NON SQUAMOUS CELL CARCINOMA OF THE LUNG WITHOUT EVIDENCE OF DRIVER MUTATIONS

Transcription

1 AFA From Bench to Bedside From KK DT1 10/27/2015 1:42 PM 01 NON SQUAMOUS CELL CARCINOMA OF THE LUNG WITHOUT EVIDENCE OF DRIVER MUTATIONS Nicholas Thatcher, MB BChir, PhD Department of Medical Oncology Christie Hospital Manchester, United Kingdom

2 Outline 2 Introduction to treatment of non-squamous NSCLC (NSCC) treatment algorithm Review of current approaches for NSCC without key driver mutations Chemotherapy Anti-angiogenic agents Immunotherapy

3 Current Treatment of NSCC Without Key Driver Mutations

4 Prevalence of NSCC Without Driver Mutations Lung Cancer Mutation Consortium 1 4 Incidence of single driver mutations Mutations found in 54% (280/516) of tumors completely tested (CI 50-59%) or 46% of completed tested tumors with no mutations detected 1 1. Kris MG et al. J Clin Oncol 29: 2011 (suppl; abstr CRA7506)

5 Current Treatment Algorithm for NSCC Without Driver Mutations (NCCN) 5 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Non-Small Cell Lung Cancer V

6 NICE s Pathways for the Treatment of NSCLC 1 Patient with non-small-cell lung cancer Surgery with curative intent Adjuvant chemotherapy NICE Pathways 5 6 Radiotherapy with curative intent 7 2 Chemoradiotherapy Before multimodality treatment Ablation procedures for primary and secondary lung cancers 8 9 Photodynamic therapy for localised inoperable endobronchial cancer 10 Chemotherapy for advanced or metastic non-smallcell lung cancer First-line and maintenance chemotherapy for advanced or metastic non-smallcell lung cancer Chemotherapy : Single 3 rd -generation drug + Carboplatin or cisplatin 1st-line options: Afatinib ##b Erlotinib Gefitinib Pemetrexed + Cisplatin Maintenance: Pemetrexed Patients with stage III or IV NSCLC and good performance status (WHO 0,1 or Karnofsky score of ) Docetaxel, gemcitabine, paclitaxel or vinorelbine 11 Second-line chemotherapy for advanced or metastic non-smallcell lung cancer 2 nd -line options: Nintedanib #a + docetaxel Erlotinib Docetaxel monotherapy content=view-index. Accessed October 05, 2015 # Nintedanib is approved in the European union (EU) under the brand name VARGATEF for use in combination with docetaxel in adult patients with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy. Registration conditions differ internationally, please refer to locally approved prescribing information. Nintedanib is not approved in other indications. a Currently is not approved for the treatment of patients with NSCLC in South Korea. ## Afatinib is approved in a number of markets, including the EU, Japan, Taiwan and Canada under the brand name GIOTRIF and in the U.S. under the brand name GILOTRIF for use in patients with distinct types of EGFR mutation-positive NSCLC. Registration conditions differ internationally, please refer to locally approved prescribing information. Afatinib is under regulatory review by health authorities in other countries worldwide. Afatinib is not approved in other indications." b Afatinib is approved for 1 st -line monotherapy in NSCLC patients with EGFR mutation in South Korea.

7 Chemotherapy for the Treatment of NSCC Without Key Driver Mutations

8 Platinum Doublet in the Treatment of NSCC ECOG 1594 trial 8 Primary endpoint Median OS (mo): Cis/pac (n=288): 7.8 Cis/gem (n=288): 8.1 Cis/doc (n=289): 7.4 Carbo/pac (n=290): 8.1 Median TTP (mo): Cis/pac (n=288): 3.4 Cis/gem (n=288): 4.2 Cis/doc (n=289): 3.7 Carbo/pac (n=290): 3.1 Schiller JH et al. N Engl J Med. 2002;346:92-98.

