The Evolving Role of Immunotherapy in Earlier Stages of Lung Cancer

1. The Evolving Role of Immunotherapy as a Component of Multimodal Therapy in Earlier Stages of Lung Cancer Rationale, Current Evidence, Key Trials, and Implications for Multidisciplinary Care This event will take place at the AATS International Thoracic Surgical Oncology Summit.

2. Disclosures • Naiyer Rizvi, MD, has a financial interest/relationship or affiliation in the form of: • Consultant for AstraZeneca; Bristol-Myers Squibb; Eli Lilly and Company; F. Hoffmann-La Roche; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; and Pfizer Inc. • Stock Shareholder in Gritstone Oncology where Dr. Rizvi is a Co-Founder. • Naiyer Rizvi, MD, does intend to discuss either non–FDA-approved or investigational use for the following products/devices: Immune checkpoint inhibitors as monotherapies or as part of combinations. • Benny Weksler, MBA, MD, has a financial interest/relationship or affiliation in the form of: • Other Financial or Material Support from Dr. Weksler is a proctor for Intuitive Surgical Inc. • Benny Weksler, MBA, MD, does intend to discuss either non–FDA-approved or investigational use for the following products/devices: Immune checkpoint inhibitors as monotherapies or as part of combinations. This CME/MOC/CE activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by an independent educational grant from AstraZeneca.

3. Disclosures CME Reviewer Siyang Leng, MDSiyang Leng, MD, has no financial interests/relationships or affiliations in relation to this activity. CE ReviewerJanice Trainor-Tellier, MSN, RNJanice Trainor-Tellier, MSN, RN, has no financial interests/relationships or affiliations in relation to this activity. Medical Director KadrinWilfong, MD PVI, PeerView Institute for Medical Education KadrinWilfong, MD, has no financial interests/relationships or affiliations in relation to this activity. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/MOC/CE activity during the past 12 months.

4. Visit us atwww.peerview.com/Lung18 • Watch for the onDemand version in the coming weeks • Download the slides and Practice Aids • Apply for CME/MOC/CE credit Need more information? Send an email to live@peerview.com Join the conversation on Twitter @PeerView

5. MasterClass Immunotherapy as a Component of Multimodal Therapy of Lung Cancer Where Are We Now and Where Are We Going Next?

6. Module 1 Evolving Role of Immunotherapy in Unresectable Stage III NSCLC Naiyer Rizvi, MDPrice Family Chair Professor of Medicine Director, Thoracic Oncology Co-Director, Cancer Immunotherapy Columbia University Medical Center New York, New York Go online to access full CME/MOC/CE information, including faculty disclosures.

7. How does cancer immunotherapy work? What are the immune checkpoint inhibitors?

8. Adaptive Immune Response1 1. Topalian SL et al. Nat Rev Cancer. 2016;16:275-287.

9. Ways to Enhance T-Cell Attack1 T-Cell Turning Up the Activating Blocking the Inhibiting 1. Mellman I et al. Nature. 2011;480:480-489.

10. Mechanism of Checkpoint Inhibition1 T-Cell T-Cell T-Cell T-Cell 1. Adapted from Pallin DJ et al.Acad Emerg Med. 2018;25:819-827.

11. Current Immune Checkpoint Inhibitors

12. Current Immunotherapy-Based Combinations

13. Current Immunotherapy Landscape in NSCLC: FDA Approvals of Checkpoint Inhibitors and Combinations Pembrolizumab PD-L1+ mNSCLC 1L Pembrolizumab +pemetrexed/carboplatin mNSCLC 1L Durvalumab stage III NSCLC 2015 2016 2017 2018 Nivolumab squamous mNSCLC 2L Pembrolizumab PD-L1 + mNSCLC 2L Nivolumab nonsquamous mNSCLC 2L Atezolizumab mNSCLC2L

14. What is the rationale for using the immune checkpoint inhibitors in locally advanced, unresectable, stage III NSCLC?

15. PACIFIC—Setting> Unresectable Stage III NSCLC

16. Tecemotide (L-BLP25) vs Placebo After CRT for Stage III NSCLC (START)1 1. Butts C et al. Lancet Oncol. 2014;15:59-68.

17. Tecemotide (L-BLP25) vs Placebo After CRT for Stage III NSCLC (START) (Cont’d)1 Overall Survival in Patients Who Received Concurrent Chemoradiotherapy 1. Butts C et al. Lancet Oncol. 2014;15:59-68.

