumab and 92% for nivolumab + ipilimumab Conclusion In patients with advanced NSCLC first-line nivolumab ± ipilimumab was well tolerated with similar findings to second-line NSCLC and other tumour types and also showed durable efficacy Gettinger et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.01

31 OA03.03: JAVELIN Solid Tumor: Safety and Clinical Activity of Avelumab (Anti- PD-L1) as First-Line Treatment in Patients with Advanced NSCLC Verschraegen C, et al Study objective To evaluate the safety and clinical activity of avelumab as first-line therapy in a cohort of patients with NSCLC (dose expansion phase, 1b) Methods Patients with stage IV or recurrent NSCLC with no prior treatment received avelumab 10 mg/kg IV (1 h) q2w Key results 16 (10.3%) patients had a potentially immune-related TRAE; grade 3 adrenal insufficiency in 1 (0.6%) patient only. No grade 3 4 pneumonitis; grade 1 2 pneumonitis in 4 (2.6%) patients and 11 (7.1%) patients discontinued treatment following a TRAE mpfs 17.6 weeks (95%CI 11.6, 23.6) with 24-week PFS rate of 37.2% ORR 22.4% (95%CI 16.2, 29.8) and DCR 65.4%. ORR was higher in those aged 65 years, females and ECOG PS 0 Conclusion Early results indicate that avelumab has a durable anti-tumour activity and is well tolerated Verschraegen et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.03

32 PL03.07: First-line Ceritinib Versus Chemotherapy in Patients With ALKrearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) De Castro G, et al Study objective To investigate the efficacy and safety of ceritinib vs. chemotherapy as first-line treatment for advanced ALK+ NSCLC Key patient inclusion criteria Stage IIIB/IV ALK+ NSCLC Treatment naïve WHO PS 0 2 Stable brain metastases (n=376) Primary endpoint PFS 1:1 Ceritinib 750 mg/day (n=189) Stratification WHO PS Brain metastases Prior neoadjuvant/adjuvant chemotherapy Chemotherapy* (n=187) CR, PR, SD Maintenance pemetrexed 500 mg/m 2 q3w Secondary endpoints OS, ORR, DoR, TTR, safety PD Ceritinib 750 mg/day PD *Pemetrexed 500 mg/m 2 + cisplatin 75 mg/m 2 or pemetrexed 500 mg/m 2 + carboplatin AUC 5 6 Castro et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.07

33 PFS probability, % PL03.07: First-line Ceritinib Versus Chemotherapy in Patients With ALKrearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) De Castro G, et al Key results Median PFS was twice as long with ceritinib compared with standard of care chemotherapy (16.6 versus 8.1 months, p<0.001) PFS Ceritinib (n=189) Chemotherapy (n=187) Events, n (%) 89 (47.1) 113 (60.4) Median (95%CI), months 16.6 (12.6, 27.2) 8.1 (5.8, 11.1) HR 0.55 (95%CI 0.42, 0.73) p< Time, months No. at risk Ceritinib Chemotherapy Castro et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.07

34 PL03.07: First-line Ceritinib Versus Chemotherapy in Patients With ALKrearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) De Castro G, et al Key results (cont.) Benefit of ceritinib on PFS was consistent across the majority of pre-specified subgroups Subgroup All patients Geographic region South America Europe Asia Pacific Age (years) <65 65 Sex Male Female Race Caucasian Asian Brain metastases at screening Absence Presence WHO PS 0 1 Prior adjuvant chemotherapy Yes No Disease burden per BIRC assessment baseline SOD for target lesions < median SOD for target lesions baseline SOD for target lesions >= median SOD for target lesions Smoking history Never smoked Ex-smoker or Current smoker No. of patients HR and 95%CI Ceritinib better Chemotherapy better HR 95%CI 0.55 (0.42, 0.73) 0.65 (0.17, 2.54) 0.54 (0.37, 0.80) 0.60 (0.38, 0.96) 0.58 (0.42, 0.80) 0.45 (0.24, 0.86) 0.41 (0.27, 0.63) 0.63 (0.43, 0.93) 0.44 (0.30, 0.66) 0.66 (0.41, 1.06) 0.48 (0.34, 0.69) 0.70 (0.44, 1.12) 0.59 (0.37, 0.96) 0.52 (0.37, 0.74) 1.41 (0.12, 15.84) 0.55 (0.41, 0.73) 0.51 (0.32, 0.80) 0.53 (0.36, 0.79) 0.56 (0.38, 0.80) 0.48 (0.30, 0.77) Castro et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.07