9 Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine as 1st-Line Treatment of NSCC (JMDB Trial) Impact of histology 9 No difference in OS or PFS between study arms Cis/pem improves OS over cis/gem in NSCC (HR: 0.81; P=0.005) Cis/gem improves OS over cis/pem in SCC (HR: 1.23; P=0.05) Scagliotti et al. J Clin Oncol. 2008;26:

10 Antiangiogenic Agents for the Treatment of NSCC Without Key Driver Mutations

11 Vascular Endothelial Growth Factor (VEGF)/VEGF Receptor (VEGFR) and Therapeutic Strategies to Inhibit VEGF Signaling 11 Anti-VEGF antibodies Ramucirumab IMC-18F1 CDP791 VEGF VEGFR Anti-VEGF antibodies Bevacizumab Ranibizumab Aptamers, soluble receptors VEGF-Trap Pegaptanib Cytoplasm PLC PKC Proliferation Ras Raf MEK ERK enos Bcl-2 PI3K Akt BAD FAK Paxillin Vascular permeability Survival Migration Tyrosine kinase inhibitors Sorafenib Sunitinb Pazopanib Vatalanib Vandetanib Axitinib Cediranib Motesanib Tiovzanib Linifanib Brivanib Nintedanib Angiogenesis and tumour development Currently is not approved for the treatment of patients with NSCLC in South Korea. 1. Koo et al. J Clin Oncol 2012;30:1137-9; 2. De Haas et al Angiogenesis 2014;17:909-20; 3. Mok et al J Thor Oncol 2014;9:

12 OS estimate OS estimate Prognostic Value of MVD/VEGF Levels in NSCLC High MVD, VEGF predicts for poor survival 1.0 MVD low 1.0 VEGF low MVD high 0.4 VEGF high P< P< Months Months MVD = microvessel density. Macchiarini et al. Lancet Meert et al. Br J Cancer Fontanini et al. Br J Cancer

13 Paclitaxel + Carboplatin + Bevacizumab vs Paclitaxel + Carboplatin in NSCC (ECOG 4599) 12.3 months vs 10.3 months 6.2 months vs 4.5 months Sandler A et al. N Engl J Med. 2006; 355;5:

14 Recently Approved Antiangiogenic Agents for the Treatment of NSCC Without Key Driver Mutations

15 REVEL: Phase III Trial Design Ramucirumab, an intravenously administered, mab against VEGFR2 015 Stage IV NSCLC Failed 1st-line platinum-based chemotherapy +/- maintenance Any histology ECOG PS 0 or 1 No prior EGFR TKI monotherapy or docetaxel R A N D O M I S E 1:1 Ramucirumab (10 mg/kg) + docetaxel (75 mg/m 2 ) n=628 Placebo + docetaxel (75 mg/m 2 ) n=625 PD PD Cycles repeat every 3 weeks until disease progression, development of unacceptable toxicity, noncompliance, or study withdrawal by the patient or per investigator decision Stratification: ECOG performance status (0 vs 1) Prior maintenance (yes vs no) Gender East-Asia vs. rest of world Primary endpoint: Overall survival Secondary endpoints: PFS (investigator review), objective response rate, safety, patient-reported outcomes Ramucirimab in combination with docetaxel, is indicated for treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy by the FDA. Garon et al. Lancet 2014;384:

16 REVEL: Overall Survival in Intent-to-Treat Population 016 Garon et al. Lancet 2014;384:

17 REVEL: Overall Survival by Histology 017 Non-squamous histology Squamous histology Garon et al. Lancet 2014;384:

18 REVEL: Haematological and Special Interest Treatment-Emergent AEs Occurring in 10% of Patients 018 Adverse events, n (%) Ramucirumab plus docetaxel group (n=627) Placebo plus docetaxel group (n=618) All grades Grade 3 All grades Grade 3 Neutropenia 345 (55%) 306 (49%) 284 (45%) 246 (39%) Leucopenia 134 (21%) 86 (14%) 117 (19%) 77 (12%) Anaemia 131 (21%) 18 (3%) 174 (28%) 35 (6%) Febrile neutropenia 100 (16%) 100 (16%) 62 (10%) 62 (10%) Thrombocytopenia 84 (13%) 18 (3%) 32 (5%) 4 (1%) Bleeding or haemorrhage 181 (29%) 15 (2%) 94 (15%) 14 (2%) Epistaxis 116 (19%) 2 (<1%) 40 (6%) 1 (<1%) Hypertension 68 (11%) 35 (6%) 30 (5%) 13 (2%) AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities Garon et al. Lancet 2014;384:

