Immunotherapy in Locally Advanced NSCLC: the perspective of a new standard

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1 Immunotherapy in Locally Advanced NSCLC: the perspective of a new standard Ani Balmanoukian MD The Angeles Clinic and Research Institute October 6, 2017

2 Conflicts of Interest Speaker s Bureau: Merck, BMS, Genentech, Astrazeneca

3 Objectives Timeline of approvals Mechanism of action of immunotherapy Treatment in stage IV disease Treatment of stage III disease Results of the PACIFIC trial Neoadjuvant Adjuvant Future direction

4 Timeline of approvals Nivo for Hodgkins Atezo for NSCLC Nivo for bladder Ipi approved for melanoma Nivo melanoma Pembro for melanoma Nivo for sq NSCLC Nivo for RCC Pembro for HNSCC Pembro for NSCLC Nivo for Ad NSCLC Atezo for bladder Nivo for HNSCC Pembro first line NSCLC Pembro for bladder Pembro for HodgkinsDurva for bladder Avelumab for bladder Pembro for MSI-H Pembro + chemo NSCLC Nivo for MSI-H Pembro for gastric Nivo for HCC

5 Timeline for NSCLC approvals Nivo for sq NSCLC Pembro for NSCLC Pembro first line NSCLC Pembro + chemo NSCLC PACIFIC trial Ipi approved for melanoma Nivo for Ad NSCLC Atezo for NSCLC

STEP 1 Tumor cell lysis and release of tumorderived antigens STEP 2 Uptake, process, and presentation of tumor antigens by APCs STEP 3 T-cell priming and activation Generation of memory T cells STEP

6 STEP 1 Tumor cell lysis and release of tumorderived antigens STEP 2 Uptake, process, and presentation of tumor antigens by APCs STEP 3 T-cell priming and activation Generation of memory T cells STEP 4 Travel of activated T cells to tumors STEP 5 T-cell infiltration into tumors STEP 6 T-cell recognition of tumor cells The Cancer-Immunity Cycle Antitumor Immune Responses Involve a Multistep Cycle STEP 7 Killing of tumor cells Memory-mediated control of tumor cell recurrence APC, antigen-presenting cell. Chen DS, et al. Immunity. 2013;39:1-10.

7 PD-1/PD-L1

9 Ribas A. NEJM 2012 June 28; 366(26):2517-9

10 Immunotherapy Agents Anti PD-1 antibody: Pembrolizumab Nivolumab AMP-514 Anti PD-L1 antibody: Atezolizumab Avelumab Durvalumab CTLA-4 antibody: Ipilimumab Tremelimumab

12 Stage IV NSCLC

13 CheckMate 017: Study Design CA was a phase 3 study comparing OS of nivolumab vs docetaxel in patients with advanced, previously treated SQ NSCLC Patients were randomized 1:1 to receive nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m 2 Q3W until PD or unacceptable toxicity Stage IIIB/IV SQ NSCLC 1 prior platinumdoublet based chemotherapy ECOG 0 1 (N = 272) Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity Endpoints Primary: OS Secondary: ORR, PFS efficacy by PD-L1 expression, symptom improvement Of the 272 treated patients, median age was 63 years, with 44% 65 years old and 11% 75 years old, and the majority were white (93%), male (76%), and had an ECOG PS of 1 (76%) Brahmer J, et al. N Engl J Med. 2015;373:

14 CA : squamous NSCLC, 2L OS (%) CheckMate 017: OS yr OS = 24% 1-yr OS = 42% Nivolumab 3 mg/kg n = 135 Docetaxel 75 mg/m 2 n = 137 Events, n (%) 110 (81) 128 (93) Median OS, months (95% CI) 9.2 (7.3, 12.6) 6.0 (5.1, 7.3) HR (95% CI) 0.62 (0.47, 0.80) 2-yr OS = 8% Number of patients at risk: 18% Time (months) 2-yr OS = 23% 15% Nivolumab Docetaxel Nivolumab Docetaxel Based on February 2016 database lock. Symbols refer to censored observations. Borghaei H, et al. Presented at: ASCO; June 3-7, 2016; Chicago, IL.

