Department of Oncology, Johns Hopkins University School of Medicine, SKCC, Washington, DC.
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
Clin Cancer Res. 2020 Oct 1;26(19):5092-5101. doi: 10.1158/1078-0432.CCR-20-1301. Epub 2020 Jul 15.
Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as , or . Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined.
We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1-7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations.
The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%.
The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation.
多达 17%的胰腺导管腺癌 (PDAC) 患者携带同源重组、DNA 损伤反应和修复 (HR-DDR) 基因中的致病变异体 (种系或体细胞) 突变，如 、或 。铂类化疗或 PARP 抑制剂治疗对这些患者特别有益。然而，当铂类药物和 PARP 抑制剂联合使用时，可能会有更大的获益。
我们对 PARP 抑制剂维利帕利与氟尿嘧啶（无氟尿嘧啶推注）和奥沙利铂（FOLFOX）联合用于转移性 PDAC 患者进行了一项单臂、开放标签、I/II 期研究。31 名患者入组了维利帕利的 I 期剂量递增（40 mg 至 250 mg，每日两次，每 14 天周期的第 1-7 天），以确定维利帕利联合用药的推荐 II 期剂量（RP2D）。另外 33 名患者入组了两项平行的 II 期试验，以评估未经治疗或既往治疗患者的客观缓解率（ORR）。如果有条件，收集种系或体细胞检测以鉴定致病变异体 HR-DDR 突变。
维利帕利和 FOLFOX 联合应用时，维利帕利的 RP2D 为每日两次 200 mg，耐受性良好。两个 II 期队列的主要终点均达到，总体 ORR 为 26%。在铂类药物初治患者和携带致病变异体 HR-DDR 突变的患者中，疗效更好。具体来说，HR-DDR 突变、铂类药物初治患者的 ORR 为 57%。
维利帕利和 FOLFOX 联合应用于转移性 PDAC 患者安全，在携带致病变异体 HR-DDR 突变的铂类药物初治疾病患者中表现出有前景的疗效。