19 Nintedanib a : A Triple-angiokinase Inhibitor 019 Oral angiokinase inhibitor targeting: 1 VEGFR 1 3 FGFR 1 3 PDGFR α/β No drug drug interaction liability via cytochrome P450 2 Manageable safety profile in combination with commonly used chemotherapy agents 3 6 Nintedanib is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy. FGFRs = fibroblast growth factor receptors; PDGFRs = platelet-derived growth factor receptors; VEGFRs = vascular endothelial growth factor receptors. a Currently is not approved for the treatment of patients with NSCLC in South Korea. 1. Hilberg F, et al. Cancer Res 2008;68: ; 2. Stopfer P, et al. Xenobiotica 2011;41: ; 3. Bousquet G, et al. Br J Cancer 2011;105:1640 5; 4. Ellis PM, et al. Clin Cancer Res 2010;16:2881 9; 5. Doebele RC, et al. Ann Oncol 2012;23: ; 6. Soria J- C, et al. Ann Oncol 2012;23(Suppl. 9):Abstract 979.

20 By Targeting FGFR, Nintedanib a May Evade Resistance to Anti-VEGF/R Therapies 020 Progression of disease to VEGF/VEGFR therapies eventually occurs VEGFR2 blockade triggers hypoxia and upregulation of other pro-angiogenic factors, such as FGFs and PDGFs, stimulating VEGF-independent angiogenesis 1,2 Blocking FGFR signalling impairs the evasion of VEGFR2 inhibition Dual blockade of VEGFR2 and FGF ligands significantly inhibits angiogenesis and tumour growth 1 Nintedanib is effective in bevacizumab-resistant tumours By targeting multiple pro-angiogenic factors, nintedanib is effective in HT-29 tumours, which are resistant to bevacizumab 3 5 CRC = colorectal cancer; FGFR = fibroblast growth factor receptor; PDGFR = platelet-derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor. a. Currently is not approved for the treatment of patients with NSCLC in South Korea. 1. Casanovas O, et al. Cancer Cell 2005;8: ; 2. Bergers G, Hanahan D. Nat Rev Cancer. 2008;8: ; 3. Mésange P, et al. Oncotarget 2014; 5: Poindessous V, et al. Clin Cancer Res 2011;17: : 5. Casanovas O, et al. Cell Cycle 2014;13:

21 Nintedanib a Does Not Induce Epithelial-Mesenchymal Transition (EMT)* 021 EMT predicts poor prognosis, promotes metastasis, and is associated with resistance to therapy 1 Poor prognosis in CRC 1 and NSCLC 2 Hypoxia is a known driver of EMT 3 Anti-angiogenic therapy may promote a more invasive phenotype by inducing hypoxia leading to EMT 3 Nintedanib does not induce EMT and does not induce an invasive phenotype (in vitro) 3 Nintedanib has been shown potentially to reverse EMT (in vitro) 4 *Anti-angiogenic agents have been shown to potentiate hypoxia-induced EMT 5 7 a Currently is not approved for the treatment of patients with NSCLC in South Korea. CRC = colorectal cancer; EMT = epithelial-mesenchymal transition; NSCLC = non-small cell lung cancer. 1. Cao H, et al. Pathol Res Pract 2015;211:557 69; 2. Soltermann A, et al. Clin Cancer Res 2008;14:7430 7; 3. Cenik B, et al. Mol Cancer Ther 2013;12: ; 4. Huang RY, et al. Oncotarget Birner P et al. Cancer Res 2000;60: Vaupel P et al. Semin Oncol 2001;28: Bos R et al. Cancer 2003; 97:

22 LUME-Lung 2 Study Design 022 Stage IIIB/IV* or recurrent non-squamous NSCLC patients after first-line chemotherapy R A N D O M I S E 1:1 Nintedanib a 200 mg BID PO, Days 2 21, + pemetrexed 500 mg/m 2 IV, Day 1, 21-day cycles (n=353) Placebo BID PO, Days 2 21, + pemetrexed 500 mg/m 2 IV, Day 1, 21-day cycles (n=360) PD PD N=713 Monotherapy with nintedanib/placebo or pemetrexed allowed after 4 cycles Primary Endpoint: PFS by independent central review Key Secondary Endpoint: OS Study was halted prematurely by DMC recommendation after preplanned interim futility analysis based on investigator-assessed PFS, there were no safety concerns Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs. no) Histology (adenocarcinoma vs. non-adenocarcinoma) Brain metastases (yes vs. no) Regions: North and South America, Europe, Asia and Australia/Oceania Accrual: 23 Dec 2008 to 04 July 2011 a Currently is not approved for the treatment of patients with NSCLC in South Korea. Hanna NH, et al. J Clin Oncol. 2013;31(suppl):Abstract 8034 and poster presentation.