35 PL03.07: First-line Ceritinib Versus Chemotherapy in Patients With ALKrearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) De Castro G, et al Key results (cont.) Overall, 5.3% ceritinib- and 11.4% chemotherapy-treated patients discontinued due to AEs suspected to be drug-related Most common AEs (occurring in >50%) with ceritinib were diarrhoea (84.7%), nausea (68.8%), vomiting (66.1%), ALT increase (60.3%) and AST increase (52.9%) Ceritinib (n=189) Chemotherapy (n=175) Median treatment exposure, weeks* AEs (all-causality), n (%) 189 (100.0) 170 (97.1) SAEs (all-causality), n (%) 70 (37.0) 62 (35.4) SAEs (study drug related), n (%) 30 (15.9) 27 (15.4) AE as primary reason for discontinuation, n (%) 21 (11.1) 29 (16.6) AE as primary reason for discontinuation (study drug related), n (%) AEs leading to dose adjustment or interruption/delay (all-causality), n (%) On-treatment deaths, n (%) Lung cancer related/other** 10 (5.3) 20 (11.4) 131 (69.3) 69 (39.4) 11 (5.8) 7 (3.7)/4 (2.1) 6 (3.4) 5 (2.9)/1 (0.6) *Median relative dose intensity (range): 78.4% ( ) for ceritinib, 95.8% ( ) for pemetrexed, 99.2% ( ) for cisplatin and 93.8% (54.6% 125.9) for carboplatin. **Ceritinib: myocardial infarction (n=1), pneumonitis (n=1), respiratory tract infection (n=1) and unknown cause (1); chemotherapy: lung infection (n=1) Castro et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.07

36 PL03.07: First-line Ceritinib Versus Chemotherapy in Patients With ALKrearranged (ALK+) NSCLC: A Randomized, Phase 3 Study (ASCEND-4) De Castro G, et al Conclusions ASCEND-4 met its primary endpoint Ceritinib compared with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in PFS The PFS improvement was robust and consistent across all pre-specified subgroups including those with and without brain metastases Clinical benefit was also supported by high ORR and DOR The safety profile of ceritinib is consistent with previous studies In patients with ALK-rearranged advanced NSCLC, ceritinib is an option in first-line Castro et al. J Thorac Oncol 2016; 11(suppl): abstr PL03.07

37 MA07.03: Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) Kim YH, et al Study objective To compare alectinib and crizotinib in ALK-inhibitor naïve ALK+ NSCLC Key patient inclusion criteria Stage IIIB/IV or recurrent ALK+ NSCLC patients ECOG PS measurable lesion R 1:1 Alectinib 300 mg bid (n=100) Stratification ECOG PS (0/1 vs. 2) Treatment line (1st vs. 2nd) Clinical stage (IIIB/IV vs. recurrence) PD 1 prior chemotherapy (n=207) Crizotinib 250 mg bid (n=100) PD Primary endpoint PFS according to blinded independent review board Secondary endpoints OS, ORR, safety Kim et al. J Thorac Oncol 2016; 11(suppl): abstr MA07.03