CA209-057: non-squamous NSCLC, 2L+ CheckMate 057: Study Design CA209-057 was a phase 3 study comparing OS of nivolumab vs docetaxel in patients with advanced, previously treated non-squamous NSCLC

15 CA : non-squamous NSCLC, 2L+ CheckMate 057: Study Design CA was a phase 3 study comparing OS of nivolumab vs docetaxel in patients with advanced, previously treated non-squamous NSCLC Patients were randomized 1:1 to receive nivolumab 3 mg/kg Q2W or docetaxel 75 mg/m 2 Q3W until PD or unacceptable toxicity Stage IIIB/IV non-squamous NSCLC 1 prior platinum-doublet based chemotherapy ECOG PS 0 1 (N = 582) Key inclusion criteria: locally advanced non-squamous cell NSCLC, ECOG PS 0-1, measurable disease per RECIST v1.1 criteria, progression during or after prior platinum-doublet based chemotherapy Key exclusion criteria: active CNS metastases, autoimmune disease, interstitial lung disease, prior therapy with anti-pd-1, anti-pd-l1/2, anti-cd-137, or anti-ctla-4 Borghaei H, et al. N Engl J Med. 2015;373: Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity (n = 292) Docetaxel 75 mg/m 2 IV Q3W until PD or unacceptable toxicity (n = 290) Endpoints Primary: OS Secondary: ORR, PFS, safety, efficacy by PD-L1 expression, PROs (LCSS)

16 CA : non-squamous NSCLC, 2L+ OS (%) CheckMate 057: OS Nivolumab 3 mg/kg (n = 292) Docetaxel 75 mg/m 2 (n = 290) Events, n (%) 228 (78) 247 (85) Median OS, months (95% CI) 12.2 (9.7, 15.1) 9.5 (8.1, 10.7) HR (95% CI) 0.75 (0.63, 0.91) Number of patients at risk: 1-yr OS = 39% 12% 1-yr OS = 51% 18 2-yr OS=16% Time (months) 13% 2-yr OS = 29% Nivolumab Docetaxel Nivolumab Docetaxel Based on February 2016 database lock. Symbols refer to censored observations. Borghaei H, et al. Presented at: ASCO; June 3-7, 2016; Chicago, IL.

17 Nivolumab FDA approved for: The treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

18 CheckMate 012: Safety and Efficacy of First line Nivolumab and Ipilimumab in Advanced NSCLC Presented By Matthew Hellmann at 2016 ASCO Annual Meeting

19 Phase 1 CheckMate 012 Study Design: <br />Nivolumab Plus Ipilimumab in First-line NSCLC Presented By Matthew Hellmann at 2016 ASCO Annual Meeting

20 Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Efficacy Across All Tumor PD-L1 Expression Levels Presented By Matthew Hellmann at 2016 ASCO Annual Meeting

CheckMate 012 Nivolumab Plus Ipilimumab: Study Design CA209-012 was a phase 1 study that included arms assessing the safety, tolerability, and clinical activity of nivolumab combined with ipilimumab