23 Probability of PFS (%) Primary Endpoint Was Met Primary endpoint by independent central review, all patients Median PFS (months) Nintedanib a + pemetrexed Placebo + pemetrexed HR = 0.83 (95% CI: ); p= No. at risk Nintedanib Placebo Time (months) a Currently is not approved for the treatment of patients with NSCLC in South Korea. Hanna NH, et al. J Clin Oncol. 2013;31(suppl):Abstract 8034 and poster presentation.

24 Hypothesis-Generating Exploratory Analysis Suggested Clinical Marker Based on the centrally assessed PFS data (non-squamous histology) 024 a Currently is not approved for the treatment of patients with NSCLC in South Korea. Prognostic variable* Adjusted hazard ratio (95% CI) p-value Time since start of first-line therapy (months) 0.95 ( ) < Adjusted hazard Ratio (95% CI) Predictive variable Time since start of first-line therapy <9 months 9 months Favours nintedanib a Hazard Ratio (95% CI) Hazard ratio (95% CI) p-value 0.72 ( ) 0.99 ( ) Favours placebo *Hazard ratio, confidence interval and p-value obtained from a model selected using a stepwise selection procedure. The model was stratified by ECOG PS (0 vs 1) and tumour histology (adenocarcinoma vs non-adenocarcinoma). An increase of 1 month in time since first-line therapy decreased the hazard ratio by 5%. Hazard ratio and confidence interval obtained from a model stratified by ECOG PS (0 vs 1), brain metastases at baseline (yes vs no), prior treatment with bevacizumab (yes vs no) and tumour histology (adenocarcinoma vs non-adenocarcinoma). a Currently is not approved for the treatment of patients with NSCLC in South Korea. Kaiser R. et al. Eur J Cancer 2013;49(Suppl. 2):Abstract 3479, Poster P

25 LUME-Lung 1: Randomised Controlled Phase III Study 025 Stage IIIB/IV* or recurrent NSCLC patients after first-line chemotherapy (all histologies) R A N D O M I S E 1:1 Nintedanib a 200 mg BID po, Days docetaxel 75 mg/m 2 IV, Day 1, 21-day cycles (n=655) Placebo BID po, Days 2 21, + docetaxel 75 mg/m 2 IV, Day 1, 21-day cycles (n=659) PD PD N=1314 Number of docetaxel cycles not restricted Monotherapy allowed after 4 cycles of combination therapy Primary Endpoint: Key Secondary Endpoint: PFS by independent central review OS, prespecified hierarchical analyses of patients with adenocarcinoma who progressed in <9 months after start of first-line therapy, all patients with adenocarcinoma, and ITT population Stratification: ECOG PS (0 vs. 1) Prior bevacizumab (yes vs. no) Histology (squamous vs. non-squamous) Brain metastases (yes vs. no) Regions: Europe/Asia/South Africa Accrual: 23 Dec 2008 to 09 Feb 2011 a Currently is not approved for the treatment of patients with NSCLC in South Korea. Reck M, et al. Lancet Oncol. 2014;15:

26 LUME-Lung 1 Statistical Methodology 026 Primary endpoint Independently assessed PFS ITT/all histologies Significant finding Key secondary endpoint An exploratory analysis of LUME-Lung 2 data showed evidence for enhanced survival benefit in early progressing adenocarcinoma tumours 1,2 To confirm this finding in LUME-Lung 1, a pre-specified stepwise testing was incorporated in the secondary endpoint OS analysis. This stepwise approach was applied to control the type I error rate 3 OS Adenocarcinoma Time since start of first-line therapy <9 months Significant finding OS All adenocarcinoma Significant finding OS ITT/all histologies Hanna N. et al. J Clin Oncol. 2013;31(suppl; abstr 8034); 2. Kaiser R. et al. Eur J Cancer 2013;49(Suppl. 2):Abstract 3479, Poster P ; 3. Reck M, et al. Lancet Oncol. 2014;15:

27 Probability of PFS (%) Probability of PFS (%) Probability of PFS (%) LUME-Lung 1: PFS by Independent Central Review 27 All patients Adenocarcinoma Squamous cell carcinoma Median PFS (months) Nintedanib a + docetaxel Placebo + docetaxel HR = 0.79 (95% CI: ); p= Median PFS (months) Nintedanib a + docetaxel Placebo + docetaxel HR = 0.77 (95% CI: ); p= Median PFS (months) Nintedanib a + docetaxel Placebo + docetaxel (95% CI: ); p= No. at risk Nintedanib Placebo Time (months) No. at risk Nintedanib Placebo Time (months) No. at risk Nintedanib Placebo Time (months) a Currently is not approved for the treatment of patients with NSCLC in South Korea. Reck M, et al. Lancet Oncol. 2014;15:

