双盲、安慰剂对照、随机 2 期研究显示促凋亡剂 AT-101 联合多西他赛二线治疗非小细胞肺癌的疗效。

Double-blind, placebo-controlled, randomized phase 2 study of the proapoptotic agent AT-101 plus docetaxel, in second-line non-small cell lung cancer.

机构信息

Duke University Medical Center, Durham, NC, USA.

出版信息

J Thorac Oncol. 2011 Apr;6(4):781-5. doi: 10.1097/JTO.0b013e31820a0ea6.

DOI:10.1097/JTO.0b013e31820a0ea6

PMID:21289522

Abstract

BACKGROUND

AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models.

METHODS

We conducted a prospective, randomized (1:1), double-blind, placebo-controlled phase 2 study. Eligible patients must have received one prior chemotherapeutic regimen for advanced or metastatic non-small cell lung cancer and may also have received therapy with an epidermal growth factor receptor inhibitor. Patients received AT-101 (40 mg b.i.d. × 3 days) or placebo in combination with docetaxel (75 mg/m on day 1) every 21 days. The primary endpoint was progression-free survival (PFS) as determined by independent review; other endpoints include overall survival and PFS by investigator determination. Approximately 102 patients were planned to provide 70 events (80% power, hazard ratio [HR] of 0.6, one-sided alpha of 0.1).

RESULTS

: One hundred six patients were assigned to treatment and 105 patients received at least one dose of AT-101 or placebo. Baseline factors were balanced between treatment groups: median age 59 years; 77% men, and 79% current or former smokers. Ninety-three percent of patients had distant metastatic disease at randomization and 56% squamous histology. The most frequently reported adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). No statistically significant differences in serious adverse events were observed between AT-101 and placebo; grade 1/2 headaches appeared more frequently with AT-101 (9% versus 0%) and neutropenia was reported more frequently in the docetaxel plus placebo arm compared with docetaxel plus AT-101 (17% versus 8%). Unlike trials with continuous daily dosing of AT-101, no cases of small bowel obstruction were reported. The response rate and median PFS were not different between the arms by independent review, PFS 7.5 weeks for docetaxel plus AT-101 and 7.1 weeks for docetaxel plus placebo arms (HR, 1.04; p = 0.57). The median overall survival was 7.8 months for docetaxel plus AT-101 versus 5.9 months for docetaxel plus placebo (HR, 0.82; p = 0.21).

CONCLUSIONS

The primary endpoint of improved PFS for AT-101 plus docetaxel was not met. AT-101 plus docetaxel was well tolerated with an adverse event profile indistinguishable from the base docetaxel regimen. AT-101 is the first oral, pan Bcl-2 family inhibitor to exhibit a possible survival benefit in a randomized study.

摘要

背景

AT-101 是一种 Bcl-2 家族蛋白抑制剂，包括 Bcl-2、Bcl-xL、Mcl-1 和 Bcl-w。体内和体外研究表明 AT-101 具有广泛的活性，包括与多西他赛在非小细胞肺癌肿瘤模型中的协同作用。

方法

我们进行了一项前瞻性、随机（1:1）、双盲、安慰剂对照的 2 期研究。合格的患者必须接受过一种用于晚期或转移性非小细胞肺癌的一线化疗方案，并且可能还接受过表皮生长因子受体抑制剂的治疗。患者接受 AT-101（40mgbid×3 天）或安慰剂联合多西他赛（75mg/m 第 1 天），每 21 天一次。主要终点是独立评估的无进展生存期（PFS）；其他终点包括研究者评估的总生存期和 PFS。计划约 102 例患者提供 70 例事件（80%的效力，风险比[HR]为 0.6，单侧α为 0.1）。

结果

106 例患者被分配至治疗组，105 例患者至少接受了一次 AT-101 或安慰剂治疗。治疗组之间的基线因素平衡：中位年龄 59 岁；77%为男性，79%为现吸烟者或既往吸烟者。93%的患者在随机分组时存在远处转移疾病，56%为鳞状组织学。最常报告的不良事件是疲劳（18%）、贫血（18%）和呼吸困难（18%）。AT-101 和安慰剂之间未观察到严重不良事件的统计学差异；1 级/2 级头痛更常发生于 AT-101 组（9% vs 0%），与多西他赛联合安慰剂组相比，多西他赛联合 AT-101 组报告的中性粒细胞减少症更为常见（17% vs 8%）。与连续每日剂量 AT-101 的试验不同，未报告小肠梗阻病例。独立评估的缓解率和中位 PFS 无差异，多西他赛联合 AT-101 组的 PFS 为 7.5 周，多西他赛联合安慰剂组为 7.1 周（HR，1.04；p=0.57）。多西他赛联合 AT-101 组的中位总生存期为 7.8 个月，多西他赛联合安慰剂组为 5.9 个月（HR，0.82；p=0.21）。