21 CheckMate 012 Nivolumab Plus Ipilimumab: Study Design CA was a phase 1 study that included arms assessing the safety, tolerability, and clinical activity of nivolumab combined with ipilimumab in chemotherapy-naïve patients with advanced NSCLC Stage IIIB/IV NSCLC (any histology); no prior chemotherapy for advanced NSCLC; ECOG PS 0 1 Link: Initial cohorts Link: Additional cohorts Randomized Nivolumab 1 mg/kg Q3W x 4 + Ipilimumab 3 mg/kg Q3W x 4 (n=24) a Nivolumab 3 mg/kg Q3W x 4 + Ipilimumab 1 mg/kg Q3W x 4 (n=25) a Nivolumab 1 mg/kg Q3W x 4 + Ipilimumab 1 mg/kg Q3W x 4 (n=31) Nivolumab 1 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W (n=40) Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q12W (n=38) Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W (n=39) Nivolumab 3 mg/kg Q2W until disease progression, unacceptable toxicity, or withdrawal of consent b Primary endpoint: safety and tolerability Secondary endpoints: ORR and PFS rate at 24 weeks Exploratory endpoints: OS, efficacy by PD-L1 expression Until disease progression, unacceptable toxicity, or withdrawal of consent b Primary endpoint: safety and tolerability Secondary endpoints: ORR and PFS rate at 24 weeks Exploratory endpoints: OS, efficacy by PD-L1 expression a Patients on this schedule were originally split into two cohorts: one each for squamous and non-squamous histology. b Patients tolerating study treatment were permitted to continue treatment beyond RECIST version 1.1-defined progression if considered to be deriving clinical benefit. Hellmann MD, et al. Lancet Oncol. 2017;18:31-41.

22 Nivo 3 Q2W + Ipi 1 Q12W/Q6W a Nivo 3 Q2W b CheckMate 012 Nivolumab Plus Ipilimumab: OS Overall and by PD-L1 in Additional Cohorts OS by tumor PD-L1 expression OS (%) OS (%) All treated patients (n = 77) 1% PD-L1 (n = 47) 50% PD-L1 (n = 13) 1-yr OS = 76% 1-yr OS = 73% 2-yr OS = 49% All treated patients (n = 52) 2-yr OS = 44% 1-yr OS = 87% 1-yr OS = 69% 2-yr OS = 58% 2-yr OS = 47% 1-yr OS = 100% 2-yr OS = 62% % PD-L1 (n = 32) 50% PD-L1 (n = 12) 1-yr OS = 83% 2-yr OS = 75% Time (months) Time (months) Time (months) a Data based on an April 2017 database lock. b Data from the nivolumab monotherapy cohort based on a September 2016 database lock (median follow-up 22 months) are provided for context. Goldman JW, et al. Presented at: ASCO; June 2-6, 2017; Chicago, IL.

23 n (%) CheckMate 012 Nivolumab Plus Ipilimumab: Safety in Initial Cohorts Nivo 1 + Ipi 3 Nivo 3 + Ipi 1 Nivo 1 + Ipi 1 Q3W x 4 (n=24) a Q3W x 4 (n=25) a Q3W x 4 (n=31) b Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 Any Grade Grade 3 or 4 Nivo 1 Q2W + Ipi 1 Q6W (n=40) b Any Grade Grade 3 or 4 Treatment-related AEs 22 (92) c 14 (58) 21 (84) d 11 (44) 26 (84) 9 (29) 29 (73) 16 (40) Treatment-related select AEs Endocrine 6 (25) 2 (8) 5 (20) 1 (4) 4 (13) 2 (6) 14 (35) 3 (8) Gastrointestinal 11 (46) 4 (17) 10 (40) 4 (16) 6 (19) 0 11 (28) 3 (8) Hepatic 7 (29) 3 (13) 1 (4) 1 (4) 3 (10) 2 (6) 11 (28) 6 (15) Pulmonary 4 (17) 2 (8) 2 (8) 1 (4) 3 (10) 1 (3) 3 (8) 0 Renal 1 (4) 1 (4) (3) 0 Skin 11 (46) 1 (4) 14 (56) e 1 (4) 16 (52) 4 (13) 15 (38) 2 (5) Hypersensitivity/infusion 1 (4) 0 3 (12) (3) 0 Treatment-related AEs leading to discontinuation 9 (38) 8 (33) 10 (40) f 6 (24) 4 (13) 3 (10) 3 (8) 3 (8) Treatment-related deaths 1 (4) 2 (8) 0 0 a Data are based on a March 2015 database lock. b Data are based on a February 2016 database lock. c One grade 5 event of respiratory failure was reported. d Two grade 5 events (pulmonary hemorrhage [n=1] and toxic epidermal necrolysis [n=1]) were reported. e Includes one grade 5 event of toxic epidermal necrolysis. f Includes one grade 5 event of pulmonary hemorrhage. Ipi 1 = ipilimumab 1 mg/kg; Ipi 3 = ipilimumab 3 mg/kg; Nivo 1 = nivolumab 1 mg/kg; Nivo 3 = nivolumab 3 mg/kg. Hellmann MD, et al. Lancet Oncol. 2017;18:31-41.

