Debate 1 Are treatments for small cell lung cancer getting better? No:

Debate 1 Are treatments for small cell lung cancer getting better? No: Taofeek Owonikoko, MD, PhD Associate Professor Department of Hematology & Medical Oncology Winship Cancer Institute of Emory University 1

Evolution of SCLC treatment Limited Stage SCLC 1973 1992 1993 1999 1999 2002 2016 VA lung study established limited stage category Concurrent XRT Pignon et al. NEJM 327 (1992), pp. 1618-1624 High dose multiagent chemotherapy Arriagada et al. NEJM 1993; 329:1848-1852 Prophylactic cranial irradiation (PCI) Aupérin A et al. NEJM. 1999 Aug 12;341(7):476-84 BID thoracic radiation superior to QD fraction Turrisi AT et al. NEJM 1999; 340:265-271 Platinum doublet with concurrent XRT Sundstrom, S. et al. JCO; 20:4665-4672 BEQ single daily fraction not superior to bid radiation Faivre-Finn C. et al. ASCO 2016 2

Evolution of treatment for SCLC Extensive Stage SCLC Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print]. 3

Different platinum doublet beyond etoposide Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print]. Hanna N, et al. J Clin Oncol. 24(13):2038-2043. Lara P, et al. J Clin Oncol. 2009;27(15):2530-2535. 4

AURORA Kinase inhibitor, Alisertib in SCLC Primary endpoint: PFS (ITT population) Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Treatment group: Censored Observations: Alisertib + Paclitaxel 0 30 60 90 120 150 180 210 240 270 300 Survival Time (days) Alisertib + Paclitaxel Placebo + Paclitaxel Placebo + Paclitaxel Median PFS: 101 days (3.32 months) vs 66 days (2.17 months) CORRECTED Hazard Ratio (95% CI): 0.71 (0.509 0.985) Log rank p-value: 0.038 Alisertib + Paclitaxel 89 74 55 41 28 13 10 6 3 0 0 Placebo + Paclitaxel 89 65 45 27 19 12 8 4 3 3 0 Disease progression evaluated according to RECIST v1.1. 5 Owonikoko T, et al. Presented at: 17 th World congress on Lung Cancer. December 4-7, 2016. Vienna, Austria. Abstract: MA11.07 5

PFS improvement in patients with c-myc expression* Survival Survival 1.00 0.75 0.50 0.25 0 1.00 0.75 0.50 0.25 0 c-myc Positive, PFS 0 100 200 300 Days c-myc Negative, PFS 0 100 200 300 Days Alisertib + Paclitaxel Placebo + Paclitaxel P binary = 0.0006 Alisertib + Paclitaxel Placebo + Paclitaxel Arm c-myc positive *Archived tumor tissue available from 46 patients. Modal intensity for c-myc positive = 1+, 2+, 3+ IHC score. Modal intensity for c-myc negative = 0 IHC score. n Median PFS (months) Alisertib + Paclitaxel 17 4.64 Placebo + Paclitaxel 16 2.27 Hazard Ratio (95% CI) 0.29 (0.12 0.72) Arm n c-myc negative Median PFS (months) Alisertib + Paclitaxel 6 3.32 Placebo + Paclitaxel 7 5.16 Hazard Ratio (95% CI) 11.8 (1.52 91.2) 6

PARP Inhibition: E2511 Study Design Extensive stage SCLC Previously untreated Good renal and hepatic function Exclusion: Brain metastasis ECOG PS 2 Stratification: Gender (Male vs. Female) LDH ( ULN vs. > ULN) Cisplatin (75mg/m 2 ) D1 Etoposide (100mg/m 2 ) D1, 2, 3 Veliparib (100mg bid) D1-7 Cisplatin (75mg/m 2 ) D1 Etoposide (100mg/m 2 ) D1, 2, 3 Placebo (100mg bid) D1-7 Patients received a maximum of 4 cycles of therapy Restaging scan obtained every 2 cycles and Q 3 months from end of treatment PCI at the discretion of the treating physician Consolidation TRT was not allowed ASCO Annual Meeting, 2017 Owonikoko TK, et al. J Clin Oncol. 2017;35(suppl): Abstract 8505. 7

Progression Free Survival Unadjusted PFS HR: 0.75; 1-sided p=0.06 Adjusted PFS HR: 0.63; 1-sided p=0.01 Median PFS: 6.1 vs. 5.5 months for CE+V and CE+P respectively Owonikoko TK, et al. J Clin Oncol. 2017;35(suppl): Abstract 8505. OS HR: 0.83 (80% CI 0.64-1.07); 1-sided p=0.17. Median OS: 10.3 vs. 8.9 months for CE+V and CE+P respectively 8

CALGB 30504 Maintenance sunitinb Ready N, et al. J Clin Oncol. 2015;33(15):1660-1665. 9

PCI for extensive stage SCLC: One step forward and back Takahashi T, et al. Lancet Oncol. 2017;18(5):663-671. Slotman B, et al. N Engl J Med. 2007;357(7):664-672. 10

Phase II studies of Amrubicin vs. Topotecan in extensive stage SCLC Overall Sensitive Refractory Jotte et al. PFS 4.5 vs. 3.3 OS 9.2 vs. 7.6 Inoue et al. PFS 3.5 vs. 2.2 Phase III Assumptions OS 8.1 vs. 8.4 Phase IIII PFS 4.1 vs. 3.5 4.5 vs. 3.3 NA 9.2 vs. 7.6 NA 3.9 vs. 3.0 2.6 vs. 1.5 9.9 vs. 11.7 5.3 vs. 5.4 Phase III 97.5% power: 6.0 vs. 8.7 months (HR: 0.69)] Enrolled 295 refractory and 342 sensitive patients OS 7.5 vs. 7.8 9.2 vs. 9.9 6.2 vs. 5.7 Inoue A, et al. J Clin Oncol. 2008;26(33):5401-5406. Jotte R, et al. J Clin Oncol. 2011;29(3):287-293. 11

