Immunotherapy advances in lung cancer

Recent advances in lung cancer management

1. Recent Developments With Immunotherapy for Patients With Advanced NSCLC Alok Gupta

2. Tasuku Honjo James P. Allison

3. Current Treatment Overview of Advanced or Metastatic NSCLC Chemotherapy Targeted Therapy Immune Checkpoint Inhibitors Standard of Care Used across all lines of therapy 1 Commonly used agents: (1L) platinum-based chemotherapy , (2L) single-agent docetaxel, pemetrexed, gemcitabine 1,2 Backbone of therapy for patients with lung cancer 3 EGFR/ALK+ Patients Mutational status rates and testing vary by market/region Commonly used agents: erlotinib, gefitinib, afatinib ( EGFR+), crizotinib, ceritinib ( ALK+ ) 1,4 Improved outcomes in patients with mutations 5–7 1L PD-L1 High Expressing Patients 2L+ All-comers or PD-L1+ Patients Indications/approvals vary by market/region Agents: (1L and 2L+) pembrolizumab (PD-L1 expression ≥ 50% and ≥ 1%, respectively) , (2L+) nivolumab and atezolizumab (all comers) 8–10 New to market ; target immunosuppressive mechanisms 11 Mutation M G1 S G2 G0 G1/S Checkpoint G2/M Checkpoint 1L = first line; 2L = second line; ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; NSCLC = non – small cell lung cancer; PD-L1 = programmed death ligand 1. Cell cycle image reprinted with permission from Samarasinghe B. The hallmarks of cancer: 2 – insensitivity to antigrowth signals. Scientific American website. http://blogs.scientificamerican.com/guest-blog/the-hallmarks-of-cancer-2-insensitivity-to-antigrowth-signals. Immune checkpoint inhibitors image adapted from Chen DS et al. Immunity . 2013;39(1):1–10. Reprinted with permission from Elsevier. 1. World Health Organization Expert Committees: 2014 Review of Cancer Medicines on the WHO List of Essential Medicines: Non–Small Cell Lung Cancer. http://www.who.int/selection_medicines/committees /expert/20/applications/ NonSmallCellLungCancer.pdf?ua =1. Accessed 5 April 2017. 2. Davies J et al. PLoS One. 2017;12(4):e0175679. 3. Carrizosa DR et al. Oncology (Williston Park). 2013;27(5):396–404. 4. Holla VR et al. Cold Spring Harb Mol Case Stud. 2017; 3(1):a001115. 5. Kwak EL et al. N Engl J Med. 2010;363(18):1693–1703. 6. Maemondo M et al. N Engl J Med. 2010;362(25):2380–2388. 7. Zhou C et al. Lancet Oncol. 2011;12(8):735–742. 8 . Keytruda Prescribing Information India, 2018 9. OPDIVO US Prescribing Information. Princeton, NJ: Bristol-Myers Squibb; January 2016. 10. TCENTRIQ US Prescribing Information. South San Francisco, CA: Genentech, Inc : October 2016. 11. Garon EB. Semin Oncol. 2015;42( Suppl 2): S11–S18.

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5. Antitumor Immune Response in Advanced or Metastatic NSCLC The body’s immune response can detect and destroy tumor cells through activated T cells and other mechanisms. 1 Tumor cells express multiple antigens that are not expressed in normal tissue. 2 T-cell–mediated Immune Response 1,2 NSCLC = non‒small cell lung cancer. Image adapted from Chen DS et al. Immunity . 2013;39(1):1–10. Reprinted with permission from Elsevier . 1. May KF Jr et al. In: Prendergast GC et al. Cancer Immunotherapy . 2nd ed. Philadelphia, PA: Elsevier; 2013:101–113 . 2 . Chen DS et al. Immunity . 2013;39(1):1–10. Tumor cell Tumor-specific antigens Dendritic cell Naïve cytotoxic T cell Tumor cell Activated cytotoxic T cell Antitumor effector mechanisms