24 Garon EB et al. N Engl J Med 2015;372:

26 Overall Survival, % OS by PD-L1 Expression, All CTA-Evaluable Patients a PS Median (95% CI), mo 50% NR (13.7-NR) 1-49% 8.8 ( ) <1% 8.8 ( ) n at risk PS 50% PS 1-49% PS <1% Time, months a Assessed in all patients whose samples were stained within 6 months of cutting. Analysis cut-off date: August 29, Garon et al AACR 2015

29 Overall Survival in the Intention-to-Treat Population. Enrolled patients with newly diagnosed NSCLC Reck M et al. N Engl J Med 2016;375:

44 Pembrolizumab FDA approved for: The treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA Metastatic NSCLC for first-line treatment of patients whose tumors have high PD-L1 Expression (Tumor Proportion Score of 50%) With No EGFR or ALK genomic tumor aberrations Combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous non small cell lung cancer (NSCLC), regardless of PD-L1 expression.

45 Atezolizumab An anti PD-L1 antibody POPLAR phase 2 (n=287) Second/third line NSCLC Randomized docetaxel or Atezolizumab Primary end point: OS Secondary end poinst: ORR, DOR Median OS 12.6 vs 9.7 with atezo vs docetaxel OAK phase 3 (n=1225) Second/third line NSCLC Randomized docetaxel or Atezolizumab Primary end point: OS Median OS 12.8 vs 9.6 with Atezo vs docetaxel

46 Atezolizumab The treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving atezolizumab.

47 Locally Advanced NSCLC

48 Locally Advanced NSCLC 5-year survival 8, % of patients with NSCLC present with locally advanced disease % Approximately 30% of patients present with locally advanced disease that is unresectable 4 10% 14% 5% 1. Cancer Research UK. Lung Cancer Risk Factors EpiCast Report: Non-Small Cell Lung Cancer (NSCLC)-Epidemiology Forecast to New York, NY: GlobalData; November Accessed 30 May ACS website. NSCLC survival rates by stage Aupérin A, et al. J Clin Oncol. 2010;28: lung-cancer/detection-diagnosis-staging/survival- 3. Provencio M, et al. J Thorac Dis. 2011;3: rates.html. Accessed May 08, Scorsetti M, et al. Radiat Oncol. 2010;5: SEER. 5. Fournel P, et al. J Clin Oncol. 2005;23: Johnson DH. Chest. 2000;117:123S-126S. Accessed February 8, % Stage IIIA Stage IIIB

49 Differences Between Resectable and Unresectable Locally Advanced NSCLC Patients with locally advanced disease make up a heterogeneous population with varying degrees of resectability 1 N1 vs N2 vs N3 disease Small (<1.5 cm) vs bulky (>3 cm) N2 disease Resectability status may change after chemoradiation therapy (CRT) 1,2 There is no universally accepted definition of unresectable stage III disease 1 o Determination of resectability is made on a case-by-case basis 1 by an experienced thoracic surgeon as part of a multidisciplinary team 2 In locally advanced disease, surgery following neoadjuvant CRT does not improve patient outcome 3 1. Patel V, Shrager JB. Oncologist. 2005;10: recent and complete version of the guideline, go online to NCCN.org. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Non-Small Cell Lung Cancer V National Comprehensive Cancer The NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. Network, Inc All rights reserved. Accessed 3. Albain KS, et al. Lancet. 2009;374: May 24, To view the most