38 PFS, % MA07.03: Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) Kim YH, et al Key results Median PFS was higher with alectinib than crizotinib (p<0.0001) Alectinib (n=103) Crizotinib (n=104) Events, n (%) 25 (24.3) 58 (55.8) Median (95% CI), months NR (20.3, NR) 10.2 (8.2, 12.0) p-value < HR 0.34 ( %CI 0.17, 0.71) 60 NR months No. at risk Alectinib Crizotinib Time, months Kim et al. J Thorac Oncol 2016; 11(suppl): abstr MA07.03

39 MA07.03: Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) Kim YH, et al Key results (cont.) Subgroup analyses showed that HRs for PFS consistently favour alectinib regardless of CNS disease Subgroup Conclusions Alectinib (n=103) Crizotinib (n=104) n Events n Events HR (95%CI)* Overall , 0.54 ECOG PS Prior chemotherapy Clinical stage Age group Smoking status Brain metastases at baseline ALK testing method Sex *Unstratified 0/ , , , , 0.83 Postoperative recurrence , 1.30 Stage IIIB/IV , , 1.19 < , 0.56 Never smoker , 0.89 Past or Current smoker , 0.42 Yes , 0.61 No , 0.64 IHC and FISH , 0.50 RT-PCR , 2.90 Female , 0.57 Male , 0.77 Favours alectinib J-ALEX met its primary endpoint demonstrating superiority of alectinib over crizotinib Alectinib showed greater efficacy suppressing CNS disease than crizotinib Favours crizotinib Kim et al. J Thorac Oncol 2016; 11(suppl): abstr MA07.03

40 MA07.05: EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results Michels S, et al Study objective To evaluate the efficacy and safety of crizotinib in ROS1-positive lung adenocarcinoma Methods A prospective phase 2 trial of crizotinib 250 mg bid in patients with advanced ROS1- positive lung adenocarcinoma, as confirmed by central FISH Baseline tumour tissue was also analysed by DNA-sequencing Key results Of 35 patients enrolled, 32 were sequenced positive for ROS1 fusion and 31 were eligible for treatment Investigator assessed ORR and DCR were 66.7% (95%CI 47.1, 82.1) and 83.3% (95%CI 64.6, 93.7), respectively Median PFS has not yet been met; longest PFS is 23.8 months with a median follow-up of 13.3 months The most common AEs of any grade related to treatment (occurring in >40%) were visual disorders (58.8%), oedema (47.1%), diarrhoea (47.1%), bradycardia (41.2%), nausea (44.1%) and ALT/AST increased (41.2%) Conclusion Crizotinib is a highly effective and well-tolerated treatment in the subset of ROS1- rearranged NSCLC patients as determined by FISH and DNA-sequencing Michels et al. J Thorac Oncol 2016; 11(suppl): abstr MA07.05

41 MA09.03: Cisplatin/Pemetrexed + Durvalumab +/- Tremelimumab in Pts with Advanced Non-Squamous NSCLC: A CCTG Phase IB Study - IND.226 Juergens RA, et al Study objective To evaluate the safety and tolerability of durvalumab, a PD-L1 inhibitor, ± tremelimumab, a CTLA-4 inhibitor, in combination with one of four standard platinum-doublet (results for pemetrexed/cisplatin presented here) regimens in advanced NSCLC Methods Regardless of PD-L1 status, patients were treated with durvalumab 10 or 15 mg/kg q3w with or without tremelimumab 1 or 3 mg/kg q6w plus standard chemotherapy Key results Adverse events that were considered related to durvalumab or tremelimumab were mainly grade 2, the most common (occurring in 15%) were fatigue (50%), vomiting (23%), diarrhoea (15%) and rash (15%) Two patients had serious related adverse events, febrile neutropenia related to chemotherapy and pneumonitis related to both chemotherapy and durvalumab + tremelimumab and was considered a dose-limiting toxicity RR for all treated patients (16/26) 61.5% (95%CI 40.6, 79.8) with 16 PR, 7 SD and 2 PD Conclusion In patients with advanced NSCLC unselected for PD-L1, durvalumab 15 mg/kg q3w and tremelimumab 1 mg/kg (multiple doses q6w) or 3 mg/kg (3 doses q6w) can be safely combined with platinum-doublet chemotherapy Juergens et al. J Thorac Oncol 2016; 11(suppl): abstr MA09.03