6. Abs = antibodies; BTLA = B and T lymphocyte attenuator; CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte–associated antigen 4 ; GITR = glucocorticoid induced tumor necrosis factor-related protein; HVEM = herpes virus entry mediator; LAG-3 = lymphocyte activation gene 3; PD-1 = programmed death receptor-1; TIM-3 = T-cell immunoglobulin domain and mucin domain-3; VISTA = V-domain immunoglobulin (Ig)-containing suppressor of T-cell activation. Image reprinted with permission from Mellman I et al. Nature. 2011;480(7378):480 – 489. 1. Pardoll DM. Nat Rev Cancer. 2012;12(4):252 – 264. 2. Mellman I et al. Nature. 2011;480(7378):480 – 489. Tumors Exploit Immune Checkpoint Pathways as One Mechanism of Immune Evasion Normal immune checkpoint pathway = elaborate series of cellular interactions that prevent excessive T-cell activity . 1 T-cell responses are regulated by a number of activating and inhibitory interactions. 1 Immune Checkpoint Receptors 2

7. In Advanced or Metastatic NSCLC, the PD-1 Pathway May Be Exploited to Evade the Immune Response 1,2 APC = antigen-presenting cell; MHC = major histocompatibility complex; NSCLC = non‒small cell lung cancer; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor. Image adapted with permission from Pardoll DM. Nat Rev Cancer. 2012;12(4):252 – 264 . 1. Keytruda Prescribing Information India, 2018 2 . Pardoll DM. Nat Rev Cancer. 2012;12(4):252 – 264. Emerging research has identified PD-1 as a key immune checkpoint pathway involved in inhibiting the T-cell–mediated immune response. Tumor cells can downregulate T-cell activity by exploiting the PD-1 checkpoint pathway through expression of the PD-­1 ligands, PD‐L1 and PD‐L2. PD-L1 and PD-L2 engage the PD-1 receptor on T cells to inactivate them, which may allow tumor cells to evade the immune response. Antigen MHC TCR Activated cytotoxic T cell Tumor cell/APC PD-L2 PD-L1 PD-1 Antigen MHC TCR Inactivated cytotoxic T cell PD-1 PD-L2 PD-L1 Tumor cell/APC

8. Phase III KEYNOTE-024: Pembrolizumab vs CT as First-line Therapy for Advanced NSCLC With PD-L1 ≥ 50% Primary endpoint: PFS Secondary endpoints: ORR, OS, and safety Patients with stage IV NSCLC and ECOG PS 0/1, no previous systemic therapy, no actionable EGFR / ALK mutations, and PD-L1 TPS ≥ 50%* (N = 305) Pembrolizumab 200 mg IV Q3W for up to 35 cycles (n = 154) Histology-based Chemotherapy † for up to 6 cycles (n = 151) Until PD or unacceptable toxicity Stratified by ECOG PS (0 vs 1), histology (squamous vs nonsquamous), and enrollment region Until PD (crossover to pembrolizumab allowed if safety criteria met) *≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay. † Investigator’s choice of: pem + carbo or cis; pac + carbo; gem + carbo or cis. Pem-containing regimens only for nonsquamous histology; these patients could receive pem maintenance treatment. Slide credit: clinicaloptions.com Reck M, et al. N Engl J Med. 2016;375:1823-1833.

9. KEYNOTE-024: Survival Slide credit: clinicaloptions.com PFS2 [1] Mos Patients at Risk, n 100 80 60 40 20 PFS2 (%) 6 3 9 12 18 15 21 24 154 151 134 121 112 99 96 64 90 56 71 36 40 18 16 6 3 1 59.7% 38.5% 51.0% 24.6% mPFS: 10.3 vs 6.0 mos [2] mPFS2: 18.3 vs 8.4 mos HR: 0.54 ( P < .001) 24 4 4 OS [1] Mos 100 80 60 40 20 OS (%) 6 3 9 12 18 15 21 154 151 136 123 121 107 112 88 106 79 88 64 57 35 20 15 70.3% 54.8% 61.0% 43.0% mOS: NR vs 14.5 mos HR: 0.63 ( P = .003) 1. Brahmer JR, et al. ASCO 2017. Abstract 9000. 2. Reck M, et al. N Engl J Med. 2016;375:1823-1833. Pembrolizumab Chemotherapy Patients at Risk, n