Approaches to the Management of Locally Advanced Stage III Unresectable NSCLC Pathologist Diagnostic and Pre-treatment Evaluation Multidisciplinary team determines resectability and treatment path

50 Approaches to the Management of Locally Advanced Stage III Unresectable NSCLC Pathologist Diagnostic and Pre-treatment Evaluation Multidisciplinary team determines resectability and treatment path Radiation oncologist Medical oncologist Pulmonologist Pulmonary function testing Bronchoscopy FDG PET/CT scan Pathologic mediastinal lymph node evaluation Brain MRI with contrast Thoracic surgeon Treatment Definitive CRT is the standard of care for stage III unresectable NSCLC Concurrent chemoradiation > Sequential chemoradiation *According to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ), determination of resectability, surgical staging, and pulmonary resection should be performed by board-certified thoracic surgeons who perform lung cancer surgery as a prominent part of their practice 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Non-Small Cell Lung Cancer V National Comprehensive Cancer Network, Inc All rights reserved. Accessed May 24, To view the most recent and complete version of the guideline, go online to NCCN.org. The NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

51 Survival Outcomes in Patients With Locally Advanced Stage III Unresectable NSCLC Concurrent CRT is the standard of care for patients with locally advanced stage III unresectable NSCLC 1 Comparison Between Sequential and Concurrent CRT 25% Overall Survival 3 Progression-free Survival 3 Sequential CRT 23.8% Concurrent CRT Sequential CRT Concurrent CRT 25% Outcomes with sequential CRT 2 : o Median OS: 17.4 months o 5-year survival rate: 17% 20% 15% 10% 18.1% 10.6% 15.1% 20% 15% 10% 13.1% 16% 9.4% 11.6% Outcomes with concurrent CRT 2 : o Median OS: 18.6 months o 5-year survival rate: 19% 5% 0% 3 Years 5 Years 5% 0% 3 Years 5 Years 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ) for Non-Small Cell Lung Cancer V National Comprehensive Cancer Network, Inc All rights reserved. Accessed May 24, To view the most recent and complete version of the guideline, go online to NCCN.org. The NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2. Van Reij EJ, et al. Acta Oncol. 2014;53(3): Aupérin A, et al. J Clin Oncol. 2010;28:

52 PACIFIC: A DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE III STUDY OF DURVALUMAB AFTER CHEMORADIATION THERAPY IN PATIENTS WITH STAGE III, LOCALLY ADVANCED, UNRESECTABLE NSCLC Luis Paz-Ares 1, Augusto Villegas 2, Davey Daniel 3, David Vicente 4, Shuji Murakami 5, Rina Hui 6, Takashi Yokoi 7, Alberto Chiappori 8, Ki Hyeong Lee 9, Maike de Wit 10, Byoung Chul Cho 11, Maryam Bourhaba 12, Xavier Quantin 13, Takaaki Tokito 14, Tarek Mekhail 15, David Planchard 16, Haiyi Jiang 17, Yifan Huang 17, Phillip A. Dennis 17, Mustafa Özgüroğlu 18 1 Hospital Universitario 12 de Octubre, CiberOnc, Universidad Complutense and CNIO, Madrid, Spain; 2 Cancer Specialists of North Florida, Jacksonville, FL, USA; 3 Tennessee Oncology, Chattanooga, TN, and Sarah Cannon Research Institute, Nashville, TN, USA; 4 Hospital Universitario Virgen Macarena, Seville, Spain; 5 Kanagawa Cancer Center, Yokohama, Japan; 6 Westmead Hospital and the University of Sydney, Sydney, NSW, Australia; 7 Kansai Medical University Hospital, Hirakata, Japan; 8 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 9 Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea; 10 Vivantes Klinikum Neukoelln, Berlin, Germany; 11 Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; 12 Centre Hospitalier Universitaire de Liège, Liège, Belgium; 13 CHU Montpellier and ICM Val d'aurelle, Montpellier, France; 14 Kurume University Hospital, Kurume, Japan; 15 Florida Hospital Cancer Institute, Orlando, FL, USA; 16 Gustave Roussy, Villejuif, France; 17 AstraZeneca, Gaithersburg, MD, USA; 18 Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey Acknowledgement: Dr. Scott J. Antonia of H. Lee Moffitt Cancer Center and Research Institute is the lead author for this study; Dr. Paz-Ares is presenting on his behalf esmo.org