28 LUME-Lung 1: OS in Adenocarcinoma Patients (Time Since Start of 1st-line Therapy <9 mo, Adenocarcinoma Patients) Key secondary endpoint, pre-specified hierarchical analysis 28 Time since start of 1st-line therapy <9 mo, adenocarcinoma a All patients with adenocarcinoma 46.8% 52.7% 34.3% 20.7% 44.7% 25.7% 10.4% 19.1% Median OS was not significantly different between the two arms in the ITT population (HR 0.94, 95% CI: , P=0.272) a Currently is not approved for the treatment of patients with NSCLC in South Korea. Reck M, et al. Lancet Oncol. 2014;15:143-55

29 Probability of survival (%) OS in Patients with Adenocarcinoma and No Response to First-Line Chemotherapy (Exploratory Analysis) Adenocarcinoma and PD as best response to first-line chemotherapy Nintedanib Placebo + + docetaxel a docetaxel Median OS (months) HR = 0.62 (95% CI: ); p= % % 1-YEAR SURVIVAL Time (months) 21.5% 5.3% 2-YEAR SURVIVAL No. at risk Nintedanib Placebo a Currently is not approved for the treatment of patients with NSCLC in South Korea. CI = confidence interval; HR = hazard ratio; OS = overall survival; PD = progressive disease. Mellemgaard A, et al. Eur J Cancer. 2013;49(suppl. 2):Abstract 3409 and oral presentation.

30 Patients (%) Patients (%) Adverse Events Commonly Associated with VEGF/VEGFR Inhibitors Adverse events of special interest in patients with adenocarcinoma ,911,1 All grades (%) Grade 3 (%) Nintedanib + docetaxel a 15 Placebo + docetaxel Placebo + docetaxel 10 a Nintedanib + docetaxel 5 0 0,3 0,3 5,3 5,4 2,8 1,2 0,9 2,1 3,4 0, ,3 1,5 0,3 0,3 2,5 3,3 0,9 0,9 0,9 0,6 0,3 0,3 ATE = arterial thromboembolism; GI = gastrointestinal; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; VTE = venous thromboembolism a Currently is not approved for the treatment of patients with NSCLC in South Korea. Reck M, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8100 and poster); Boehringer Ingelheim data on file.

31 Addition of Nintedanib a to Docetaxel Did Not Further Compromise Patient s Self-Reported Quality of Life EORTC QLQ-C30 and QLQ-LC13 prespecified symptoms of interest 031 p-value Cough (QLQ-LC13) NS Dyspnoea (QLQ-LC13) NS Dyspnoea at rest NS Dyspnoea after walking NS Dyspnoea after climbing stairs NS Short of breath (QLQ-C30) NS Pain (QLQ-C30) NS Have pain Pain affecting daily activities NS Pain in chest (QLQ-LC13) Pain in arm and shoulder (QLQ-LC13) Pain in other parts (QLQ-LC13) NS Global health status/qol NS Favours nintedanib Difference in mean score Favours placebo EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality Of Life Questionnairecore 30; EORTC QLQ-LC13; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire and Lung Cancer-13; NS = non-significant; QoL = Quality-of-life a Currently is not approved for the treatment of patients with NSCLC in South Korea. Novello S, et al. Eur J Cancer 2014:DOI: /j.ejca

32 Immunotherapy in the Treatment of NSCC Without Key Driver Mutations: Emerging Data

33 CheckMate-057: Phase 3 Trial of Nivolumab vs Docetaxel in Patients With Non-Squamous NSCLC Stage IIIb/IV non-squamous NSCLC Failed one prior platinum-based doublet Prior TKI therapy allowed for known ALK translocation or EGFR mutation Prior maintenance therapy allowed ECOG PS: 0-1 Maintenance therapy included pemetrexed, bevacizumab or erlotinib (not considered a separate line of therapy) Endpoints: Primary: OS N=582 n=292 n=290 Nivolumab: 3 mg/kg IV Q2Wk Docetaxel: 75 mg/m 2 IV Q3Wk Patients stratified by prior maintenance therapy and line of therapy (2 nd vs 3 rd -line) Secondary: ORR, PFS, correlation between PD-L1 expression and efficacy PD-L1 expression measured using the Dako/BMS automated IHC assay R 1:1 Fully validated with analytical performance having met all pre-determined acceptance criteria for sensitivity, specificity, precision, and robustness Borghaei H et al. N Engl J Med Sep 27. [Epub ahead of print]. Until PD or unacceptable toxicity

34 CheckMate-057: OS (Primary Endpoint) and PFS Symbols represent censored observations. CI = confidence interval; HR = hazard ratio. Borghaei H et al. N Engl J Med Sep 27. [Epub ahead of print].