18. Addressing Unmet Needs: Emergence of Immunotherapy in Stage III NSCLC Immunotherapy is providing new hope and changing the management of stage III NSCLC 1. Aupérin A et al. J Clin Oncol. 2010;28:2181-2190. 2. Yoon SM et al. World J Clin Oncol. 2017;8:1-20. 3. Ahn JS et al. J Clin Oncol. 2015;33:2660-2666. 4. Furuse J et al. Clin Oncol. 1999;17:2692-2699. 5. Belderbos J et al. Eur J Cancer. 2007;43:114-121. 6. Clamon G et al. J Clin Oncol. 1999;17:4-11.

19. Radiation Can Be Immunogenic1 • 46 case reports between 1969 and 2014 • Wide variety of tumor types, treatment sites, dose schedules • “Abscopal response” occurred at 0 to 12 months 1. Abuodeh Y et al. Curr Probl Cancer. 2016;40:25-37.

20. Radiation Can Induce Abscopal Response in Presence of Immune Checkpoint Inhibition (Anti–CTLA-4)1 September 2013 PET/CT August 2012 PET/CT August 2012 CT/sim 1. Golden EB et al. Cancer Immunol Res. 2013;1:365-372. August 2012 PET/CT January 2013 PET/CT

21. In the context of KEYNOTE-001, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not • 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab, (39%) extracranial, and (25%) thoracic radiotherapy HR 0.58 (95% CI 0.36-0.94); P = .026 • Median overall survival: 10.7 months vs 5.3 months • Extracranial radiotherapy: • HR 0·59, P = ·034

22. Chemotherapy-Induced Immunogenic Cell Death1 T-cell 1. Gotwals P et al. Nat Rev Cancer. 2017;17:286-301.

23. What clinical evidence supports the use of immune checkpoint inhibition in locally advanced, unresectable, stage III NSCLC?

24. Stage III NSCLC: Key Immune Checkpoint Inhibitor Trials • Design: Consolidation therapy a This trial also has a concurrent immunotherapy part.

25. PACIFIC Trial: Design1,2 Phase 3 randomized, double-blind, placebo-controlled, multicenter, international study Endpoints • Co-primary: PFS by BICRa (RECIST v1.1), and OS • Key secondary: ORR per BICRb, DOR (per BICR), safety/tolerability, and PROs • Stage III, locally advanced, unresectable NSCLC • No progression following definitive platinum-based cCRT (≥2 cycles) • ≥18 years of age • WHO PS score 0 or 1 • Estimated life expectancy ≥12 wk • All-comers population Durvalumab 10 mg/kg Q2W (up to 12 mo) n = 476 1-42 days post-cCRT 2:1 randomization stratified by age, sex, and smoking history R Placebo 10 mg/kg Q2W (up to 12 mo) n = 237 a Time from randomization to the first documented tumor progression, or death in the absence of progression. b ORR as measured from baseline scan post-CRT completion 1. 1. Paz-Ares L et al. 2017 European Society for Medical Oncology Annual Meeting (ESMO 2017). Abstract LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.

26. Patient Characteristics1 1. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.

27. PFS by BICR in the ITT Population1,2 Stratified HRa = 0.52 (95% CI, 0.42-0.65) Two-sided P < .001 a Time from randomization to the first documented tumor progression, or death in the absence of progression. 1. Paz-Ares L et al. ESMO 2017. Abstract LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.

28. Time to Death or Distant Metastasis in the ITT Population1 Stratified HR for death = 0.53 (95% CI, 0.41-0.68) 1. Antonia SJ et al. N Engl J Med. 2018 Sep 25 [Epub ahead of print].

29. OS in the ITT Population1,2 Stratified HR for death = 0.68 (99.73% CI, 0.47-0.997) Two-sided P = .0025 No. at Risk 1. Antonia SJ et al. 2018 IASLC 19th World Conference on Lung Cancer (WCLC 2018). Abstract PL02.01. 2. Antonia SJ et al. N Engl J Med. 2018 Sep 25 [Epub ahead of print].

30. PFS and OS by Subgroup in the ITT Population1 PFS HR (95% CI) OS HR (95% CI) All patients Male Female <65 years ≥65 years Smoker Nonsmoker Stage IIIA Stage IIIB Squamous Nonsquamous Cisplatin Carboplatin CR PR SD Positive Negative Unknown Sex Age at randomization Smoking status Disease stage Tumor histologic type Prior definitive CT NA NA Best response to prior treatment NA EGFR status 0.25 0.50 1.00 2.00 0.25 0.50 1.00 2.00 Durvalumab better Placebo better Durvalumab better Placebo better 1. Antonia SJ et al. WCLC 2018. Abstract PL02.01.