Durvalumab Blocks PD-L1 Binding to PD-1 and CD80 Tumorantigen

antibody-dependent cell-mediated cytotoxicity T cell TCR MHC

effector T-cell function and tumor cell killing Tumor cell

Activation Inhibition X CD28 PD-L1 CD80 PD-1 CD80 Immune cell

complex; PD-1, programmed cell dealth-1; PD-L1, programmed

53 Durvalumab Blocks PD-L1 Binding to PD-1 and CD80 Tumorantigen Durvalumab 1 Human IgG1 mab, engineered to prevent antibody-dependent cell-mediated cytotoxicity T cell TCR MHC II Blocks PD-1-mediated inhibitory signalling Enhances effector T-cell function and tumor cell killing Tumor cell Durvalumab PD-L1 MHC I Tumorantigen PD-1 CD80 Inhibition X TCR Activation Inhibition X CD28 PD-L1 CD80 PD-1 CD80 Immune cell PD-L1 mab, monoclonal antibody; MHC, major histocompatibility complex; PD-1, programmed cell dealth-1; PD-L1, programmed cell death ligand-1; TCR, T-cell receptor 1. Stewart R, et al. Cancer Immunol Res 2015;3:

54 PACIFIC STUDY DESIGN Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study Patients with stage III, locally advanced, unresectable NSCLC who have not progressed following definitive platinum-based ccrt ( 2 cycles) Durvalumab 10 mg/kg q2w for up to 12 months N=476 Co-primary endpoints PFS by BICR using RECIST v1.1* OS 18 years or older WHO PS score 0 or 1 Estimated life expectancy of 12 weeks 1 42 days post-ccrt R 2:1 randomization, stratified by age, sex, and smoking history N=713 Key secondary endpoints ORR (per BICR) Archived tissue was collected DoR (per BICR) All-comers population Placebo 10 mg/kg q2w for up to 12 months N=237 Safety and tolerability PROs *Defined as the time from randomization (which occurred up to 6 weeks post-ccrt) to the first documented event of tumor progression or death in the absence of progression. ClinicalTrials.gov number: NCT BICR, blinded independent central review; ccrt, concurrent chemoradiation therapy; DoR, duration of response; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PROs, patient-reported outcomes; PS, performance status; q2w, every 2 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; WHO, World Health Organization

55 Statistical Analysis Planned sample size: N = 702 patients (2:1 randomization) Co-primary endpoints: PFS and OS PFS assumption: study has 95% power to detect an HR of 0.67 with 458 events, using a 2-sided level log rank test Interim analysis (IA) of PFS was planned after ~367 (80%) of events OS assumption: study has 85% power to detect an HR of 0.73 with 491 deaths, using a 2-sided level log rank test Study remains blinded to OS at this time. Final analysis of OS planned after target number of deaths has been reached HR, hazard ratio; ITT, intention-to-treat;os, overall survival; PFS, progression-free survival

