KEYNOTE604 Final Analysis Addition of Pembrolizumab to Etoposide

KEYNOTE-604 Final Analysis: Addition of Pembrolizumab to Etoposide and Platinum in Extensive-Stage SCLC CCO Independent Conference Coverage* Highlights of the 2020 ASCO Virtual Scientific Meeting, May 29 -31, 2020 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This activity is provided by Clinical Care Options, LLC Supported by educational grants from Astra. Zeneca; Daiichi Sankyo, Inc. ; Ipsen Pharma; Jazz Pharmaceuticals, Inc. ; and Merck Sharp & Dohme Corp.

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KEYNOTE-604: Background § SCLC: ~15% of all lung cancers; 5 -yr OS of ~6% to 7%[1 -3] ‒ Etoposide + platinum chemotherapy is established standard first-line therapy § Pembrolizumab approved for use as third-line or later therapy for metastatic SCLC with progression on or after platinum-based chemotherapy in US and elsewhere based on phase III KEYNOTE-028 and KEYNOTE-158 trials[4] § Combination of etoposide and platinum with PD-L 1–targeted therapy (atezolizumab or durvalumab) approved as first-line treatment for extensive-stage SCLC in US and elsewhere based on phase III data showing OS benefit[5, 6] § Current study assessed safety and efficacy of pembrolizumab vs placebo in combination with etoposide plus platinum as first-line therapy for extensive-stage SCLC[7] 1. Govindan. J Clin Oncol. 2006: 24; 4539. 2. Gaspar. Clin Lung Cancer. 2012: 13; 115. 3. Wang. Sci Rep. 2017: 7; 1339. 4. Chung. J Thorac Oncol. 2020; 15: 618. 5. Paz-Ares. Lancet. 2019; 394: 1929. 6. Horn. N Engl J Med. 2018; 379: 2220. 7. Rudin. ASCO 2020. Abstr 9001. Slide credit: clinicaloptions. com

KEYNOTE-604: Study Design § Multicenter, double-blind, randomized phase III trial Stratified by platinum (cisplatin vs carboplatin), ECOG PS (0 vs 1), LDH (≤ ULN vs > ULN) Patients with stage IV SCLC, no previous systemic therapy, ECOG PS 0/1 with adequate organ function, life expectancy ≥ 3 mos, no unstable brain metastases* (N = 453) Pembrolizumab 200 mg Day 1 + Etoposide 100 mg/m 2 Days 1 -2 + Platinum CT† Day 1 x 4 Q 3 W cycles (n = 228) Pembrolizumab 200 mg Day 1 for ≤ 31 Q 3 W cycles + optional PCI‡ Placebo (normal saline) Day 1 + Etoposide 100 mg/m 2 Days 1 -2 + Platinum CT† Day 1 x 4 Q 3 W cycles (n = 225) Placebo (normal saline) Day 1 for ≤ 31 Q 3 W cycles + optional PCI‡ *Pts required to have sample available for biomarker assessment. †Carboplatin AUC 5 or cisplatin 75 mg/m 2 on Day 1. ‡Pts with CR or PR after Cycle 4 were eligible for ≤ 25 Gy of PCI in 10 fractions at investigator’s discretion. § Primary endpoints: PFS per RECIST v 1. 1 by BICR (IA 2 superiority threshold: one-sided P =. 0048), OS (FA superiority threshold: one-sided P =. 0128) § Secondary endpoints: ORR and Do. R per RECIST v 1. 1 by BICR, safety Rudin. ASCO 2020. Abstr 9001. Rudin. JCO. 2020 [Online ahead of print]. Slide credit: clinicaloptions. com

