维利帕利联合替莫唑胺或卡铂/紫杉醇对比安慰剂联合卡铂/紫杉醇治疗 BRCA1/2 局部复发/转移性乳腺癌患者的随机 II 期研究。
Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study.
机构信息
Moffitt Cancer Center, Tampa, USA.
Institut Curie, Paris, France, USA.
出版信息
Ann Oncol. 2018 Jan 1;29(1):154-161. doi: 10.1093/annonc/mdx505.
BACKGROUND
Homologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer.
PATIENTS AND METHODS
Eligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1 : 1 : 1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR).
RESULTS
Of 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536-1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503-1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278-2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032-2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP.
CONCLUSION
Numerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population.
CLINICAL TRIAL INFORMATION
NCT01506609.
背景
BRCA1/2 突变肿瘤中的同源重组缺陷导致对聚（ADP-核糖）聚合酶抑制剂的敏感性，该抑制剂干扰 DNA 损伤修复。Veliparib 是一种强效的聚（ADP-核糖）聚合酶抑制剂，在早期临床试验中增强了铂类药物和替莫唑胺的抗肿瘤活性。本 II 期研究检查了在 BRCA1/2 突变的乳腺癌患者中，间歇使用 Veliparib 联合卡铂/紫杉醇（VCP）或替莫唑胺（VT）的安全性和疗效。
患者和方法
≥18 岁的局部复发性或转移性乳腺癌和有害 BRCA1/2 种系突变的患者符合条件，按 1：1：1 随机分配至 VCP、VT 或安慰剂联合卡铂/紫杉醇（PCP）组。主要终点是无进展生存期（PFS）；次要终点包括总生存期（OS）和总缓解率（ORR）。
结果
在 290 名随机患者中，284 名为 BRCA+，由中心实验室确认。与 PCP 相比，VCP 组的中位 PFS 为 14.1 个月和 12.3 个月[风险比（HR）0.789；95%置信区间（CI）0.536-1.162；P=0.227]，中位 OS 分别为 28.3 个月和 25.9 个月（HR 0.750；95%CI 0.503-1.117；P=0.156），ORR 分别为 77.8%和 61.3%（P=0.027）。与 PCP 相比，VT 组的中位 PFS 为 7.4 个月（HR 1.858；95%CI 1.278-2.702；P=0.001），中位 OS 为 19.1 个月（HR 1.483；95%CI 1.032-2.131；P=0.032），ORR 为 28.6%（P<0.001）。卡铂/紫杉醇组之间的安全性特征相当。与 PCP 相比，VT 组的中性粒细胞减少症、贫血、脱发和神经病变等所有等级的不良事件发生率较低。
结论
与 PCP 相比，接受 VCP 治疗的 BRCA1/2 突变复发性/转移性乳腺癌患者的 PFS 和 OS 均有数值上但无统计学意义的增加。与卡铂/紫杉醇联合使用 Veliparib 可显著提高 ORR。与 PCP 相比，VCP 并未增加毒性。一项正在进行的 III 期试验正在评估 VCP 与 PCP 的疗效，在该患者人群中，如果化疗未进展而停止，可选择继续使用 Veliparib/安慰剂进行单药治疗。
临床试验信息
NCT01506609。
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