Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation
Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation
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DOI：
10.1200/jco.19.02931
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发表时间：
2020-05-01
影响因子：
45.3
通讯作者：
Kelsen, David P.
中科院分区：
文献类型：
--
作者：
O'Reilly, Eileen M.;Lee, Jonathan W.;Kelsen, David P.
目的 5% 至 9% 的胰腺导管腺癌 (PDAC) 发生于具有种系 BRCA1/2 或 PALB2 (gBRCA/PALB2+) 突变的患者。一项使用顺铂、吉西他滨和维利帕尼治疗的试验的 IB 期数据表明，该人群具有较高的缓解率 (RR)、疾病控制率 (DCR) 和总生存率 (OS)。我们设计了一项开放标签、随机、多中心、双臂 II 期试验，以研究顺铂和吉西他滨联合或不联合维利帕利治疗 gBRCA/PALB2+ PDAC。 患者和方法 符合条件的患者患有未经治疗的 gBRCA/PALB2+ PDAC，可测量 III 至 IV 期疾病，东部肿瘤合作组表现状态为 0 至 1。A 组患者的治疗包括 第3天和第10天静脉注射顺铂25 mg/m(2)和吉西他滨600 mg/m(2)； B组患者的治疗与A组患者的治疗相同，A组还接受veliparib 80 mg口服，每天两次，第1至12天，每3周一个周期。主要终点是使用西蒙两阶段设计分别评估 A 组和 B 组的 RR。次要终点是无进展生存期、DCR、OS、安全性和相关分析。 结果通过改良的意向治疗分析对 50 名患者进行了评估。 A 组的 RR 为 74.1%，B 组的 RR 为 65.2% (P = .55)；双臂都超过了预先设定的活动阈值。 A 组的 DCR 为 100%，B 组的 DCR 为 78.3% (P = .02)。 A 组的中位无进展生存期为 10.1 个月（95% CI，6.7 至 11.5 个月），B 组为 9.7 个月（95% CI，4.2 至 13.6 个月；P = 0.73）。 A 组的中位 OS 为 15.5 个月（95% CI，12.2 至 24.3 个月），B 组为 16.4 个月（95% CI，11.7 至 23.4 个月；P = 0.6）。整个队列的两年 OS 率为 30.6%（95% CI，17.8% 至 44.4%），3 年 OS 率为 17.8%（95% CI，8.1% 至 30.7%）。 A 组与 B 组的 3 至 4 级血液学毒性分别为：中性粒细胞减少症为 13 级 (48%) 与 7 级 (30%)；血小板减少症为 15 级 (55%) 为 2 级 (9%)；贫血为 14 级 (52%) 与 8 级 (35%)。 结论 顺铂和吉西他滨是晚期 gBRCA/PALB2+ PDAC 的有效治疗方案。同时使用 veliparib 并没有改善 RR。这些数据将顺铂和吉西他滨确立为 gBRCA/PALB2+ PDAC 的标准方法。
PURPOSEFive percent to 9% of pancreatic ductal adenocarcinomas (PDACs) develop in patients with a germline BRCA1/2 or PALB2 (gBRCA/PALB2+) mutation. Phase IB data from a trial that used cisplatin, gemcitabine, and veliparib treatment demonstrated a high response rate (RR), disease control rate (DCR), and overall survival (OS) in this population. We designed an open-label, randomized, multicenter, two-arm phase II trial to investigate cisplatin and gemcitabine with or without veliparib in gBRCA/PALB2+ PDAC.PATIENTS AND METHODSEligible patients had untreated gBRCA/PALB2+ PDAC with measurable stage III to IV disease and Eastern Cooperative Oncology Group performance status of 0 to 1. Treatment for patients in arm A consisted of cisplatin 25 mg/m(2) and gemcitabine 600 mg/m(2) intravenously on days 3 and 10; treatment for patients in arm B was the same as that for patients in arm A, and arm A also received veliparib 80 mg orally twice per day on days 1 to 12 cycled every 3 weeks. The primary end point was RRs of arm A and arm B evaluated separately using a Simon two-stage design. Secondary end points were progression-free survival, DCR, OS, safety, and correlative analyses.RESULTSFifty patients were evaluated by modified intention-to-treat analysis. The RR for arm A was 74.1% and 65.2% for arm B (P = .55); both arms exceeded the prespecified activity threshold. DCR was 100% for arm A and 78.3% for arm B (P = .02). Median progression-free survival was 10.1 months for arm A (95% CI, 6.7 to 11.5 months) and 9.7 months for arm B (95% CI, 4.2 to 13.6 months; P = .73). Median OS for arm A was 15.5 months (95% CI, 12.2 to 24.3 months) and 16.4 months for arm B (95% CI, 11.7 to 23.4 months; P = .6). Two-year OS rate for the entire cohort was 30.6% (95% CI, 17.8% to 44.4%), and 3-year OS rate was 17.8% (95% CI, 8.1% to 30.7%). Grade 3 to 4 hematologic toxicities for arm A versus arm B were 13 (48%) versus seven (30%) for neutropenia, 15 (55%) versus two (9%) for thrombocytopenia, and 14 (52%) versus eight (35%) for anemia.CONCLUSIONCisplatin and gemcitabine is an effective regimen in advanced gBRCA/PALB2+ PDAC. Concurrent veliparib did not improve RR. These data establish cisplatin and gemcitabine as a standard approach in gBRCA/PALB2+ PDAC.