KEYNOTE-604: Baseline Characteristics Pembrolizumab + EP (n = 228) Placebo + EP (n = 225) Median age, yrs (range) 64 (24 -81) 65 (37 -83) Male, n (%) 152 (66. 7) 142 (63. 1) ECOG PS 1, n (%) 168 (73. 7) 169 (75. 1) Former or current smoker, n (%) 220 (96. 5) 217 (96. 4) LDH > ULN, n (%) 127 (55. 7) 129 (57. 3) Brain metastases, n (%) 33 (14. 5) 22 (9. 8) Liver metastases, n (%) 95 (41. 7) 92 (40. 9) 134. 8 (24. 4 -431. 7) 126. 6 (20. 8 -408. 8) PD-L 1 CPS ≥ 1, n (%)* 88 (38. 6) 97 (43. 1) Received carboplatin, n (%) 161 (70. 6) 156 (69. 3) Characteristic Median sum of largest diameters of target lesions, mm (range) *CPS unknown in 18. 9% of pts in pembrolizumab arm vs 22. 2% in placebo arm. Rudin. ASCO 2020. Abstr 9001. Rudin. JCO. 2020 [Online ahead of print]. Slide credit: clinicaloptions. com

KEYNOTE-604: PFS in ITT Population 2 nd Interim Analysis Median PFS, Mos (95% CI) Pembro-EP 4. 5 Pembro + EP 4. 5 (4. 3 -5. 4) Placebo-EP 4. 3 Placebo + EP 4. 3 (4. 2 -4. 4) HR: 0. 75 (95% CI: 0. 61 -0. 91); P =. 0023 100 80 6 -mo rate 34. 1% 23. 8% 12 -mo rate 13. 6% 3. 1% 60 40 60 20 0 0 3 6 Pts at risk, n Pembro + EP 228 181 71 Placebo + EP 225 187 50 9 12 15 18 21 24 27 30 33 Mos 31 14 15 3 5 1 1 1 0 0 Rudin. ASCO 2020. Abstr 9001. Reproduced with permission. 12 -mo rate 15. 9% 18 -mo rate 5. 0% 10. 8% 40 20 0 Median PFS, Mos (95% CI) Pembro + EP 4. 8 (4. 3 -5. 4) Placebo + EP 4. 3 (4. 2 -4. 5) HR: 0. 73 (95% CI: 0. 60 -0. 88) 100 PFS (%) 80 Final Analysis 2. 1% 0 3 6 Pts at risk, n Pembro + EP 228 182 76 Placebo + EP 225 189 56 9 12 15 18 21 24 27 30 33 Mos 42 23 32 11 26 4 15 3 10 1 1 1 0 0 Slide credit: clinicaloptions. com

KEYNOTE-604: OS in ITT and As-Treated Populations at Final Analysis ITT 12 -mo rate 45. 1% 39. 6% 60 24 -mo rate 22. 5% 11. 2% 20 3 6 60 44 100 12 -mo rate 46. 0% 39. 9% 31 19 Rudin. ASCO 2020. Abstr 9001. Reproduced with permission. 15 8 3 3 1 0 60 24 -mo rate 23. 0% 11. 3% 40 20 9 12 15 18 21 24 27 30 33 Mos Pts at risk, n Pembro + EP 228 201 175 132 102 87 Placebo + EP 225 212 170 122 89 63 Pembro + EP 10. 8 (9. 7 -12. 9) Placebo + EP 9. 7 (8. 6 -10. 7) HR 0. 78 (95% CI: 0. 63 -0. 97), P =. 0124 80 40 0 Median OS, Mos (95% CI) OS (%) 80 OS (%) Median OS, Mos (95% CI) Pembro + EP 10. 8 (9. 2 -12. 9) Placebo + EP 9. 7 (8. 6 -10. 7) HR 0. 80 (95% CI: 0. 64 -0. 98), P =. 0164 100 0 As Treated 0 0 3 6 9 12 15 18 21 24 27 30 33 Mos Pts at risk, n Pembro + EP 223 198 174 132 102 87 Placebo + EP 223 211 169 122 89 63 60 44 31 19 15 8 3 3 1 0 0 0 Slide credit: clinicaloptions. com