56 Baseline Characteristics (ITT) Durvalumab (N=476) Placebo (N=237) Age Median (range), years 65 years, % 64 (31 84) (23 90) 45.1 Male, % WHO performance status 0 / / / 51.5 score, %* Smoking status, % Current / Former / Never 16.6 / 74.4 / / 75.1 / 8.9 Disease stage, % IIIA / IIIB 52.9 / / 45.1 Histology, % Squamous / Non-squamous 47.1 / / 57.0 PD-L1 status, % Known: TC <25% / TC 25% Unknown 39.3 / / Prior chemotherapy, % Induction / Definitive ccrt 25.8 / / 99.6 Prior radiotherapy, %* <54 Gy 54 to 66 Gy >66 to 74 Gy Best response to prior CR / PR / SD / PD 1.9 / 48.7 / 46.6 / ccrt, % / 46.8 / 48.1 / 0 *Not reported or missing (durvalumab, placebo, total): WHO performance status (0.4% each), prior radiotherapy (0.2%, 0.4%, 0.3%). Other: durvalumab, 2.5%; placebo, 2.1%; total, 2.4%. No sample collected or no valid test result. Not evaluable/not applicable: durvalumab, 2.3%; placebo, 2.1%; total, 2.2%. ccrt, concurrent chemoradiation therapy; CR, complete response; ITT, intention-to-treat; PD, progressive disease; PD-L1, programmed cell death ligand-1; PR, partial response; SD, stable disease; TC, tumor cell; TC 25%, 25% PD-L1 expression on tumor cells; TC <25%, <25% PD-L1 expression on tumor cells; WHO, World Health Organization

57 PFS probability PFS by BICR (Primary Endpoint; ITT) Stratified hazard ratio, 0.52 (95% CI, ) Two-sided P< Placebo Durvalumab Durvalumab (N=476) Placebo (N=237) Median PFS (95% CI), 16.8 ( ) 5.6 ( ) months 12-month PFS rate (95% CI) 55.9% ( ) 35.3% ( ) 18-month PFS rate (95% CI) 44.2% ( ) 27.0% ( ) No. at risk Durvalu Time from randomization (months) mab Placebo BICR, blinded independent central review; CI, confidence interval; ITT, intention-to-treat; PFS, progression-freesurvival

58 % patients (95% CI) Antitumor Activity by BICR (ITT) 35 Objective Response P<0.001 Durvalu mab (N=443) * Place bo (N=21 3)* Treatment effect (HR [95% CI]) 30 Best overall response, n (%) 25 Complete response 6 (1.4) 1 (0.5) 20 ( ) Partial response 120 (27.1) 33 (15.5) 15 Stable disease 233 (52.6) 119 (55.9) Durvalumab (N=443)* ( ) 16.0 Placebo (N=213)* Treatment effect (RR [95% CI]) : 1.78 ( ) Progressive disease 73 (16.5) 59 (27.7) Non-evaluable 10 (2.3) 1 (0.5) Duration of response, months Median (95% Cl) Ongoing response at data cutoff, % At 12 months At 18 months NR 13.8 (6.0 NR) ( ) *Patients with measurable disease at baseline, as determined by either of the two independent reviewers; One patient could not be grouped into any of the best overall response categories due to inconsistency in the baseline assessment for measurable disease between the two independent central reviewers. Percentages calculated by Kaplan-Meier method; Placebo was the reference group when RR and HR were calculated; therefore, an RR value greater than 1 is in favor of durvalumab and an HR value less than 1 is in favor of durvalumab BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; NR, not reached; RR, relative risk

Probability of death or distant metastasis Time to Distant Metastasis or Death by BICR (ITT) Stratified hazard ratio, 0.52 (95% CI, 0.39 0.69) Two-sided P<0.0001 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.

59 Probability of death or distant metastasis Time to Distant Metastasis or Death by BICR (ITT) Stratified hazard ratio, 0.52 (95% CI, ) Two-sided P< Median time (95% CI), months Durvalumab Durvalumab Placebo 23.2 (23.2 NR) 14.6 ( ) Placebo No. at risk Durvalumab 476 Placebo Time from randomization (months) BICR, blinded independent central review; ITT, intention-to-treat