42 PL04a.01: Health-Related Quality of Life for Pembrolizumab vs Chemotherapy in Advanced NSCLC with PD-L1 TPS 50%: Data from KEYNOTE-024 Brahmer J, et al Study objective To investigate the efficacy and safety of pembrolizumab vs. platinum-doublet chemotherapy as first-line treatment of stage IV NSCLC Key patient inclusion criteria Untreated stage IV NSCLC PD-L1 TPS 50% No activating EGFR mutation or ALK translocation No untreated brain metastases No active autoimmune disease requiring systemic therapy (n=305) 1:1 Pembrolizumab 200 mg IV q3w for 2 years (n=154) Platinum-doublet chemotherapy, 4 6 cycles (n=151) PD PD* PRO endpoints Change from baseline to Week 15 in EORTC QLQ-C30 global health status/qol score Time to deterioration in EORTC QLQ-LC13 composite endpoint of cough, chest pain and dyspnoea *Patients could switch to pembrolizumab IV 200 mg q3w for 2 years Brahmer et al. J Thorac Oncol 2016; 11(suppl): abstr PL04a.01

43 Time to deterioration (survival analysis) PL04a.01: Health-Related Quality of Life for Pembrolizumab vs Chemotherapy in Advanced NSCLC with PD-L1 TPS 50%: Data from KEYNOTE-024 Brahmer J, et al Key results Pembrolizumab was associated with a significantly greater improvement from baseline to Week 15 in HRQoL vs. platinum-doublet therapy (difference in LS mean 7.8 [95%CI 2.8, 12.8], p=0.002) Pembrolizumab showed slower deterioration in HRQoL due to symptoms (p=0.029) Time to deterioration (EORTC QLQ-LC13 composite endpoint of cough, chest pain and dyspnea) Events, n (%) HR (95%CI) Pembro (n=51) 46 (30.5) 0.66 (0.44, 0.97) Chemo (n=148) 58 (39.2) p= Time, months Conclusion For first-line treatment of advanced NSCLC with PD-L1 expression TPS 50%, pembrolizumab may be a new standard of care showing superior PFS and OS and HRQoL benefits Brahmer et al. J Thorac Oncol 2016; 11(suppl): abstr PL04a.01

44 OA23.06: Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients Yoshida K, et al Study objective To investigate OS, prognostic factors and treatments patterns in patients with EGFR m+ NSCLC in real-world clinical practice Methods Retrospective study of 1,660 patients with histologically or cytologically diagnosed EGFR m+ NSCLC who started first-line treatment between 1/1/2008 and 31/12/2012 at 17 hospitals in Japan Patient characteristics, including treatment histories and survival status, were extracted from the medical records Yoshida et al. J Thorac Oncol 2016; 11(suppl): abstr OA23.06

45 OA23.06: Overall Survival (OS) of EGFR Mutation Positive Non-Small Cell Lung Cancer Patients: Real-World Treatment Patterns of 1,660 Japanese Patients Yoshida K, et al Key results Overall, 61.47% of patients were treated with EGFR-TKI Median OS of all patients was 29.7 months (95%CI 28.13, 31.40) with a 5-year survival rate of 21.5% Greater age at the start of treatment, more advanced clinical stage, positive smoking history, non-adenocarcinoma and minor EGFR mutation were all found to reduce OS Conclusion Month of treatment Survival rate, % Patients alive, n 1,656 1, Patients dead, n ,033 1,102 Censored, n EGFR-TKIs are important in the treatment of patients with EGFR m+ NSCLC in Japan Yoshida et al. J Thorac Oncol 2016; 11(suppl): abstr OA23.06