KEYNOTE-604: PFS and OS by Subgroup at Final Analysis (ITT) OS PFS HR (95% CI) Events/Participants 416/453 Overall Age 197/216 < 65 yrs 219/237 ≥ 65 yrs Sex 272/294 Male 144/159 Female ECOG PS 102/116 0 314/337 1 Region of enrollment 77/84 East Asia 339/369 Non-east Asia Smoking status 260/281 Current 141/156 Former LDH concentration 168/195 < ULN 246/256 > ULN No. of metastatic sites 146/161 <3 270/292 ≥ 3 Baseline brain metastasis 50/55 Yes 366/398 No Baseline liver metastasis 179/187 Yes 237/266 No PD-L 1 CPS 163/175 <1 167/185 ≥ 1 Platinum administered 120/129 Cisplatin 290/317 Carboplatin 0. 25 0. 73 (0. 60 -0. 88) 0. 71 (0. 54 -0. 95) 0. 72 (0. 55 -0. 94) 0. 66 (0. 52 -0. 84) 0. 76 (0. 54 -1. 06) 0. 63 (0. 43 -0. 94) 0. 75 (0. 60 -0. 94) 0. 60 (0. 37 -0. 95) 0. 72 (0. 58 -0. 90) 0. 70 (0. 55 -0. 90) 0. 71 (0. 50 -0. 99) 0. 67 (0. 49 -0. 90) 0. 75 (0. 59 -0. 95) 0. 67 (0. 48 -0. 93) 0. 75 (0. 59 -0. 95) 1. 06 (0. 60 -1. 86) 0. 67 (0. 54 -0. 83) 0. 88 (0. 65 -1. 18) 0. 62 (0. 48 -0. 81) 0. 72 (0. 53 -0. 98) 0. 67 (0. 49 -0. 92) 0. 60 (0. 42 -0. 87) 0. 75 (0. 59 -0. 95) 0. 5 1 2 4 Favors Pembro-EP Favors Placebo-EP Rudin. ASCO 2020. Abstr 9001. Reproduced with permission. HR (95% CI) Events/Participants 357/453 Overall Age 168/216 < 65 yrs 289/237 ≥ 65 yrs Sex 237/294 Male 120/159 Female ECOG PS 84/116 0 273/337 1 Region of enrollment 64/84 East Asia 293/369 Non-east Asia Smoking status 227/281 Current 118/156 Former LDH concentration 137/195 < ULN 219/256 > ULN No. of metastatic sites 115/161 <3 242/292 ≥ 3 Baseline brain metastasis 44/55 Yes 313/398 No Baseline liver metastasis 163/187 Yes 194/266 No PD-L 1 CPS 146/175 <1 134/185 ≥ 1 Platinum administered 100/129 Cisplatin 251/317 Carboplatin 0. 25 0. 80 (0. 60 -0. 98) 0. 83 (0. 61 -1. 12) 0. 78 (0. 59 -1. 05) 0. 76 (0. 59 -0. 98) 0. 88 (0. 61 -1. 26) 0. 68 (0. 44 -1. 05) 0. 86 (0. 68 -1. 09) 0. 72 (0. 44 -1. 19) 0. 84 (0. 67 -1. 06) 0. 86 (0. 66 -1. 11) 0. 71 (0. 49 -1. 02) 0. 72 (0. 52 -1. 01) 0. 84 (0. 65 -1. 10) 1. 04 (0. 72 -1. 50) 0. 71 (0. 55 -0. 92) 1. 32 (0. 72 -2. 42) 0. 75 (0. 60 -0. 94) 0. 75 (0. 55 -1. 02) 0. 82 (0. 62 -1. 08) 0. 80 (0. 58 -1. 11) 0. 84 (0. 60 -1. 18) 0. 73 (0. 49 -1. 08) 0. 83 (0. 65 -1. 07) 0. 5 1 2 4 Favors Pembro-EP Favors Placebo-EP Slide credit: clinicaloptions. com