10. Recent Developments With Immunotherapy for Patients With Advanced NSCLC

11. Why Combine Chemotherapy With Immunotherapy? Cytotoxic agents enhance antigen presentation and immunogenic cell death [1] Chemotherapy disrupts immune evasion mechanisms in the tumor microenvironment [2,3] Dose, schedule, and drug dependent [4,5] Slide credit: clinicaloptions.com 1. Zitvogel L, et al. Immunity. 2013;39:74-88. 2. Mouw KW, et al. Cancer Discov. 2017;7:675-693. 3. Fukumura D, et al. Nat Rev Clin Oncol. 2018;15:325-340. 4. Emens LA, et al. Curr Opin Mol Ther. 2001;3:77-84. 5. Chen G, Emens LA. Cancer Immunol Immunother. 2013;62:203-216.

12. Primary endpoint: PFS by RECIST v1.1 (BICR), OS Secondary endpoints: ORR and DoR by RECIST v1.1 (BICR), safety Phase III KEYNOTE-407: CT ± Pembrolizumab in Untreated Metastatic Squamous NSCLC Paz-Ares LG, et al. ASCO 2018. Abstract 105. ClinicalTrials.gov. NCT02775435. Slide credit: clinicaloptions.com Pembrolizumab + Carboplatin + Paclitaxel or nab-Paclitaxel 3-wk cycle x 4 (n = 278) Patients with untreated stage IV squamous NSCLC, ECOG PS 0/1, available tumor biopsy for PD-L1 assessment, no brain mets, and no pneumonitis requiring systemic steroids (N = 559) Stratified by PD-L1 TPS (< 1% vs ≥ 1%), taxane (paclitaxel vs nab-paclitaxel), region (east Asia vs other) Carboplatin AUC 6 Q3W, nab-paclitaxel 100 mg/m 2 QW, paclitaxel 200 mg/m 2 Q3W, pembrolizumab 200 mg Q3W. *Upon confirmation of PD by BICR and fulfillment of safety criteria, optional crossover could occur during combination or monotherapy. Placebo + Carboplatin + Paclitaxel or nab-Paclitaxel 3-wk cycle x 4 (n = 281) Pembrolizumab up to 31 cycles Placebo up to 31 cycles Pembrolizumab up to 35 cycles Crossover allowed* PD

13. KEYNOTE-407: PFS by RECIST v1.1 (BICR) in ITT Population ORR: 58.4% vs 35%, P = .0004, pembro + chemo vs chemo, respectively. Paz-Ares LG, et al. ASCO 2018. Abstract 105. Slide credit: clinicaloptions.com Mos Patients at Risk, n PFS (%) Median PFS, Mos (95% CI) 6.4 (6.2-8.3) 4.8 (4.3-5.7) 100 80 60 40 20 3 6 9 12 15 18 21 Pembro + Chemo Chemo 54.7 70.1 0.56 (0.45-0.70) < .0001 Events, % HR (95% CI) P Value 278 281 223 190 142 90 57 26 23 12 5 4

14. 50 50 50 KEYNOTE-407: PFS by PD-L1 Expression Level Paz-Ares LG, et al. ASCO 2018. Abstract 105. Slide credit: clinicaloptions.com TPS < 1% TPS 1% to 49% TPS ≥ 50% Mos PFS (%) 21 3 6 9 12 15 18 100 90 80 70 60 40 30 20 10 Median PFS, Mos (95% CI) 6.3 (6.1-6.5) 5.3 (4.4-6.2) Events, % HR (95% CI) Pembro + chemo 57.9 0.68 (0.47-0.98) Placebo + chemo 67.7 Patients at Risk, n 95 99 78 71 48 35 16 11 5 6 1 BICR, blinded, independent central review. Data cutoff date: Apr 3, 2018. Mos PFS (%) 21 3 6 9 12 15 18 100 90 80 70 60 40 30 20 10 Median PFS, Mos (95% CI) 7.2 (6.0-11.4) 5.2 (4.2-6.2) 103 104 79 79 49 40 26 8 13 4 5 1 Events, % HR (95% CI) 52.4 0.56 (0.39-0.80) 70.2 Mos PFS (%) 21 3 6 9 12 15 18 100 90 80 70 60 40 30 20 10 Median PFS, Mos (95% CI) 8.0 (6.1-10.3) 4.2 (2.8-4.6) 73 73 60 38 41 13 12 5 4 2 2 Events, % HR (95% CI) 53.4 0.37 (0.24-0.58) 75.3 Patients at Risk, n Patients at Risk, n