46 MA16.03: Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers Gautschi O, et al Study objective To provide data on the efficacy of RET-directed targeted therapies administered outside the context of a clinical trial Methods Patients with pathologically confirmed NSCLC harbouring a RET rearrangement were identified by thoracic oncologists in Europe, Asia and the USA Response to RET tyrosine kinase inhibition (TKI) administered off-protocol was determined by RECIST 1.1 The objectives were to determine ORR, PFS and OS Results Of 165 patients with a median age of 61 years (range 28 89), 53 were treated with RET inhibitor, most commonly Cabozantinib (n=21) Vandetanib (n=11) Sunitinib (n=10) Gautschi et al. J Thorac Oncol 2016; 11(suppl): abstr MA16.03

47 MA16.03: Global RET Registry (GLORY): Activity of RET-Directed Targeted Therapies in RET-Rearranged Lung Cancers Gautschi O, et al Results (cont.) ORR was evaluable in 50 patients RET Inhibitor Cabozantinib Best response, % (95%CI) 37 (16.3, 61.6) Median PFS, months (95%CI) 3.6 (1.3, 7.0) Median OS, months (95%CI) 4.9 (1.9, 14.3) Vandetanib Sunitinib 18 (2.3, 51.8) 22 (2.8, 60.0) 2.9 (1.0, 6.4) 2.2 (0.7, 5.0) 10.2 (2.4, NR) 6.8 (1.1, NR) Conclusion Response rates to RET inhibitors in the RET registry were consistent with clinical trials, but PFS was inferior in the real world Gautschi et al. J Thorac Oncol 2016; 11(suppl): abstr MA16.03

48 OA03.06: Evaluation of Toxicity Profile of PD-1 versus PD-L1 Inhibitors in Non- Small Cell Lung Cancer (NSCLC) Pillai RN, et al Study objective A systematic review of trials investigating differences in the toxicities of PD-1 and PD-L1 inhibitors Methods Literature search of MEDLINE, EMBASE and conference proceedings for trials utilising PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, avelumab) in patients with NSCLC Studies that did not report toxicities were excluded A meta-analysis was conducted with clinical and demographic characteristics, response and toxicity data compared between PD-1 and PD-L1 inhibitors Pillai et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.06

49 OA03.06: Evaluation of Toxicity Profile of PD-1 versus PD-L1 Inhibitors in Non- Small Cell Lung Cancer (NSCLC) Pillai R, et al Key results Twenty-three studies were included in the analysis; 12 were studies with PD-1 inhibitors and 11 were with PD-L1 inhibitors A total of 5,899 patients were evaluated for toxicity, including 3,284 patients treated with PD-1 and 2,615 treated with PD-L1 inhibitors ORR was similar between the groups (19% for PD-1 and 17% for PD-L1; p=0.7) AEs were reported in 72% and 65% of patients with fatigue being the most common event (19% and 21%) in the PD-1 and PD-L1 inhibitor groups, respectively There was a slightly higher incidence of immune-related AEs (16% vs. 11%; p=0.04) and pneumonitis (4% vs. 2%; p=0.01) with PD-1 inhibitors compared with PD-L1 inhibitors Conclusions There was a similar rate of overall AEs between PD-1 and PD-L1 inhibitors In an unselected population of patients with NSCLC, the response rate appears to be similar for PD-1 and PD-L1 inhibitors Pillai et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.06

50 Advanced NSCLC Not radically treatable stage III and stage IV Later lines

51 OA03.05: Analysis of Early Survival in Patients with Advanced Non-Squamous NSCLC Treated with Nivolumab vs Docetaxel in CheckMate 057 Peters S, et al Study objective A post-hoc analyses of CheckMate 057 to explore the relationships between baseline patient/disease characteristics, including PD-L1 expression, and death within the first 3 months of treatment Key patient inclusion criteria Stage IIIB/IV non-squamous NSCLC ECOG PS prior platinum-based chemotherapy Prior TKIs for known ALK translocation or EGFR mutation Prior maintenance therapy allowed Pre-treatment tumour samples for PD-L1 analysis (n=582) R Nivolumab 3 mg/kg IV q2w (n=292) Stratification Prior maintenance therapy Line of therapy (2L vs. 3L) Docetaxel 75 mg/m 2 q3w (n=290) PD/ toxicity PD/ toxicity Primary endpoint OS Secondary endpoints ORR, PFS, efficacy by tumour PD-L1 expression, safety, QoL Peters et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.05

