Maiorano Brigida Anna, Maiorano Mauro Francesco Pio, Cormio Gennaro, Maglione Annamaria, Lorusso Domenica, Maiello Evaristo
Oncology Department, Fondazione Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo, Italy.
Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy.
Front Oncol. 2022 Apr 14;12:844801. doi: 10.3389/fonc.2022.844801. eCollection 2022.
Endometrial cancer (EC) represents the sixth most common female tumor. In the advanced setting, the prognosis is dismal with limited treatment options. Platinum-based chemotherapy represents the actual standard of care in first-line chemotherapy, but no standard second-line chemotherapy is approved, with less than 1/4 of patients responding to second-line chemotherapy. In the last 10 years, immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many solid tumors.
The review was conducted according to the PRISMA guidelines. We searched EMBASE, MEDLINE, Cochrane Database, and conference abstracts from international societies, up to November 2021. Clinical trials employing ICIs in advanced EC, written in English, were included. Reviews, letters, and commentaries were excluded. The overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety (number and grade of treatment-related adverse events [TRAEs]) were evaluated.
15 studies, for a total of 1,627 patients, were included: 14 non-randomized phase I/II trials and 1 randomized phase III trial. Anti-PD1 (pembrolizumab, nivolumab, dostarlimab) and anti-PD-L1 agents (avelumab, atezolizumab, durvalumab) were administered as single agents; pembrolizumab and nivolumab were combined with the tyrosine-kinase inhibitors (TKI) lenvatinib and cabozantinib, respectively; and durvalumab was associated with anti-CTLA4 tremelimumab. 4 studies selected only MSI patients. Single agents determined an ORR from 26.7% to 58% among MSI patients, from 3% to 26.7% among MSS patients. DCR ranged from 53.5% to 88.9% in MSI, 31.4% to 35.2% in MSS patients. The combination of TKI and ICIs determined 32% to 63.6% of ORR in all-comers, 32%-36.2% in MSS patients. 54.2% to 76% of patients developed TRAEs. The combination of ICIs and TKI achieved a higher toxicity rate than single agents (≥G3 TRAEs 88.9%).
ICIs represent an effective option for pretreated advanced EC patients with a tolerable profile. Given the encouraging results in MSI patients, every woman diagnosed with EC should be investigated for MS status. In MSS women, the combination of ICIs and TKI is more effective than monotherapy, notwithstanding safety concerns. PD-L1 cannot predict ICI response, whereas other biomarkers such as MSI and tumor mutational burden seem more accurate. Ongoing randomized trials will further clarify the role of these therapeutic options.
PROSPERO, CRD42021293538.
子宫内膜癌（EC）是女性第六大常见肿瘤。在晚期情况下，预后不佳，治疗选择有限。铂类化疗是一线化疗的实际标准治疗方案，但尚无获批的标准二线化疗方案，不到四分之一的患者对二线化疗有反应。在过去十年中，免疫检查点抑制剂（ICI）改变了许多实体瘤的治疗格局。
本综述按照PRISMA指南进行。我们检索了截至2021年11月的EMBASE、MEDLINE、Cochrane数据库以及国际学会的会议摘要。纳入了用英文撰写的在晚期EC中使用ICI的临床试验。排除综述、信函和评论。评估了总缓解率（ORR）、无进展生存期（PFS）、总生存期（OS）和安全性（治疗相关不良事件[TRAEs]的数量和级别）。
纳入15项研究，共1627例患者：14项非随机的I/II期试验和1项随机III期试验。抗PD1（帕博利珠单抗、纳武利尤单抗、多斯塔利单抗）和抗PD-L1药物（阿维鲁单抗、阿特珠单抗、度伐利尤单抗）作为单药使用；帕博利珠单抗和纳武利尤单抗分别与酪氨酸激酶抑制剂（TKI）乐伐替尼和卡博替尼联合使用；度伐利尤单抗与抗CTLA4的曲美替尼联合使用。4项研究仅选择微卫星高度不稳定（MSI）患者。单药在MSI患者中的ORR为26.7%至58%，在微卫星稳定（MSS）患者中为3%至26.7%。MSI患者的疾病控制率（DCR）为53.5%至88.9%，MSS患者为31.4%至35.2%。TKI与ICI联合在所有患者中的ORR为32%至63.6%，MSS患者为32% - 36.2%。54.2%至76%的患者出现TRAEs。ICI与TKI联合的毒性率高于单药（≥3级TRAEs为88.9%）。
ICI是预处理晚期EC患者的有效选择，且耐受性良好。鉴于MSI患者的结果令人鼓舞，每个被诊断为EC的女性都应进行MS状态检测。在MSS女性中，尽管存在安全性问题，但ICI与TKI联合比单药治疗更有效。PD-L1不能预测ICI反应，而其他生物标志物如MSI和肿瘤突变负荷似乎更准确。正在进行的随机试验将进一步阐明这些治疗选择所起的作用。
PROSPERO，CRD42021293538