15. KEYNOTE-407: OS in ITT Population Paz-Ares LG, et al. ASCO 2018. Abstract 105. Slide credit: clinicaloptions.com Mos Patients at Risk, n OS (%) Median OS, Mos (95% CI) 15.9 (13.2-NE) 11.3 (9.5-14.8) 100 80 60 40 20 3 6 9 12 15 18 21 Pembro + Chemo Chemo 30.6 42.7 0.64 (0.49-0.85) .0008 Events, % HR (95% CI) P Value 278 281 256 246 188 175 124 93 62 45 17 16 2 4

16. 40 Paz-Ares LG, et al. ASCO 2018. Abstract 105. Slide credit: clinicaloptions.com KEYNOTE-407: OS by PD-L1 Expression Level (Second Interim Analysis) 50 50 50 TPS < 1% TPS 1% to 49% TPS ≥ 50% Mos OS (%) 21 3 6 9 12 15 18 100 90 80 70 60 40 30 20 10 Median OS, Mos (95% CI) 15.9 (13.1-NE) 10.2 (8.6-13.8) Events, % HR (95% CI) Pembro + chemo 30.5 0.61 (0.38-0.98) Placebo + chemo 44.4 95 99 78 92 62 63 41 32 20 14 5 4 1 1 Data cutoff date: Apr 3, 2018. Mos OS (%) 21 3 6 9 12 15 18 100 90 80 70 60 40 30 20 10 Median OS, Mos (95% CI) 14.0 (12.8-NE) 11.6 (8.9-17.2) 103 104 95 90 68 66 50 37 25 21 9 6 1 Events, % HR (95% CI) 30.1 0.57 (0.36-0.90) 43.3 Mos OS (%) 21 3 6 9 12 15 18 100 90 80 70 60 30 20 10 Median OS, Mos (95% CI) NR (11.3-NE) NR (7.4-NE) 73 73 66 60 53 42 28 21 15 9 3 5 2 Events, % HR (95% CI) 31.5 0.64 (0.37-1.10) 41.1 Patients at Risk, n Patients at Risk, n Patients at Risk, n

17. Phase III IMpower131: CT ± Atezolizumab in Untreated Metastatic Squamous NSCLC Coprimary endpoints: investigator-assessed PFS per RECIST v1.1, OS (ITT) Secondary endpoints: PFS, OS in PD-L1 subgroups; ORR, DoR, safety Jotte RM, et al. ASCO 2018. Abstract LBA9000. Slide credit: clinicaloptions.com Patients with stage IV squamous NSCLC*; no prior CT; ECOG PS 0/1; any PD-L1 status † (N = 1021) Atezolizumab 1200 mg IV Q3W + Carboplatin/Paclitaxel ‡ for 4-6 cycles (n = 338) Carboplatin/nab-Paclitaxel ‡ for 4-6 cycles (n = 340) Atezolizumab 1200 mg IV Q3W + Carboplatin/nab-Paclitaxel ‡ for 4-6 cycles (n = 343) Until PD or loss of clinical benefit Stratified by sex; PD-L1 expression; liver metastases Atezolizumab Atezolizumab BSC Until PD *Patients with EGFR or ALK aberrations must have PD or intolerance to ≥ 1 targeted tx. † PD-L1 assessed by SP142 IHC assay. ‡ Carboplatin AUC 6 IV Q3W; nab-paclitaxel 100 mg/m 2 IV QW; paclitaxel 200 mg/m 2 IV Q3W. Maintenance (no crossover allowed)