35 CheckMate-057: OS by PD-L1 Expression 35 Borghaei H et al. N Engl J Med Sep 27. [Epub ahead of print].

36 CheckMate 057: Anti-PD-1/PD-L1 in Patients With Key Driver Mutations? Treatment effect on OS in predefined subgroups Overall Age Categorization (years) <65 65 and <75 75 N Unstratified HR (95% CI) 0.75 (0.62, 0.91) 0.81 (0.62, 1.04) 0.63 (0.45, 0.89) 0.90 (0.43, 1.87) Gender Male Female (0.56, 0.96) 0.78 (0.58, 1.04) Baseline ECOG PS 0 1 Smoking Status Current Smoker Never Smoked EGFR Mutation Status Positive Not Detected Not Reported (0.44, 0.93) 0.80 (0.63, 1.00) PFS in overall population 0.70 (0.56, 0.86) 1.02 (0.64, 1.61) 1.18 (0.69, 2.00) 0.66 (0.51, 0.86) 0.74 (0.51, 1.06) All randomized patients (nivolumab n=292; docetaxel n=290) Nivolumab Docetaxel Borghaei H et al. N Engl J Med Sep 27. [Epub ahead of print].

37 Other Anti-PD/PD-L1 Agents in Clinical Development: Pembrolizumab, Atezolizumab (MPDL3280A), and MEDI4736 Agents Patients Treatment ORR, % PFS/OS Pembrolizumab 1 Pembrolizumab 1 Pembrolizumab 2 Atezolizumab (POPLAR) 3 Atezolizumab 4 Atezolizumab 5 MEDI Untreated NSCLC Previously treated NSCLC 2 nd -line advanced NSCLC Previously treated NSCLC Untreated NSCLC Previously treated Previously treated Pembro /16.2 Pembro /12.0 Pembro + ipi 39 --/-- Atez vs docetaxel Atez + platinum doublet 15 vs 15 Atez: 2.8/11.4 Doc: 3.4/ /-- Atez 24 --/-- MEDI 16 --/-- 1.Garon D et al. N Engl J Med. 2015;372: ; 2. Patnaik A et al. J Clin Oncol 33, 2015 (supp; abstr 8011); 3. Spira AI et al. J Clin Oncol 33, 2015 (suppl; abstr 8010); 4. Liu SV et al. J Clin Oncol (supp; abstr 8030) 5. Spigel DR et al. J Clin Oncol (suppl; abstr 8008); 6 Rizvi NA et al. J Clin Oncol. 33, 2015 (suppl; abstr 8032)

38 Immune Checkpoint Inhibition Is an Active Area of Clinical Development in NSCLC: Multiple Phase 3 Trials Ipilimumab: 2 Phase 3 trials NCT ; NCT Nivolumab: 3 Phase 3 trials NCT ; NCT ; NCT Pembrolizumab: 2 Phase 3 trials NCT ; NCT MEDI4736: 5 Phase 3 trials NCT ; NCT ; NCT ; NCT ; NCT ) Atezolizumab (MPDL3280A): 6 Phase 3 trials NCT ; NCT ; NCT ; NCT ; NCT ; NCT First line checkpoint inhibitor alone v. standard CT alone Squamous only Accessed October 15, 2015.

39 Summary and Conclusions The treatment landscape for NSCC is rapidly evolving Until recently, most advances in the treatment of NSCLC were restricted to patients with targetable driver mutations However, advances in the understanding of pathways crucial to tumour proliferation and survival have led to the development of new therapeutic options that improve survival This continues to be an active area of research

40 AFA From Bench to Bedside From KK DT1 10/27/2015 1:42 PM 040 CONVERSATIONS IN ONCOLOGY ORCHESTRATING THE INSTRUMENTS OF LUNG CANCER TREATMENT