52 OS, % OA03.05: Analysis of Early Survival in Patients with Advanced Non-Squamous NSCLC Treated with Nivolumab vs Docetaxel in CheckMate 057 Peters S, et al Key results Risk of death was numerically higher with nivolumab (59/292) vs. docetaxel (44/290) in the first 3 months of treatment, which was most commonly attributed to disease progression Post-hoc analysis suggested that nivolumab-treated patients with poorer prognostic features and/or aggressive disease when combined with lower or no tumour PD-L1 expression may be at higher risk 100 ITT population Nivolumab (n=292) Docetaxel (n=290) Median OS, mo Events HR (95%CI) 0.73 (0.59, 0.89) 100 Alive at 3 months: all patients Nivolumab (n=232) Docetaxel (n=244) Median OS, mo Events HR (95%CI) 0.59 (0.47, 0.74) 100 Alive at 3 months: patients with <1% PD-L1 expression Nivolumab (n=82) Docetaxel (n=87) Median OS, mo Events HR (95%CI) 0.66 (0.45, 0.97) Nivolumab Docetaxel 20 Nivolumab Docetaxel 20 Nivolumab Docetaxel Months Months Conclusion In the first 3 months of treatment there was an absolute difference in deaths of 15 patients, although after this the OS rate was consistently in favour of nivolumab over 2 years Months Peters et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.05

53 OA03.07: KEYNOTE 010: Durable Clinical Benefit in Patients with Previously Treated, PD-L1-Expressing NSCLC Who Completed Pembrolizumab Herbst RS, et al Study objective To assess outcomes in patients who completed the maximum 24 months of pembrolizumab in the phase 3 KEYNOTE-010 study Key patient inclusion criteria Advanced NSCLC that progressed after 1 line of chemotherapy PD-L1 TPS 1% ECOG PS 0 1 (n=1034) Primary endpoints PFS, OS R 1:1:1 Stratification ECOG PS (0 vs. 1) Pembrolizumab 2 mg/kg q3w for 24 months Pembrolizumab 10 mg/kg q3w for 24 months Docetaxel 75 mg/m 2 q3w per local guidelines Region (East Asia vs. Non-East Asia) PD-L1 status (TPS 50% vs. 1 49%) Secondary endpoints ORR, DoR, safety PD/ toxicity/ other PD/ toxicity/ other PD/ toxicity/ other Herbst et al. J Thorac Oncol 2016; 11(suppl): abstr OA03.07

54 Overall survival, % OA03.07: KEYNOTE 010: Durable Clinical Benefit in Patients with Previously Treated, PD-L1-Expressing NSCLC Who Completed Pembrolizumab Herbst RS, et al Key results OS in the total population Pembrolizumab 2 mg/kg q3w (n=344) Pembrolizumab 10 mg/kg q3w (n=344) Docetaxel 75 mg/m 2 (n=343) Events, n (%) 233 (68) 214 (62) 257 (75) mos, months (95%CI) HR (95%CI) p-value (vs. docetaxel) 24-mo OS rate, % (95%CI) 10.5 (9.6, 12.4) 0.72 (0.60, 0.86) 13.4 (11.2, 17.0) 0.60 (0.49, 0.72) 8.6 (7.9, 9.8) < (25.0, 35.4) 37.5 (32.2, 42.9) 14.5 (10.5, 19.2) Median follow-up: 2.1 years (range, years) Docetaxel 75 mg/m 2 (n=343) Pembrolizumab 2 mg/kg q3w (n=344) Pembrolizumab 10 mg/kg q3w (n=344) 0 5 No. at risk: Docetaxel 75 mg/m 2 Pembro 2 mg/kg q3w Pembro 10 mg/kg q3w Months Conclusion After 2 years of treatment the clinical benefit of pembrolizumab is durable with most patients remaining in response including those with stable disease once treatment was stopped Herbst et al. J Thorac Oncol 2016; 11(suppl): abstr OA