18. IMpower131: Survival Outcomes in ITT Populations (Coprimary Endpoints) PD-L1 high: median OS, 23.6 vs 14.1 mos (HR: 0.56; 95% CI: 0.32-0.99); 12-mo OS, 67% vs 52%; 24-mo OS, 47% vs 30% Jotte RM, et al. ASCO 2018. Abstract LBA9000. Slide credit: clinicaloptions.com Atezolizumab + Carbo/nab-Pac (n = 343) Carbo/nab-Pac (n = 340) Median PFS, mos (95% CI) 6.3 (5.7-7.1) 5.6 (5.5-5.7) Mos 12.0 % 24.7 % 12-mo PFS PFS (%) 20 40 60 80 100 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Atezolizumab + Carbo/nab-Pac (n = 343) Carbo/nab-Pac (n = 340) Median OS, Mos (95% CI) 14.0 (12.0-17.0) 13.9 (12.3-16.4) 100 HR: 0.71 (95% CI: 0.60-0.85; P = .0001) Mi nimum follow-up: 9.8 mos Median follow-up: 17.1 mos 55.6 % 56.9 % 31.9 % 12-mo OS 24.1 % 24-mo OS OS (%) 20 40 60 80 HR: 0.96 (95% CI: 0.78-1.18; P = .6931) Mos 32 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

19. IMpower131: Investigator-Assessed PFS by PD-L1 Slide credit: clinicaloptions.com Jotte RM, et al. ASCO 2018. Abstract LBA9000. HR: 0.70 (95% CI: 0.53-0.92) HR: 0.44 (95% CI: 0.27-0.71) HR: 0.81 (95% CI: 0.64-1.03) Atezolizumab + Carbo/nab-Pac Carbo/ nab-Pac Atezolizumab + Carbo/nab-Pac Carbo/ nab-Pac Atezolizumab + Carbo/nab-Pac Carbo/ nab-Pac Patients, n 53 48 129 121 160 171 12-mo PFS, % 48 20 20 9 20 12 Median PFS, mos 10.1 5.5 6.0 5.6 5.7 5.6 PD-L1 High (TC3 or IC3) PD-L1 Low (TC1/2 or IC1/2) PD-L1 Negative (TC0 and IC0) 28 20 40 60 80 100 2 4 6 8 10 12 18 Mos PF S (%) 14 16 20 22 24 26 20 40 60 80 2 4 6 8 10 12 18 PFS (%) 14 16 20 22 24 100 28 20 40 60 80 100 2 4 6 8 10 12 18 PFS (%) 14 16 20 22 24 26 30 Mos Mos

20. 28 IMpower131: Interim OS by PD-L1 Slide credit: clinicaloptions.com Jotte RM, et al. ASCO 2018. Abstract LBA9000. Atezolizumab + Carbo/nab-Pac Carbo/ nab-Pac Atezolizumab + Carbo/nab-Pac Carbo/ nab-Pac Atezolizumab + Carbo/nab-Pac Carbo/ nab-Pac Patients, n 53 48 129 121 160 171 12-mo OS, % 67 52 54 64 53 53 24-mo OS, % 47 30 28 37 30 16 Median OS, mos 23.6 14.1 12.4 16.6 13.8 12.5 PD-L1 High (TC3 or IC3) PD-L1 Low (TC1/2 or IC1/2) PD-L1 Negative (TC0 and IC0) 20 40 60 80 100 2 4 6 8 10 12 18 Mos O S (%) HR: 0.56 (95% CI: 0.32-0.99) 14 16 20 22 24 26 20 40 60 80 2 4 6 8 10 12 18 O S (%) HR: 1.34 (95% CI: 0.95-1.90) 14 16 20 22 24 26 100 28 20 40 60 80 100 2 4 6 8 10 12 18 O S (%) HR: 0.86 (95% CI: 0.65-1.15) 14 16 20 22 24 26 30 32 Mos Mos

