Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC. Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy ([NCT02826486][1]). Subjects received a priming phase of motixafortide daily on days 1–5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability. Results: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen. Conclusions: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02826486&atom=%2Fclincanres%2F27%2F18%2F5020.atom

中文翻译：

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Motixafortide 和 Pembrolizumab 联合纳米脂质体伊立替康、氟尿嘧啶和亚叶酸治疗转移性胰腺癌：COMBAT/KEYNOTE-202 试验

目的：胰腺导管腺癌 (PDAC) 在很大程度上对检查点抑制剂无反应。CXCR4/CXCL12 轴的阻断增加了活化 T 细胞的肿瘤内运输，同时抑制了免疫抑制元件。本研究评估了 PDAC 中化疗对 CXCR4 和 PD1 的双重阻断。患者和方法：多中心、单臂、II 期研究，以评估莫替沙福肽和派姆单抗联合化疗在一线吉西他滨治疗中新发转移性 PDAC 和疾病进展患者的安全性和有效性（[NCT02826486][1 ]）。受试者在第 1-5 天每天接受莫替沙福特的启动阶段，然后每周两次重复循环莫替沙福特；派姆单抗每 3 周一次；和纳米脂质体伊立替康、氟尿嘧啶和亚叶酸每 2 周一次（NAPOLI-1 方案）。主要目标是客观反应率（ORR）。次要目标包括总生存期（OS）、无进展生存期（PFS）、疾病控制率（DCR）、安全性和耐受性。结果：共纳入 43 名患者。根据 RECISTv1.1，ORR 为 21.1%，确认的 ORR 为 13.2%。DCR 为 63.2%，中位临床获益持续时间为 5.7 个月。在意向治疗人群中，中位 PFS 为 3.8 个月，中位 OS 为 6.6 个月。三联疗法安全且耐受性良好，毒性与 NAPOLI-1 方案相当。值得注意的是，3 级或更高级别的中性粒细胞减少和感染的发生率为 7%，低于该化疗方案的预期。结论：motixafortide、pembrolizumab 和化疗的三联组合安全且耐受性良好，并在预后不良和侵袭性疾病的人群中显示出疗效迹象。[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02826486&atom=%2Fclincanres%2F27%2F18%2F5020.atom