Phase III 2 nd -line SCLC: ACT-1 Trial Small Cell Lung Cancer (SCLC) Extensive or Limited Disease Sensitive or refractory disease (Progression 90 or <90 days after completion of 1 st line chemotherapy, Response to 1 st line chemo) 1 prior chemotherapy regimen ECOG performance status 0-1 Stratified: Sensitive/Refractory; Extensive/Limited R A N D O M I Z E 2 to 1 AMR IV 40 mg/m 2 1x daily on d 1-3 q 3 w Topotecan IV 1.5 mg/m 2 1x daily on d 1-5 q 3 w Primary endpoint: Overall Survival Secondary endpoints: ORR, PFS, TTP, quality of life, safety, sparse PK Analyses: Interim (deaths = 294), Final (deaths = 490) [97.5% power: 6.0 vs. 8.7 months (HR: 0.69)] 12

Median OS in Sensitive and Refractory Patient Subgroups Survival Probability Survival Probability 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Sensitive Patients Topotecan Topotecan Time (months) Time (months) Amrubicin 0 3 6 9 12 15 18 21 24 27 30 33 Refractory Patients Amrubicin 0 3 6 9 12 15 18 21 24 27 AMR Topo HR N/events 225/168 117/89 AMR Topo HR N/events 199/168 96/86 P Value* OS (mo) 6.2 5.7 0.766 0.0469 95% CI 5.5-6.7 4.1-7.0 0.589 0.997 * Unstratified log-rank test P Value* OS (mo) 9.2 9.9 0.936 0.6164 95% CI 8.5-10.6 8.5-11.5 0.724 1.211 13

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC - Non-Randomized Cohort 100 90 Events/number at risk Median OS, months (95% CI) Minimum followup, a months 80 Nivolumab 82/98 4.1 (3.0, 6.8) 19.6 70 Nivolumab + Ipilimumab 47/61 7.8 (3.6, 14.2) 20.2 OS (%) 60 50 40 30 1-yr OS = 40% 1-yr OS = 27% 2-yr OS = 26% 20 10 2-yr OS = 14% Number of patients at risk Nivolumab Nivolumab + Ipilimumab 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) 98 56 39 35 26 21 17 12 7 7 6 4 4 0 61 43 33 28 24 21 19 16 14 7 3 1 1 0 OS = overall survival; a Between first dose and database lock; follow-up shorter for patients who died prior to database lock Antonia SJ, et al. Lancet Oncol. 2016;17(7):883-895. 14

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC - 3-month PFS a and OS Rates Nivo randomized cohort Nivo + ipi randomized cohort Nivo non-randomized cohort Nivo + ipi non-randomized cohort 70 90 60 80 50 70 60 PFS (%) 40 30 20 10 18 30 27 36 OS (%) 50 40 30 20 10 65 64 59 72 0 n 147 95 98 61 n 0 147 95 98 61 Randomized cohort Non-randomized cohort Randomized cohort Non-randomized cohort Minimum follow-up time was 12 weeks at the time of database lock PFS = progression-free survival; Error bars indicate 95% CIs; a Per BICR Antonia SJ, et al. Lancet Oncol. 2016;17(7):883-895. 15

Phase II study of maintenance pembrolizumab in extensive stage small cell lung cancer patients Shirish M. Gadgeel, Jaclyn Ventimiglia, Gregory P. Kalemkerian, Mary J. Fidler, Wei Chen, Ammar Sukari, Balazs Halmos, Julie Boerner, Antoinette Wozniak, Cathy Galasso, Nathan A. Pennell

Progression Free Survival 1.0 N = 45 90% CI PFS (probability) 0.8 0.6 Median PFS 1.4 mo. 1.3-2.8 6-month PFS 21% 0.12-0.32 0.4 0.2 0.0 0 3 6 9 12 15 18 Month from first date of treatment No. at risk 45 17 9 5 2 0 0 Gadgeel SM, et al. J Clin Oncol. 2017;35(suppl): Abstract 8504. 17

Immunotherapy in SCLC Phase II trial of ipilimumab + chemotherapy Phase III trial of ipilimumab + chemotherapy Reck M, et al. Ann Oncol. 2012;24(1):75-83. Reck M, et al. J Clin Oncol. 2016 Jul 25 [Epub ahead of print]. 18

Progress in SCLC management: Is it just movement or real motion? Facts do not cease to exist just because they are ignored! Aldous Leonard Huxley - British Author (1894 1963) 19

What does real progress look like 20

Strategies for novel targeted therapies for SCLC Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print]. 21

SCLC A Personalized Approach to Systemic Therapy Newly diagnosed SCLC - Chemotherapy Platinum-doublet responsive (70%) Predictive biomarker? Platinum-doublet refractory (30%) SCLC VS. 2 nd line chemotherapy or immunotherapy Relapsed SCLC Re-biopsy MYC amplified AURKA inhibitor Schalfen11+ PARP inhibitor DLL 3 + Rova-T Activating driver mutations Kinase inhibitor 22

Ongoing studies of targeted therapy for extensive stage small-cell lung cancer Sabari JK, et al. Nat Rev Clin Oncol. 2017 May 23 [Epub ahead of print]. 23

What will you do for your next newly diagnosed SCLC patient? Limited stage SCLC Extensive stage SCLC Doublet chemotherapy and XRT Consistent with SOC practice in 1992 Platinum doublet chemotherapy Same as SOC practice in 1985 24

Conclusion Res ipsa loquitur Thank you! 25