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

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1 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

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

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

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

5 AURORA Kinase inhibitor, Alisertib in SCLC Primary endpoint: PFS (ITT population) Survival Probability Treatment group: Censored Observations: Alisertib + Paclitaxel 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 ( ) Log rank p-value: Alisertib + Paclitaxel Placebo + Paclitaxel Disease progression evaluated according to RECIST v Owonikoko T, et al. Presented at: 17 th World congress on Lung Cancer. December 4-7, Vienna, Austria. Abstract: MA

6 PFS improvement in patients with c-myc expression* Survival Survival c-myc Positive, PFS Days c-myc Negative, PFS Days Alisertib + Paclitaxel Placebo + Paclitaxel P binary = 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 Placebo + Paclitaxel Hazard Ratio (95% CI) 0.29 ( ) Arm n c-myc negative Median PFS (months) Alisertib + Paclitaxel Placebo + Paclitaxel Hazard Ratio (95% CI) 11.8 ( ) 6

7 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

8 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 OS HR: 0.83 (80% CI ); 1-sided p=0.17. Median OS: 10.3 vs. 8.9 months for CE+V and CE+P respectively 8

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

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

11 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 vs. 3.3 NA 9.2 vs. 7.6 NA 3.9 vs vs vs 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 vs vs. 5.7 Inoue A, et al. J Clin Oncol. 2008;26(33): Jotte R, et al. J Clin Oncol. 2011;29(3):

12 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

13 Median OS in Sensitive and Refractory Patient Subgroups Survival Probability Survival Probability Sensitive Patients Topotecan Topotecan Time (months) Time (months) Amrubicin Refractory Patients Amrubicin AMR Topo HR N/events 225/ /89 AMR Topo HR N/events 199/168 96/86 P Value* OS (mo) % CI * Unstratified log-rank test P Value* OS (mo) % CI

14 CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC - Non-Randomized Cohort Events/number at risk Median OS, months (95% CI) Minimum followup, a months 80 Nivolumab 82/ (3.0, 6.8) Nivolumab + Ipilimumab 47/ (3.6, 14.2) 20.2 OS (%) yr OS = 40% 1-yr OS = 27% 2-yr OS = 26% yr OS = 14% Number of patients at risk Nivolumab Nivolumab + Ipilimumab Time (months) 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):

15 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 PFS (%) OS (%) n n 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):

16 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

17 Progression Free Survival 1.0 N = 45 90% CI PFS (probability) Median PFS 1.4 mo month PFS 21% Month from first date of treatment No. at risk Gadgeel SM, et al. J Clin Oncol. 2017;35(suppl): Abstract

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

19 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 ( ) 19

20 What does real progress look like 20

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

22 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

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

24 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

25 Conclusion Res ipsa loquitur Thank you! 25