Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes
Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes
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DOI：
10.1016/j.eururo.2017.12.001
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发表时间：
2018-05-01
期刊：
影响因子：
23.4
通讯作者：
Uzilov, Andrew V.
中科院分区：
文献类型：
--
作者：
Galsky, Matthew D.;Wang, Huan;Uzilov, Andrew V.
背景：化疗可能发挥免疫调节作用，从而与免疫检查点阻断有利地结合。此类组合的药效作用和潜在的预测生物标志物尚未得到探索。 目的：确定吉西他滨和顺铂 (GC) 加伊匹单抗的安全性、有效性和免疫调节作用，并探讨体细胞 DNA 损伤反应基因改变对抗肿瘤活性的影响。 设计、设置和参与者：多中心单臂 2 期研究，招募了 36 名初治过化疗的转移性尿路上皮癌患者。对所有患者连续进行外周血流式细胞术，并对 28/36 名患者进行存档肿瘤组织的全外显子组测序。干预：两个周期的 GC，然后是四个周期的 GC 加伊匹单抗。结果测量和统计分析：主要终点是 1 年总生存 (OS)。次要终点包括安全性、客观缓解率和无进展生存期。结果和局限性：81% 的患者发生 3 级以上不良事件，其中大多数是血液学不良事件。客观缓解率为 69%，1 年 OS 为 61%（90% 置信区间下限：51%）。探索性分析表明，单独 GC 后循环免疫细胞的组成和频率没有显着变化。然而，添加伊匹单抗后，循环 CD4 细胞显着增加，这与生存率的提高相关。具有有害体细胞 DNA 损伤反应突变的患者的反应率显着较高（敏感性 = 47.6%，特异性 = 100%，阳性预测值 = 100%，阴性预测值 = 38.9%）。局限性与样本量和单臂设计有关。结论：GC + ipilimumab 未达到 1 年 OS >60% 的 90% 置信区间下限这一主要终点。然而，在小型单臂试验的背景下，从可行性、适当的细胞毒性骨架和潜在的预测生物标志物的角度来看，结果可能会为当前化疗加免疫疗法相结合的方法提供信息。试验注册：ClinicalTrials.gov NCT01524991。患者总结：在转移性尿路上皮癌患者中联合化疗和免疫检查点阻断是可行的。需要进一步的研究来完善最佳组合并评估可能识别最有可能受益的患者的测试。 (C) 2017 年欧洲泌尿外科协会。由 Elsevier B.V. 出版。保留所有权利。
Background: Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored.Objective: To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity.Design, setting, and participants: Multicenter single arm phase 2 study enrolling 36 chemotherapy-naive patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients.Intervention: Two cycles of GC followed by four cycles of GC plus ipilimumab.Outcome measurements and statistical analysis: The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival.Results and limitations: Grade >= 3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity = 47.6%, specificity = 100%, positive predictive value = 100%, and negative predictive value = 38.9%). Limitations are related to the sample size and single-arm design.Conclusions: GC + ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers. Trial registration: ClinicalTrials.gov NCT01524991.Patient summary: Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.