31. Subgroup Analysis by PD-L1 Status1 PFS HR (95% CI) OS HR (95% CI) All patients ≥25% <25% Unknown ≥1% 1-24% <1% PD-L1 status (prespecified) PD-L1 status (post-hoc) 0.25 0.50 1.00 2.00 0.25 0.50 1.00 2.00 Durvalumab better Placebo better Durvalumab better Placebo better • Important facts regarding PD-L1 status • PD-L1 testing was not required • 37% of patients with unknown PD-L1 status • PD-L1 status was obtained pre-CRT (getting a sample post-CRT medically not feasible) • PD-L1 expression-level cutoff 1% was part of an unplanned post-hoc analysis requested by a health authority ✓ 1. Antonia SJ et al. WCLC 2018. Abstract PL02.01.

32. Antitumor Activity by BICR in the ITT Population1,2 Treatment Effectb HR = 0.43 (95% CI, 0.22-0.84) a Patients with measurable disease at baseline as determined by 1 of 2 independent central reviewers. b Placebo = reference group when RR and HR were calculated—RR >1 in favor of durvalumab, HR <1 in favor of durvalumab. c One patient could not be included in any best-OR categories because of inconsistency in baseline assessment for measurable disease between 2 independent central reviewers. d Calculated by Kaplan–Meier method. 1. Paz-Ares L et al. ESMO 2017. Abstract LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.

33. Safety Summary1,2 1. Paz-Ares L et al. ESMO 2017. Abstract LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.

34. Most Frequent AEs1,2 a Occurring in >11% of patients in either treatment arm. b Assessed by investigators with subsequent review and adjudication by study sponsor; pneumonitis includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis. 1. Paz-Ares L et al. ESMO 2017. Abstract LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.

35. Immune-Related or Radiation Pneumonitis1,2 a Assessed by investigators with subsequent review and adjudication by study sponsor; pneumonitis includes acute interstitial pneumonitis, interstitial lung disease, pneumonitis, and pulmonary fibrosis. 1. Paz-Ares L et al. ESMO 2017. Abstract LBA1. 2. Antonia SJ et al. N Engl J Med. 2017;377:1919-1929.

36. PACIFIC Trial Summary • Durvalumab demonstrated statistically significant and robust improvement in PFS vs placebo • Durvalumab therapy resulted in significantly longer OS vs placebo • Durvalumab demonstrated clinically meaningful benefit in ORR, with durable responses vs placebo • Patients receiving durvalumab had a lower incidence of new lesions, including new brain metastases compared with patients receiving placebo • Safety profile of durvalumab was consistent with other immunotherapies and with its own safety profile as monotherapy in patients with more advanced disease; no new safety signals were identified

37. FDA Approved New SOC Option for Patients With Unresectable Stage III NSCLC • September 28, 2017: NCCN guidelines were updated to include durvalumab for treatment of stage III locally advanced, unresectable NSCLC with no disease progression after CRT • October 17, 2017: FDA granted priority review status to sBLA for approval of durvalumab for treatment of stage III locally advanced, unresectable NSCLC with no disease progression after concurrent CRT • February 16, 2018: FDA approved durvalumab for patients with unresectable stage III NSCLC whose disease has not progressed following concurrent CRT PFS and OS benefit confirmed + FDA approval  New SOC

38. Module 2 Potential Role of Immunotherapy in Resectable NSCLC Benny Weksler, MBA, MDSystem Chief of Thoracic Surgery Allegheny Health Network Pittsburgh, Pennsylvania Go online to access full CME/MOC/CE information, including faculty disclosures.

39. What is the rationale for using cancer immunotherapy in resectable NSCLC? • Are there any trials and data in neoadjuvant or adjuvant settings?

40. What About Resectable NSCLC?1 Die Despite Chemo Alive Due to Surgery Alive Due to Chemo LACE (N = 4,584) Stage IB Stage II Stage III n = 1,371 HR = 0.92 5-y risk 36% n = 1,616 HR = 0.83 5-y risk 61% n = 1,247 HR = 0.83 5-y risk 74% Note: 6th TNM edition staging was used. 1. Pignon JP et al. J Clin Oncol. 2008;26:3552-3559.

41. Adjuvant Immunotherapy in Melanoma1 Primary Endpoint: Relapse-Free Survival 1. Weber J et al. N Engl J Med. 2017;377:1824-1835.

