A randomized phase II study of carboplatin (C) and etoposide (E) with or without pan-BCL-2 antagonist obatoclax (Ob) in extensive-stage small cell lung cancer (ES-SCLC).

Abstract

7001 Background: Ob is a pan-BCL-2 antagonist that is synergistic in vitro with cisplatin and E. A phase I study concluded that a 3-hr Ob infusion in combination with C and E was favored over a 24-hr infusion (ASCO 2010, Ab e13531). Methods: Patients (pts) with chemotherapy-naive ES-SCLC, measurable disease, and PS 0-2 were randomized to receive six 21-day cycles of CE (C AUC 5 D1, and E 100 mg/m2 D1-3) or CEOb (CE plus Ob [30 mg as a 3-hr infusion D1-3]). 73 evaluable pts were planned for each arm. 1° endpoint was ORR (confirmed CR & PR); 2° endpoints included PFS and OS. After completing 6 cycles, responders received prophylactic cranial irradiation; pts on CEOb continued Ob as maintenance therapy. Results: 165 pts were randomized; 155 pts (77 CEOb; 78 CE) received treatment. The arms were well balanced for gender, PS, and metastatic sites; 21% in each arm had brain mets. CNS adverse events (AEs) (such as somnolence [46% all grades] and euphoric mood [31% all grades]) occurred during and shortly after the Ob infusion. The only Grade 3/4 non-heme AE with ≥ 5% increase in absolute frequency in the Ob arm was somnolence (8 vs 0%). Grade 3/4 febrile neutropenia was rare (5% both arms). Grade 3/4 hematologic lab data were similar for each arm (CEOb vs CE): anemia (8 vs 15%), neutropenia (61 vs 58%), and thrombocytopenia (17 vs 10%). 74% of the pts on the CEOb arm alive without progression after 6 cycles started maintenance therapy. Efficacy data, including death or progression during initial 6 cycles of chemotherapy (refractory rate) are summarized in the table below. Conclusions: The CEOb arm demonstrated a trend for improved ORR, PFS, 12 mo and overall survival (OS). Most importantly, consistent with its in vitro synergy, Ob markedly decreased the rate of refractoriness to the initial 6 cycles of chemotherapy by 36.5%. Pts with screening PS of 2 did poorly in either arm; OS in PS 0-1 pts will be evaluated in a phase III trial comparing CE to CEOb. Study arm ORR PFS 12-month survival OS OS (PS 0-1) Refractory rate (PS 0-1) CEOb 64.9% 6.0 mos* 45.5% 10.6 mos* 11.9 mos* 25.4% CE 53.8% 5.4 mos* 37.2% 9.9 mos* 10.1 mos* 40.0% One-sided p value 0.11 0.08 0.19 0.0506 0.052 0.05 Hazard ratio - 0.79 - 0.72 0.71 - * Median