21. Phase III KEYNOTE-189: First-line Pembrolizumab + CT vs CT in Stage IV Nonsquamous NSCLC Patients with stage IV nonsquamous NSCLC and ECOG PS 0/1, any PD-L1 status, no actionable EGFR / ALK mutations (N = 616) Pembrolizumab 200 mg Q3W + Plt/pemetrexed Q3W (n = 410) Placebo Q3W + Plt/pemetrexed Q3W (n = 206) 4 cycles Pembrolizumab* + Pemetrexed Q3W Placebo* + Pemetrexed Q3W Stratified by PD-L1 TPS (≥ 1% vs < 1%), platinum agent (carboplatin vs cisplatin ), smoking history (never vs former/current) Until PD or unacceptable toxicity; crossover from placebo allowed *Up to total of 35 cycles. No PD No PD Baseline PD-L1 TPS, % < 1% 1% to 49% ≥ 50% Not estimable Pembro + chemotherapy 31.0 31.2 32.2 5.6 Placebo + chemotherapy 30.6 28.2 34.0 7.3 Slide credit: clinicaloptions.com Gandhi L, et al. N Engl J Med. 2018;378:2078-2092.

22. Median PFS, Mos Pembro + CT 8.8 Pbo + CT 4.9 KEYNOTE-189: Survival PFS OS 20 40 60 80 100 3 6 9 12 15 18 21 Mos PFS (%) 410 206 322 141 256 80 149 40 60 16 17 3 5 1 HR: 0.52 (95% CI: 0.43-0.64; P < .001) Patients at Risk, n Pembro + CT Pbo + CT 20 40 60 80 100 3 6 9 12 15 18 21 Mos OS (%) 410 206 377 183 347 149 278 104 163 59 71 25 18 8 HR: 0.49 (95% CI: 0.38-0.64; P < .001) Median OS, Mos Pembro + CT NR Pbo + CT 11.3 Slide credit: clinicaloptions.com Gandhi L, et al. N Engl J Med. 2018;378:2078-2092.

23. KEYNOTE-189: OS by PD-L1 TPS TPS < 1% TPS ≥ 50% TPS 1% to 49% 20 40 60 80 100 3 6 9 12 15 18 21 Mos OS (%) 127 63 113 54 104 45 79 32 42 21 20 6 6 1 HR: 0.59 (95% CI: 0.38-0.92) Pembro + CT Pbo + CT Patients at Risk, n Pembro + CT Pbo + CT 128 58 119 54 108 47 84 32 52 17 21 5 5 2 HR: 0.55 (95% CI: 0.34-0.90) Pembro + CT Pbo + CT 132 70 122 64 114 50 96 35 56 19 25 13 6 4 HR: 0.42 (95% CI: 0.26-0.68) Pembro + CT Pbo + CT 20 40 60 80 100 3 6 9 12 15 18 21 20 40 60 80 100 3 6 9 12 15 18 21 Mos Mos Slide credit: clinicaloptions.com Gandhi L, et al. N Engl J Med. 2018;378:2078-2092.

24. KEYNOTE-189: PFS by PD-L1 TPS TPS < 1% TPS ≥ 50% TPS 1% to 49% 20 40 60 80 100 3 6 9 12 15 18 21 Mos PF S (%) 127 63 88 4 4 60 27 31 16 12 4 3 2 HR: 0.75 (95% CI: 0.53-1.05) Patients at Risk, n Pembro + CT Pbo + CT 128 58 101 4 4 84 23 47 11 21 6 6 1 2 HR: 0.55 (95% CI: 0.37-0.81) 132 70 112 43 95 26 60 11 23 5 7 2 1 1 HR: 0.36 (95% CI: 0.25-0.52) 20 40 60 80 100 3 6 9 12 15 18 21 20 40 60 80 100 3 6 9 12 15 18 21 Mos Mos Slide credit: clinicaloptions.com Pembro + CT Pbo + CT Pembro + CT Pbo + CT Pembro + CT Pbo + CT Gandhi L, et al. N Engl J Med. 2018;378:2078-2092.

