Unit of Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
Clinical Trial Office, Scientific Direction, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
Cancer Treat Rev. 2024 Apr;125:102701. doi: 10.1016/j.ctrv.2024.102701. Epub 2024 Feb 27.
Various randomized trials have explored the efficacy of combining immune checkpoint inhibitors (ICIs) with first-line chemotherapy in advanced endometrial cancer. We aimed to summarize available data and clarify the benefit of adding immunotherapy according to the DNA mismatch repair status (deficient, dMMR or proficient, pMMR) and the specific type of agent used (anti-PD1 or anti-PD-L1).
To assess whether the addition of ICIs to standard platinum-based chemotherapy enhances progression-free survival (PFS) for patients with advanced endometrial cancer both overall and based on DNA mismatch repair status.
Electronic databases (PubMed, Embase and Cochrane Library) and conference proceedings were searched for first line, randomized and controlled trials integrating ICIs with chemotherapy for the treatment of advanced endometrial cancer published or presented by November 1, 2023.
Five studies, comprising 2456 patients (1308 received ICIs with chemotherapy and 1148 treated with chemotherapy alone) met the selection criteria and were included in the analysis. Experimental arms included pembrolizumab, dostarlimab (anti-PD1) and durvalumab, atezolizumab and avelumab (anti-PD-L1) combined with standard three-weekly carboplatin-paclitaxel chemotherapy backbone. Endometrial carcinosarcoma were included in 3 out of 5 trials.
For comparison of PFS outcomes, extrapolation of hazard ratios (HRs), 95% confidence intervals (CI) and PFS events was performed for each included study in the overall population and according to subgroups. Data analysis was conducted using a random-effects model.
The addition of ICIs to chemotherapy improved PFS compared to chemotherapy alone in the overall population (pooled HR, 0.63; 95 % CI, 0.52--0.76; P <.001). In the dMMR subgroup the benefit was more pronounced (pooled HR, 0.34; 95 % CI, 0.27--0.44; P <.001) and not affected by drugs used with pooled HRs of 0.39 (95 % CI, 0.28--0.55; P <.001) and 0.34 (95 % CI, 0.27--0.44; P <.001) for PD-L1 and PD1 inhibitors, respectively. For pMMR patients, a statistically significant benefit in terms of PFS was confirmed only when anti-PD1 were used (anti-PD-1: HR 0.64, 95 % CI: 0.46-0.90, P =.010 vs anti-PD-L1: HR 0.87, 95 % CI: 0.73-1.03, P =.104) CONCLUSIONS AND RELEVANCE: This meta-analysis confirmed the advantage in terms of PFS of adding ICIs to standard platinum-based chemotherapy. While dMMR patients benefit from the incorporation of both anti PD-1 or anti PD-L1, this benefit is confined to the association of anti-PD1 agents in pMMR patients. Updated analysis of trials is awaited to clarify the impact of immunotherapy on overall survival.
各种随机试验已经探索了将免疫检查点抑制剂（ICI）与一线化疗联合用于晚期子宫内膜癌的疗效。我们旨在总结现有数据，并根据 DNA 错配修复状态（缺陷，dMMR 或功能正常，pMMR）和使用的特定药物类型（抗 PD-1 或抗 PD-L1）来阐明添加免疫疗法的益处。
评估ICI 联合标准铂类化疗是否能提高晚期子宫内膜癌患者的无进展生存期（PFS），总体上以及根据 DNA 错配修复状态。
电子数据库（PubMed、Embase 和 Cochrane Library）和会议记录，搜索了截至 2023 年 11 月 1 日发表或展示的将 ICI 与化疗联合用于治疗晚期子宫内膜癌的一线、随机对照试验。
五项研究，共纳入 2456 名患者（1308 名接受 ICI 联合化疗，1148 名单独接受化疗）符合入选标准并纳入分析。实验臂包括 pembrolizumab、dostarlimab（抗 PD-1）和 durvalumab、atezolizumab 和 avelumab（抗 PD-L1），联合标准三周一次卡铂-紫杉醇化疗方案。5 项试验中有 3 项纳入了子宫内膜癌肉瘤。
为了比较 PFS 结果，对每个纳入研究在总体人群中和根据亚组进行了危险比（HR）、95%置信区间（CI）和 PFS 事件的外推。使用随机效应模型进行数据分析。
ICI 联合化疗与单独化疗相比，改善了晚期子宫内膜癌患者的 PFS（总体人群：合并 HR，0.63；95%CI，0.52-0.76；P<.001）。在 dMMR 亚组中，获益更为明显（合并 HR，0.34；95%CI，0.27-0.44；P<.001），且不受药物影响，合并 HR 分别为 0.39（95%CI，0.28-0.55；P<.001）和 0.34（95%CI，0.27-0.44；P<.001），用于 PD-L1 和 PD1 抑制剂。对于 pMMR 患者，仅当使用抗 PD-1 时才能在 PFS 方面确认具有统计学意义的获益（抗 PD-1：HR 0.64，95%CI：0.46-0.90，P=.010 vs 抗 PD-L1：HR 0.87，95%CI：0.73-1.03，P=.104）。
这项荟萃分析证实了在标准铂类化疗基础上加用 ICI 可提高 PFS。虽然 dMMR 患者受益于抗 PD-1 或抗 PD-L1 的联合应用，但这种益处仅限于 pMMR 患者中抗 PD1 药物的联合应用。期待对试验进行更新分析，以阐明免疫疗法对总生存期的影响。
