Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study
Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study
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DOI：
10.1634/theoncologist.2019-0473
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发表时间：
2019-11-19
期刊：
影响因子：
5.8
通讯作者：
Mulcahy, Mary
中科院分区：
文献类型：
--
作者：
Kamath, Suneel D.;Kalyan, Aparna;Mulcahy, Mary
背景胰腺导管腺癌（PDAC）由于其促纤维增生间质和免疫抑制肿瘤微环境的存在，对化疗和免疫治疗仍具有耐药性。协同细胞毒性T淋巴细胞相关抗原4（CTLA-4）免疫检查点阻断与化疗可以克服这些障碍。在这里，我们介绍了一项Ib期试验，伊匹单抗和吉西他滨联合治疗晚期PDAC的结果。材料和方法这是一项单机构研究，采用3 + 3剂量递增设计。主要目的是确定最大耐受剂量（MTD）。次要目的包括确定毒性特征、客观缓解率（ORR）、中位无进展生存期（PFS）和总生存期（OS）。结果21例患者入组，13例在剂量递增期间，8例在MTD。中位年龄为66岁，62%为女性，95%患有IV期疾病，67%既往接受过至少一线治疗。在伊匹单抗3 mg/kg和吉西他滨1，000 mg/m2的剂量下实现了确立MTD的主要目标（2）。最常见的3级或4级不良事件为贫血（48%）、白细胞减少症（48%）和中性粒细胞减少症（43%）。ORR为14%（3/21），7例患者病情稳定。三名应答者的中位应答持续时间为11个月，其中一名应答持续时间为19.8个月。中位PFS为2.78个月（95%置信区间[CI]，1.61-4.83个月），中位OS为6.90个月（95% CI，2.63-9.57个月）。结论吉西他滨联合伊匹单抗治疗PDAC疗效与单用吉西他滨相似，是一种安全、可耐受的治疗方案。与其他免疫治疗试验一样，本研究中的反应相对持久。吉西他滨联合伊匹单抗治疗晚期胰腺癌安全可行。尽管本研究中的一名患者有近20个月的相对持久的反应，但在晚期胰腺癌中，吉西他滨加用伊匹单抗似乎并不比单用吉西他滨更有效。
Background Pancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC. Materials and Methods This was a single-institution study with a 3 + 3 dose-escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression-free survival (PFS), and overall survival (OS). Results Twenty-one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m(2). The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61-4.83 months), and median OS was 6.90 months (95% CI, 2.63-9.57 months). Conclusion Gemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study. Implications for Practice Gemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.