25. Additive Toxicity With Chemotherapy in NSCLC KEYNOTE 024 KEYNOTE 189 Slide credit: clinicaloptions.com 1. Reck M, et al. N Engl J Med. 2016;375:1823-1833. 2. Gandhi L, et al. N Engl J Med. 2018;378:2078-2092. KEYNOTE-189 [2] KEYNOTE-024 [1] Treatment-Related AE, % Pembro (n = 154) Chemo (n = 150) Any Gr Gr ≥ 3 Any Gr Gr ≥ 3 Any 73.4 26.6 90.0 53.3 Anemia 5.2 1.9 44.0 19.3 Nausea 9.7 43.3 2.0 Fatigue 10.4 1.3 28.7 3.3 Neutropenia 0.6 22.7 13.3 Vomiting 2.6 0.6 20.0 0.7 Diarrhea 14.3 3.9 13.3 1.3 Thrombocytopenia 11.3 5.3 Pyrexia 10.4 5.3 Immune mediated 29.2 9.7 4.7 0.7 Any-Cause AE, % Pembro + Chemo (n = 405) Chemo (n = 202) Any Gr Gr ≥ 3 Any Gr Gr ≥ 3 Any 99.8 67.2 99.0 65.8 Anemia 46.2 16.3 46.5 15.3 Nausea 55.6 3.5 52.0 3.5 Fatigue 40.7 5.7 38.1 2.5 Neutropenia 27.2 15.8 24.3 11.9 Vomiting 24.2 3.7 23.3 3.0 Diarrhea 30.9 5.2 21.3 3.0 Thrombocytopenia 18.0 7.9 14.4 6.9 Pyrexia 19.5 0.2 14.9 Immune mediated 22.7 8.9 11.9 4.5

26. IMpower132 Phase III Study Design: First-line Atezo + Carboplatin/ Cisplatin + Pemetrexed in Stage IV NSCLC Coprimary endpoints: Investigator-assessed PFS and OS Secondary endpoints: Investigator-assessed ORR and DoR, patient-reported outcomes, safety Exploratory analyses: clinical and biomarker subgroups Patients with stage IV nonsquamous NSCLC without EGFR or ALK alterations and no prior chemotherapy (N = 578) Maintenance until PD or loss of clinical benefit Atezolizumab 1200 mg + Carboplatin AUC 6 or Cisplatin 75 mg/m 2 + Pemetrexed 500 mg/m 2 Q3W x 4 or 6 cycles (n = 292) Carboplatin AUC 6 or Cisplatin 75 mg/m 2 + Pemetrexed 500 mg/m 2 Q3W x 4 or 6 cycles (n = 286) Slide credit: clinicaloptions.com Stratified by sex, smoking status, ECOG PS (0 vs 1), chemotherapy regimen Atezolizumab + Pemetrexed 4 or 6 cycles Pemetrexed 4 or 6 cycles Induction Maintenance Papadimitrakopoulou VA, et al. WCLC 2018. Abstract OA05.07.

27. 23 IMpower132: PFS, ORR, DoR Slide credit: clinicaloptions.com Papadimitrakopoulou VA, et al. WCLC 2018. Abstract OA05.07. Minimum follow-up: 11.7 mos Median follow-up: 14.8 mos Outcome Atezolizumab, Platinum, Pemetrexed (n = 292) Platinum, Pemetrexed (n = 286) PFS, % 6 mos 59.1 40.9 12 mos 33.7 17.0 ORR, % 47 32 CR 2 1 PR 45 32 Median DoR, mos 10.1 7.2 Median OS, mos 18.1 13.6 Atezo + chemo Chemo 7.6 5.2 0.60 (95% CI: 0.49-0.72) < .0001 Median PFS, Mos HR (95% CI) P Value APP PP 100 90 80 70 60 50 40 30 20 10 PFS (%) Mos 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patients at Risk, n APP PP 292 286 2 280 273 260 236 231 195 224 178 19 142 169 115 149 98 140 87 120 72 110 59 109 53 88 44 48 15 43 11 31 6 26 6 11 3 10 3 2 74 39

