Langer Corey J, Albert Istvan, Ross Helen J, Kovacs Peter, Blakely L Johnetta, Pajkos Gabor, Somfay Attila, Zatloukal Petr, Kazarnowicz Andrzej, Moezi Mehdi M, Schreeder Marshall T, Schnyder Judy, Ao-Baslock Ada, Pathak Ashutosh K, Berger Mark S
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, United States.
Mátrai Gyógyintézet, Mátraháza, Hungary.
Lung Cancer. 2014 Sep;85(3):420-8. doi: 10.1016/j.lungcan.2014.05.003. Epub 2014 May 13.
This randomized phase II study assessed the efficacy and safety of obatoclax mesylate, a small-molecule Bcl-2 inhibitor, added to carboplatin/etoposide chemotherapy as initial treatment for extensive-stage small-cell lung cancer (ES-SCLC).
Chemotherapy-naïve subjects with ES-SCLC and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 received carboplatin/etoposide with (CbEOb) or without (CbE) obatoclax for up to six cycles. Responders to CbEOb could receive maintenance obatoclax until disease progression. The primary endpoint was objective response rate (ORR).
155 subjects (median age 62, 58% male, 10% ECOG PS 2) were treated with CbEOb (n=77) or CbE (n=78); 65% and 59% of subjects, respectively, completed six cycles. ORR was 62% with CbEOb versus 53% with CbE (1-sided p=0.143). Clinical benefit (ORR+ stable disease) trended better with CbEOb (81% versus 68%; p=0.054). Median progression-free survival (PFS) and overall survival (OS) were 5.8 months (95% confidence interval [CI]: 5.3-6.5) and 10.5 months (8.9-13.8) with CbEOb and 5.2 months (95% CI: 4.1-5.7) and 9.8 months (7.2-11.2) with CbE. Median OS was 10.5 months (95% CI: 8.9-13.8) and 9.8 months (7.2-11.2) with a nonsignificant hazard ratio for OS, 0.823; 1-sided p=0.121. Grade 3/4 adverse events (AEs) were primarily hematologic and similar in frequency between treatment arms. Obatoclax-related somnolence and euphoria were grade 1/2, transient, and did not require treatment discontinuation.
Obatoclax was well tolerated when added to carboplatin/etoposide in first-line treatment of ES-SCLC, but failed to significantly improve ORR, PFS, or OS.
本随机II期研究评估了甲磺酸 obatoclax（一种小分子Bcl-2抑制剂）联合卡铂/依托泊苷化疗作为广泛期小细胞肺癌（ES-SCLC）初始治疗的疗效和安全性。
既往未接受过化疗、ECOG体能状态（ECOG PS）为0-2的ES-SCLC患者接受卡铂/依托泊苷联合（CbEOb）或不联合（CbE）obatoclax治疗，最多6个周期。CbEOb治疗的缓解者可接受维持obatoclax治疗直至疾病进展。主要终点为客观缓解率（ORR）。
155例患者（中位年龄62岁，58%为男性，10%为ECOG PS 2）接受了CbEOb（n=77）或CbE（n=78）治疗；分别有65%和59%的患者完成了6个周期的治疗。CbEOb组的ORR为62%，CbE组为53%（单侧p=0.143）。临床获益（ORR+疾病稳定）CbEOb组趋势更佳（81%对68%；p=0.054）。CbEOb组的中位无进展生存期（PFS）和总生存期（OS）分别为5.8个月（95%置信区间[CI]：5.3-6.5）和10.5个月（8.9-13.8），CbE组分别为5.2个月（95%CI：4.1-5.7）和9.8个月（7.2-11.2）。OS的中位生存期分别为10.5个月（95%CI：8.9-13.8）和9.8个月（7.2-11.2），OS的风险比无统计学意义，为0.823；单侧p=0.121。3/4级不良事件（AE）主要为血液学方面，各治疗组发生率相似。与obatoclax相关的嗜睡和欣快感为1/2级，短暂性，无需停药。
在ES-SCLC的一线治疗中，obatoclax联合卡铂/依托泊苷耐受性良好，但未能显著改善ORR、PFS或OS。