55 OA08.02: Phase II Study of Erlotinib in Advanced Non-Small Cell Lung Cancer Patients with Leptomeningeal Metastasis (LOGIK1101) Ota K, et al Study objective Phase 2 trial to evaluate the efficacy of erlotinib in patients with NSCLC and leptomeningeal metastases (LM) Key patient inclusion criteria Patients with advanced/metastatic NSCLC and cytologically confirmed LM Age 20 years PS 1 3 EGFR + or wt (n=21) Erlotinib 150 mg/day PD Primary endpoint(s) Cytological clearance rate* *Number of patients who achieved complete remission in CSF out of number of all LM confirmed patients 4 weeks after treatment Note: This study was closed because of low accrual with only 21 of required 32 (66%) patients accrued Secondary endpoints Time to progression, OS, AEs, symptoms PK in CSF Ota et al. J Thorac Oncol 2016; 11(suppl): abstr OA08.02

56 Time to LM progression, months Survival time, months OA08.02: Phase II Study of Erlotinib in Advanced Non-Small Cell Lung Cancer Patients with Leptomeningeal Metastasis (LOGIK1101) Ota K, et al Key results Cytological clearance rate was 35.3% in the EGFR mutant group and 0% in the wild-type group Significantly longer time to progression and OS were observed in EGFR-mutant than in EGFR wild-type (p= and p=0.0054, respectively) 100 Time to progression (n=21) 100 OS (n=21) Median TTP, mo EGFR mutant (n=17) 2.7 EGFR wild (n=4) 0.9 Median TTP, mo EGFR mutant (n=17) 4.0 EGFR wild (n=4) HR 0.29 (0.02, 0.52); p= HR 0.25 (0.01, 0.42); p= Time, days from enrolment Conclusion Time, days from enrolment Erlotinib treatment for leptomeningeal metastasis is active, especially in patients with EGFR mutation Ota et al. J Thorac Oncol 2016; 11(suppl): abstr OA08.02

57 OA08.05: Efficacy and Cerebrospinal Fluid Concentration of Afatinib in NSCLC Patients with EGFR Mutation Developing Leptomeningeal Carcinomatosis Tamiya A, et al Study objective To evaluate the CSF penetration rate and efficacy of afatinib 40 mg/day in patients with EGFR-positive NSCLC and leptomeningeal carcinomatosis (LC) Methods Afatinib levels were measured in blood and CSF before administration on the eighth day Key results 11 patients were enrolled in the study; afatinib levels were measured in the blood and CSF in 10 and 8 patients, respectively 5 patients had EGFR exon 19 deletion, 3 had exon 21 L858R and 3 had exon18 mutations The median blood level of afatinib was 88.2 ng/ml (range ), the median CSF level was 1.4 ng/ml (range ), with median CSF penetration rate of 1.7% (range ) mpfs was 61 days (range ) and mos 115 days (32 410), with 1 SD and 3 PR (2 in those with exon 18 mutaitons) Toxicity was generally mild; although grade 3 AEs of skin toxicities, diarrhoea, stomatitis and neutropenia occurred, especially in patients with poor PS Conclusions The median CSF penetration rate of afatinib was higher than previously reported, with evidence for better responses in patients with EGFR exon 18 mutations Management of diarrhoea and skin toxicities is important Tamiya et al. J Thorac Oncol 2016; 11(suppl): abstr OA08.05