28. Phase III IMpower150: Atezo + CT ± Bev vs CT + Bev in Untreated Advanced Nonsquamous NSCLC Coprimary endpoints: investigator-assessed PFS and OS Slide credit: clinicaloptions.com Patients with stage IV or recurrent metastatic nonsquamous NSCLC, no prior CT,* and tumor tissue available for biomarker analysis (N = 1202) Atezolizumab 1200 mg IV Q3W + Carboplatin/Paclitaxel † (n = 402) Bevacizumab + Carboplatin/Paclitaxel † § (n = 400) Atezolizumab 1200 mg IV Q3W + Bevacizumab + Carboplatin/Paclitaxel † (n = 400) Stratified by sex, PD-L1 expression, liver metastases Atezolizumab Atezolizumab + Bevacizumab Bevacizumab Data cutoff: January 22, 2018. *If sensitizing EGFR mutation or ALK translocation present, must have PD on or intolerance to ≥ 1 approved targeted therapy. † Bevacizumab 15 mg/kg; carboplatin AUC 6; paclitaxel 200 mg/m 2 ; all given IV Q3W for 4 or 6 cycles. ‡ No crossover permitted. § Control arm. Atezolizumab until PD or loss of clinical benefit and/or bevacizumab until PD Maintenance ‡ Socinski MA, et al. ASCO 2018. Abstract 9002. Socinski MA, et al. N Engl J Med. 2018; 378:2288-2301.

29. 1 16 17 1 IMpower150: Updated PFS in ITT WT Population* Slide credit: clinicaloptions.com *ITT WT: patients without EGFR or ALK genetic alterations; 87% of randomized patients. Atezolizumab + Bev + Carbo/Pac Bev + Carbo/Pac Median PFS, mos (95% CI) 8.3 (7.7-9.8) 6.8 (6.0-7.1) 6-mo PFS, % 66 56 12-mo PFS, % 38 20 18-mo PFS, % 27 8 Median follow-up: ~ 20 mos. HR: 0.59 (95% CI: 0.50-0.70; P < .0001) PFS (%) Mos 100 90 80 70 60 50 40 30 20 10 34 2 3 4 5 6 7 8 9 10 11 12 13 14 15 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Socinski MA, et al. ASCO 2018. Abstract 9002. Atezolizumab + Bev + Carbo/Pac Bev + Carbo/Pac Patients, n 359 337 Median OS, mos (95% CI) 19.2 (17.0-23.8) 14.7 (13.3-16.9) 12-mo OS, % 67 61 18-mo OS, % 53 41 24-mo OS, % 43 34 34 50 OS (%) HR: 0.78 (95% CI: 0.64-0.96; P = .0164) Mos 100 90 80 70 60 40 30 20 10 33 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + +

30. IMpower150: PFS by Subgroup Slide credit: clinicaloptions.com Favors Atezolizumab + Bev + Carbo/Pac Favors Bev + Carbo/Pac 0.25 1.00 1.25 Patients, n (%) HR (95% CI) Median PFS, Mos Population 0.61 (0.52-0.72) 0.59 (0.37-0.94) 0.62 (0.52-0.74) 0.39 (0.25-0.60) 0.50 (0.39-0.64) 0.56 (0.41-0.77) 0.68 (0.56-0.82) 0.77 (0.61-0.99) 0.51 (0.38-0.68) 0.76 (0.60-0.96) 8.3 9.7 8.3 12.6 11.0 8.3 8.0 7.1 11.3 7.3 6.8 6.1 6.8 6.8 6.8 6.6 6.8 6.9 6.8 7.0 800 (100) 108 (14) 692 (87) 135 (20) 354 (51) 224 (32) 557 (80) 338 (49) 284 (43) 374 (57) ITT population Patients with EGFR or ALK genetic alterations WT population PD-L1 subgroups (in WT population)* TC3 or IC3 TC1/2/3 or IC1/2/3 TC1/2 or IC1/2 TC0/1/2 and IC0/1/2 TC0 and IC0 Teff subgroups (in WT population) High gene signature expression Low gene signature expression ABCP BCP Socinski MA, et al. N Engl J Med. 2018; 378:2288-2301. *TC3 or IC3: PD-L1 expression ≥ 50% TCs or ≥ 10% TI immune cells; TC1/2/3 or IC1/2/3: ≥ 1% TCs or TI immune cells; TC1/2 or IC1/2: ≥ 1% TCs or TI immune cells and < than 50% of tumor cells or < 10% of TI immune cells; TC0/1/2 and IC0/1/2: < 50% of TCs and < 10% of TI immune cells; and TC0 and IC0, < 1% TCs and TI immune cells.

31. Thank You