60 Most Frequent AEs

61 Durvalumab demonstrated a statistically significant and robust improvement in PFS versus placebo (HR 0.52; P<0.0001; median improvement of >11 months) at a planned interim analysis PFS improvement with durvalumab was observed across all pre-specified subgroups Durvalumab demonstrated a clinically meaningful benefit in ORR (28.4% vs 16.0%; P<0.001), with durable responses versus placebo (median DoR not reached vs 13.8 months) Patients receiving durvalumab had a lower incidence of new lesions, including new brain metastases, compared with patients receiving placebo The study remains blinded to OS Risk of pneumonitis? Will need to assess how to apply to a heterogeneous population 1. Antonia SJ, et al. Poster presented at the 41st European Society for Medical Oncology Annual Meeting, Copenhagen, October 7 11, DoR, duration of response; HR, hazard ratio; ORR, overall response rate; PFS, progression-free survival

63 Neoadjuvant Therapy

64 Neoadjuvant Trials NCT : Neoadjuvant Anti PD-1 Immunotherapy in Resectable Non-small Cell Lung Cancer NCT : Neoadjuvant Nivolumab, or Nivolumab in Combination With Ipilimumab, in Resectable Non-Small-Cell Lung Cancer. NCT : Neoadjuvant chemo/immunotherapy for treatment of resectable stage IIIA non small cell lung cancer(nsclc): A Phase II Multicenter exploratory study NCT : Anti PD-1 Neo-adjuvant Treatment for Early Stage NSCLC - Phase I Study NCT : A Phase II, Open-Label, Multicenter, Single-Arm Study to Investigate the Efficacy and Safety of Atezolizumab as Neoadjuvant and Adjuvant Therapy in Patients With Stage IB, II, or IIIA Resectable and Untreated Non-Small Cell Lung Cancer NCT : A Single-arm Phase 2 Study of Atezolizumab as Induction Therapy in Stage IB-IIIA Non N2 Resectable and Untreated Non-small Cell Lung Cancer (NSCLC) NCT : Randomized, OpenLabel, Phase 3 Trial of Nivolumab Plus Ipilimumab or Nivolumab Plus Platinum Doublet Chemotherapy Versus Platinum Doublet Chemotherapy in Early Stage NSCLC NCT : Anti-PD-L1 Antibody MEDI4736 in Addition to Neoadjuvant Chemotherapy in Patients With Stage IIIA(N2) Non-small Cell Lung Cancer (NSCLC). A Multicenter Single-arm Phase II Trial. NCT : A Phase II Prospective Immune Neoadjuvant Therapy Study od Durvalumab (MEDI4736) in Early Stage Non-small Cell Lung Cancer

65 Adjuvant Trials

66 Adjuvant trials NCT : Phase II, Single-arm Study of Adjuvant Pembrolizumab in N2 Positive Non-small Cell Lung Cancer Treated With Neoadjuvant Concurrent Chemoradiotherapy Followed by Curative Resection NCT : A Randomized, Phase 3 Trial With Anti-PD-1 Monoclonal Antibody Pembrolizumab (MK-3475) Versus Placebo for Patients With Early Stage NSCLC After Resection and Completion of Standard Adjuvant Therapy (PEARLS) NCT : A Phase III Prospective Double Blind Placebo Controlled Randomized Study of Adjuvant MEDI4736 In Completely Resected Non- Small Cell Lung Cancer NCT : Identification of Tumor Neoantigens During Immune Checkpoint Blockade in Resectable Non-Small Cell Lung Cancer (NSCLC) NCT : Adjuvant Nivolumab in Resected Lung Cancers (ANVIL)-A Randomized Phase III Study of Nivolumab After Surgical Resection and Adjuvant Chemotherapy in Non-small Cell Lung Cancers

68 Thank You

Immunoterapia. Giuseppe Curigliano MD, PhD Istituto Europeo di Oncologia Milano, Italia

Immunoterapia. Giuseppe Curigliano MD, PhD Istituto Europeo di Oncologia Milano, Italia Immunoterapia Giuseppe Curigliano MD, PhD Istituto Europeo di Oncologia Milano, Italia Immunotherapy in combination Immunotherapy in combination PD1-PDL1 spectrum of activity CTLA-4 spectrum of activity