KEYNOTE-604: Responses at Final Analysis (ITT) Duration of Response (Do. R) Placebo + EP (n = 225) 70. 6 (64. 2 -76. 4) 61. 8 (55. 1 -68. 2) § CR 4 (1. 8) 2 (0. 9) § PR 157 (68. 9) 137 (60. 9) § SD 40 (17. 5) 56 (24. 9) § PD 8 (3. 5) 12 (5. 3) § NE* 6 (2. 6) 5 (2. 2) § NA† 13 (5. 7) 13 (5. 8) ORR, % (95% CI) Best response, n (%) *Post-baseline imaging assessment not evaluable. †No post-baseline imaging assessment. Rudin. ASCO 2020. Abstr 9001. Rudin. JCO. 2020 [Online ahead of print]. Reproduced with permission. 100 Ongoing Response (%) Pembrolizumab + EP (n = 228) Response 80 60 40 Pembro + EP Placebo + EP Median Do. R, mos (range) 4. 2 (1. 0 -26. 0+) 3. 7 (1. 4 -26. 8+) 12 -mo rate 19. 3% 3. 3% 18 -mo rate 16. 3% 1. 3% 20 0 0 3 6 9 12 15 18 21 24 27 30 33 Mos No. at risk 161 107 49 32 25 18 139 82 17 8 4 3 8 1 3 1 1 1 0 0 0 Slide credit: clinicaloptions. com

KEYNOTE-604: All-Cause AEs in As-Treated Population at Final Analysis Incidence (%) 100 80 60 57. 0 53. 4 All AEs, % Pembrolizumab + EP (n = 223) Placebo + EP (n = 223) Any grade 100 99. 6 Grade 3/4 76. 7 74. 9 Grade 5* 6. 3 5. 4 Leading to d/c, any tx 14. 8 6. 3 Leading to d/c, all tx 4. 0 3. 6 48. 4 46. 6 40 43. 0 38. 6 33. 6 37. 7 30. 9 20 0 e nia u p o r t Ne e An a mi Na ea s u ia ec p Alo *2. 7% of events in each arm were considered related to treatment. Rudin. ASCO 2020. Abstr 9001. Reproduced with permission. p p A ↓ te i t e 24. 7 tip s n 29. 6 27. 4 26. 5 on i t a Fa e it gu Co AEs With Incidence ≥ 20% 26. 5 Pembro + EP Placebo + EP 22. 0 22. 4 20. 6 ia on b e om enia kop r Th top Leu cy Grade 1 -2 3 -5 21. 1 18. 8 19. 7 20. 2 a a Di e h r r gh u o C Slide credit: clinicaloptions. com

KEYNOTE-604: Immune-Mediated AEs in As-Treated Population at Final Analysis 100 Pembrolizumab + EP (n = 223) Placebo + EP (n = 223) Any grade 24. 7 10. 3 Grade 3 -4 7. 2 1. 3 0 0. 4* Leading to d/c, any tx 5. 8 0. 9 Leading to d/c, all tx 0. 9 0 Leading to death 80 Incidence (%) All AEs, % 60 *Pneumonitis. 10. 3 40 6. 7 20 r hy ot p y ism d i o Rudin. ASCO 2020. Abstr 9001. ism d i o r hy rt e p Hy 4. 0 2. 7 2. 2 0 H Pembro + EP Placebo + EP Grade 1 -2 3 -5 is nit o Pn m eu 2. 2 0. 9 1. 8 0 1. 3 0. 9 kin tis i S i l t o a re ons C p e e i v H Se eact R Aes With Incidence ≥ 20% 0. 9 0. 4 0. 9 al cy tis n i e s n r hy Ad fficie p po u y s H In 0. 9 0 0 itis r h p Ne Slide credit: clinicaloptions. com

KEYNOTE-604: Conclusions § Addition of pembrolizumab to etoposide and platinum chemotherapy significantly improved PFS in untreated patients with extensive-stage SCLC ‒ HR: 0. 75, P =. 0023 (significance threshold P =. 0048) § Improvement of OS with addition of pembrolizumab did not reach statistical significance ‒ HR: 0. 80, P =. 0164 (significance threshold P =. 0128) § Durable responses seen in approximately 20% of patients § No new safety signals § Authors conclude these data support use of immunotherapy in SCLC Rudin. ASCO 2020. Abstr 9001. Slide credit: clinicaloptions. com

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