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Debate 1Are 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

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

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

  4. 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 . Winship Cancer Institute | Emory University 4

  5. AURORA Kinase inhibitor, Alisertib in SCLC Primary endpoint: PFS (ITT population) Treatment group: Alisertib + Paclitaxel Placebo + Paclitaxel Censored Observations: Alisertib + Paclitaxel Placebo + Paclitaxel 1.0 Median PFS: 101 days (3.32 months) vs 66 days (2.17 months) Survival Probability 0.9 0.8 CORRECTED 0.7 0.6 Hazard Ratio (95% CI): 0.71 (0.509–0.985) 0.5 Log rank p-value: 0.038 0.4 0.3 0.2 0.1 0 0 30 60 90 120 150 180 210 240 270 300 Survival Time (days) 89 74 55 41 28 13 10 6 3 0 0 Alisertib + Paclitaxel 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 Winship Cancer Institute | Emory University 5

  6. PFS improvement in patients w ith c-Myc expression* c-Myc Positive, PFS c-Myc positive † 1.00 Arm Median PFS 0.75 n Survival (months) Alisertib + Paclitaxel 0.50 Placebo + Paclitaxel 17 4.64 Alisertib + Paclitaxel 0.25 16 2.27 Placebo + Paclitaxel 0 Hazard Ratio (95% CI) 0.29 (0.12–0.72) 0 100 200 300 Days P binary = 0.0006 c-Myc Negative, PFS 1.00 c-Myc negative ‡ 0.75 Arm Median PFS Survival n (months) Alisertib + Paclitaxel 0.50 Placebo + Paclitaxel 6 3.32 Alisertib + Paclitaxel 0.25 Placebo + Paclitaxel 7 5.16 0 0 100 200 300 11.8 (1.52–91.2) Hazard Ratio (95% CI) Days • * 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. • Winship Cancer Institute | Emory University 6

  7. PARP Inhibition: E2511 Study Design Extensive stage SCLC Previously untreated Good renal and hepatic function Exclusion: Stratification: Brain metastasis • Gender (Male vs. Female) ECOG PS ≥2 • LDH ( ≤ ULN vs. > ULN) Cisplatin (75mg/m 2 ) D1 Cisplatin (75mg/m 2 ) D1 Etoposide (100mg/m 2 ) D1, 2, 3 Etoposide (100mg/m 2 ) D1, 2, 3 Veliparib (100mg bid) D1-7 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 ASCO Annual Meeting, 2017 PCI at the discretion of the treating physician • • Consolidation TRT was not allowed Owonikoko TK, et al. J Clin Oncol. 2017;35(suppl): Abstract 8505. Winship Cancer Institute | Emory University 7

  8. Progression Free Survival OS HR: 0.83 (80% CI 0.64-1.07); 1-sided p=0.17. Unadjusted PFS HR: 0.75; 1 -sided p=0.06 Median OS: 10.3 vs. 8.9 months for CE+V and CE+P respectively 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. Winship Cancer Institute | Emory University 8

  9. CALGB 30504 – Maintenance sunitinb Ready N, et al. J Clin Oncol . 2015;33(15):1660-1665. Winship Cancer Institute | Emory University 9

  10. PCI for extensive stage SCLC: One step forw ard 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. Winship Cancer Institute | Emory University 10

  11. Phase II studies of Amrubicin vs. Topotecan in extensive stage SCLC Overall Sensitive Refractory Jotte et al. PFS 4.5 vs. 4.5 vs. 3.3 NA 3.3 OS 9.2 vs. 9.2 vs. 7.6 NA 7.6 Inoue et al. PFS 3.5 vs. 3.9 vs. 3.0 2.6 vs. 1.5 2.2 OS 8.1 vs. 9.9 vs. 11.7 5.3 vs. 5.4 8.4 Phase III Phase III 97.5% power: 6.0 vs. 8.7 months (HR: Assumptions 0.69)] Enrolled 295 refractory and 342 sensitive patients Phase IIII PFS 4.1 vs. 3.5 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. Winship Cancer Institute | Emory University 11

  12. Phase III 2 nd -line SCLC: ACT-1 Trial R • Small Cell Lung Cancer (SCLC) AMR IV A 40 mg/m 2 • Extensive or Limited Disease N 1x daily on D • Sensitive or refractory disease d 1-3 q 3 w O (Progression ≥ 90 or <90 days after M completion of 1 st line chemotherapy, I Response to 1 st line chemo) Z • 1 prior chemotherapy regimen E Topotecan IV • ECOG performance status 0-1 1.5 mg/m 2 2 1x daily on • Stratified: Sensitive/Refractory; to d 1-5 q 3 w 1 Extensive/Limited • 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)] Winship Cancer Institute | Emory University 12

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

  14. CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC - Non-Randomized Cohort 100 Events/number Median OS, Minimum follow- up, a months 90 at risk months (95% CI) Nivolumab 82/98 4.1 (3.0, 6.8) 19.6 80 Nivolumab + Ipilimumab 47/61 7.8 (3.6, 14.2) 20.2 70 60 OS (%) 50 1-yr OS = 40% 40 2-yr OS = 26% 1-yr OS = 27% 30 20 10 2-yr OS = 14% 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Time (months) Number of patients at risk Nivolumab 98 56 39 35 26 21 17 12 7 7 6 4 4 0 Nivolumab + Ipilimumab 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. Winship Cancer Institute | Emory University 14

  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 70 90 80 60 70 50 60 PFS (%) OS (%) 40 50 40 30 72 65 64 30 59 20 36 20 30 27 10 10 18 0 0 n 147 95 98 61 n 147 95 98 61 Randomized Non-randomized Randomized Non-randomized cohort cohort cohort 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. Winship Cancer Institute | Emory University 15

  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) 0.8 Median PFS 1.4 mo. 1.3-2.8 0.6 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. Winship Cancer Institute | Emory University 17

  18. Immunotherapy in SCLC Phase III trial of ipilimumab + chemotherapy Phase II 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]. Winship Cancer Institute | Emory University 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 (1894 –1963) Winship Cancer Institute | Emory University 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. 2017 May 23 [Epub ahead of print]. Winship Cancer Institute | Emory University 21

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