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New Developments in the Treatment of SCLC

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New Developments in the Treatment of SCLC

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  1. Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to obtain permission from the publication source and/or author. Links to view the actual reference materials have been provided for your use in place of any omitted slides.

  2. New Developments in the Treatment of SCLC Alan Sandler, MD Oregon Health & Science University

  3. Outline • Amrubicin vs topotecan in second-line SCLC • Randomized Phase II study of carboplatin & etoposide with or without pan-BCL-2 antagonist obatoclax in ES-SCLC • Bendamustine in previously treated SCLC

  4. Randomized Phase 3 Trial of Amrubicin versus Topotecan as Second-line Treatment for SCLC Although SCLC is often responsive to 1st-line chemotherapy, relapse remains common and prognosis is poor with 5-year OS of 6% Topotecan (Topo) is approved in the US and EU for 2nd-line SCLC treatment based on response rates of 11-31% in sensitive pts Amrubicin (AMR) is a 3rd-generation anthracycline and potent topoisomerase II inhibitor approved in Japan for treatment of SCLC and NSCLC Efficacy and safety of AMR and Topo were compared as 2nd-line treatment in patients with SCLC sensitive or refractory to 1st-line platinum-based chemotherapy Jotte, et al ASCO 2011

  5. Phase III 2nd-line SCLC: ACT-1 Trial R A N D O M I Z E 2 to1 • Small Cell Lung Cancer (SCLC) • Extensive or Limited Disease • Sensitive or refractory disease (Progression ≥90 or <90 days after completion of 1st-line chemotherapy, Response to 1st-line chemo) • 1 prior chemotherapy regimen • ECOG performance status 0-1 • Stratified: Sensitive/Refractory; Extensive/Limited AMR IV 40 mg/m2 1x daily on d 1-3 q 3 w Topotecan IV 1.5 mg/m2 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)]

  6. Baseline Characteristics

  7. PFS – ITT Population RR = 31.1 (A) vs 16.6% (T) p= 0.0001 * Unstratified log-rank test

  8. OS – ITT Population * Unstratified log-rank test

  9. Median OS in Sensitive and Refractory Patient Subgroups Sensitive Patients Refractory Patients * Unstratified log-rank test

  10. Most Frequently Observed Grade 3 or 4 TEAEs (≥ 5% in Any Treatment Group) by System Organ Class (Safety Population) P<0.05 for highlighted values.

  11. Randomized Phase II Study of Carboplatin & Etoposide with or without pan-BCL-2 Antagonist Obatoclax in Extensive Stage Small Cell Lung Cancer (ES-SCLC) C. Langer, I. Albert, P. Kovacs, J. Blakely, G. Pajkos, P. Petrov, A. Somfay, A. Szczesna, P. Zatloukal, A. Kazarnowicz, M. Moezi, M. Schreeder, J. Schnyder, M. S. Berger, and GEM017 ES-SCLC Investigators

  12. Obatoclax (Ob) • Pro-apoptotic small molecule • Mimetic of BCL-2 family BH3 proteins • Synergistic with cisplatin and etoposide in vitro

  13. Obatoclax Phase 2b: Trial Design Investigational Arm (CbEOb) N=77 Obatoclax 30 mg flat dose/3 hr days 1, 2 and 3 Carboplatin AUC 5 IV day 1 Etoposide 100 mg/m2 days 1, 2, 3 Tx every 3 wks X 6, followed by Maintenance obatoclax [single-agent - same schedule until PD] R Control Arm (CbE) N=78 Carboplatin AUC 5 IV day 1 Etoposide 100 mg/m2 days 1, 2, 3 Tx every 3 wks X 6 Primary endpoint - Response rate based on RECIST criteria

  14. Eligibility Criteria Extensive-stage SCLC No prior chemotherapy exposure PS 0-2 Age ≥ 18 yrs Adequate end-organ indices No symptomatic brain metastases

  15. Relevant Non-hematologic Toxicities (%)AEs ≥10% Difference Between Arms * Transient - During infusion

  16. Hematologic and Lab Toxicity

  17. Response Rate Analysis • All responses, including SD, confirmed by 2nd evaluation 6 + wks later • CR/PR/SD = disease control rate

  18. Overall Kaplan-Meier Actuarial Estimated PFS • CbE, 5.4 mos • CbeOb, 6.0 mos • Overall HR (CbEOb/CE) = 0.795 • p = 0.084

  19. Kaplan-Meier Actuarial Estimated Survival • CbE, 9.9 mos • CbeOb, 10.6 mos • Overall HR (CEOb/CE) = 0.724 • One-sided p-value = 0.052

  20. Kaplan-Meier Actuarial Estimated Survival in PS 0-1 Patients (PS at Screening) • CbE, 10.1 mos • CbeOb, 11.9 mos • Overall HR (CEOb/CE) = 0.711 • One-sided p-value = 0.054

  21. Survival by Chemotherapy Sensitivity Status in PS 0-1 Patients (PS at Screening) • CE Sensitive, 12.8 mos • CbEOb Sensitive, 15.4 mos • Sensitive HR (CbEOb/CE) = 0.732 • One-sided p-value = 0.146 Sensitive = Alive without progression after 6 cycles combination chemotherapy

  22. Bendamustine in SCLC • Bendamustine is an alkylating agent • Bendamustine in combination with carboplatin has shown efficacy as first line therapy in extensive stage SCLC with RR 73%, TTP 5.2 months and OS 8.3 months [Köster, et al, JTO 2007]. Lovely, et al ASCO 2012

  23. Bendamustine in 2nd/3rd line SCLC • Single-arm, multicenter phase II trial • Eligible patients had previously treated ES-SCLC, up to 2 prior regimens, ECOG performance status 0-2, evaluable/measurable disease, and adequate marrow, renal and hepatic function.  Patients with stable treated brain metastases were allowed • Patients were treated with bendamustine (120mg/m2 IV days 1 and 2 every 3 weeks) for up to 6 cycles • Primary endpoint was TTP; secondary endpoints include RR, PFS, OS, and toxicity

  24. Results • 48 patients were enrolled and 33 patients were evaluable for response. • 56% were male and 96% were Caucasian. • There was 1 CR, 9 PR, 13 SD (48% disease control rate). • Median TTP was 3.37 months (95% CI 2.30 to 4.47 months). • Median overall survival of 4.77 months (95% CI 3.67 to 6.07 months). 

  25. Toxicity • Grade 3/4 AEs included fatigue (18.8%), dyspnea (14.5%), infection without neutropenia (12.5%), anemia (8.3%), neutropenia (8.3%) and diarrhea (8.3%). • 5 patients (10.4%) required dose reductions due to AEs, 2 due to fatigue, 1 due to neutropenia, 1 due to pancytopenia and 1 due to pneumonia.

  26. Conclusions • Primary endpoint of OS in ITT was not significantly different (7.5 mo amrubicin vs. 7.8 mo topotecan, HR 0.880, p=0.1701). • An improvement in OS in refractory patients was observed (6.2 mo amrubicin vs. 5.7 mo topotecan, HR 0.766, p=0.0469). • In ES-SCLC, obatoclax in combination with carboplatin/etoposide (CbEOb) demonstrated a trend for improved ORR, PFS, and OS compared to CbE.

  27. Sunday, February 12, 2012Hollywood, Florida Co-Chairs Rogerio C Lilenbaum, MD Mark A Socinski, MD Co-Chair and Moderator Neil Love, MD Faculty Walter J Curran Jr, MD David Jablons, MD Mark G Kris, MD Suresh Ramalingam, MD Alan B Sandler, MD

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