42. Selected Trials of Adjuvant Immunotherapy for NSCLC

43. Immunologic Effects of Chemotherapies1 Immunosuppressive cells Indirect immunostimulation 5-Fluorouracil Cyclophosphamide Docetaxel Gemcitabine Oxaliplatin Paclitaxel Bevacizumab Dasatinib Decitabine Lapatinib Sorafenib Sunitinib Treg cells MDSCs Best Studied • Anthracycline • Cyclophosphamide • Platinum(especially oxaliplatin) • Gemcitabine • Taxanes M2 TAMs Direct immunostimulation Immune effector cells Gemcitabine Paclitaxel Pemetrexed Dasatinib Imatinib Sorafenib CTLs NK cells Increased immunogenicity Poorly immunogenic tumor 5-Fluorouracil Doxorubicin Gemcitabine Idarubicin Oxaliplatin Radiation Cetuximab Dabrafenib Decitabine Erlotinib Gefitinib Trametinib 1. Galluzzi L et al. Cancer Immunol Res. 2016;4:895-902.

44. Impact of Chemotherapy on TME in Neoadjuvant Setting1 Methods • FFPE surgical resections from 112 NSCLC cases with clinical information • 61 chemo-naïve • 51 neoadjuvant-treated • Multiplex IF: Opal-7 color kit™ • Image acquisition: Vectra™ • Image data analysis: InForm™, Spotfire™ 1. Parra E et al. WCLC 2016. Abstract OA20.05.

45. Neoadjuvant-Treated NSCLC ShowedHigher Inflammatory Infiltrate1 Median Values of Chemo-Naïve and Neoadjuvant Cases a Mann Whitney U test. 1. Parra ER et al. J Immunother Cancer. 2018;6:48.

46. Neoadjuvant Anti–PD-1 + Anti-CD137 is Better Than Adjuvant (At Least in Mice)1 1. Liu J et al. Cancer Discov. 2016;6:1382-1399.

47. Neoadjuvant Nivolumab Schema1 Newly diagnosed resectable stage I (>2 cm)/II/IIIA NSCLC Nivolumab 3 mg/kg IV (day -14 and day -28) Surgical Resection (day 0) SOC (post-operative treatment) Tumor Biopsy Tumor and Lymph Node Assessment • Primary endpoints: Safety and feasibility • Also evaluated: Tumor pathological response; expression of PD-L1; mutational burden; and mutation-associated, neoantigen-specific T-cell responses 1. Forde PM et al. N Engl J Med. 2018;378:1976-1986.

48. Pathological Assessment of Response to Neoadjuvant Nivolumab1 % of Pathological Regression According to Subgroup • Major pathological response occurred in 9/20 resected tumors (45%; 95% CI, 23-68) • Responses occurred in both PD-L1–positive/–negative tumors 1. Forde PM et al. N Engl J Med. 2018;378:1976-1986.

49. Mutation Burden Is Associated With Pathologic Response to Neoadjuvant Nivolumab1 Number of Sequence Alterations in Pretreatment Tumor Correlation Between # of Sequence Alterations and % of Residual Tumor 400 Sequence Alterations, n 400 Spearman’s rho, -0.75 P = .008 Sequence Alterations, n 350 P = .01 350 300 300 250 250 200 200 150 150 AC SCC AS 100 100 50 50 0 0 0 20 40 60 80 100 MD01-005 MD01-019 MD01-004 MD01-024 NY016-016 NY016-014 NY016-007 MD043-008 MD043-006 MD043-011 MD043-012 Residual Tumor, % Major Pathological Response (N = 3) No Major Pathological Response (N = 8) 1. Forde PM et al. N Engl J Med. 2018;378:1976-1986.

50. Neoadjuvant Atezolizumab in Resectable NSCLC: Updated Results From a Multicenter Study (LCMC3)1 The efficacy-evaluable population comprised 45 patients who were treated with atezolizumab and underwent surgical resection • Per protocol, 5 patients with EGFR or ALK genetic alterations were excluded from the efficacy-evaluable population • 3 patients had pCR and 10 patients had a MPR • No patients in the TC0 and IC0 subgroup had pCR or MPR • Percent change in lesion size from baseline did not appear to associate with percent viable tumor cells TC1/2/3 or IC1/2/3 = PD-L1+ ≥1% on TC or IC; TC0 and IC0 = PD-L1+ <1% on TC and IC. Pathological regression defined as viable tumor cells (%) – 100 (%). Data cutoff: February 5, 2018. 1. Rusch V. WCLC 2018. MA04.09.