Green Angela K, Feinberg Jacqueline, Makker Vicky
Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.
Am Soc Clin Oncol Educ Book. 2020 Mar;40:1-7. doi: 10.1200/EDBK_280503.
Approximately 30% of primary endometrial cancers are microsatellite instability high/hypermutated (MSI-H), and 13% to 30% of recurrent endometrial cancers are MSI-H or mismatch repair deficient (dMMR). Given the presence of immune dysregulation in endometrial cancer as described, immune checkpoint blockade (ICB) has been explored as a therapeutic mechanism, both as monotherapy and in combination with cytotoxic chemotherapy, other immunotherapy, or targeted agents. In MSI-H or dMMR advanced endometrial cancers, PD-1 inhibitors dostarlimab and pembrolizumab have shown response rates of 49% and 57%, respectively, whereas PD-L1 inhibitors avelumab and durvalumab have shown response rates of 27% and 43%, respectively. In microsatellite stable (MSS) or PD-L1-positive advanced endometrial cancers, modest activity of PD-1 inhibitors nivolumab and dostarlimab and PD-L1 inhibitors atezolizumab, avelumab, and durvalumab has been seen, with response rates ranging from 3% to 23%. Based on substantial activity in a phase Ib/II study, the U.S. Food and Drug Administration (FDA) granted lenvatinib and pembrolizumab combination therapy accelerated approval in 2019 for the treatment of advanced endometrial cancer that is not MSI-H or dMMR and has progressed following prior therapy. Although these developments have been highly impactful, a more robust understanding of the molecular and immunologic drivers of response and resistance will be critical to optimally design next-generation studies in endometrial cancer.
大约30%的原发性子宫内膜癌为微卫星高度不稳定/高突变（MSI-H），13%至30%的复发性子宫内膜癌为MSI-H或错配修复缺陷（dMMR）。鉴于上述子宫内膜癌中存在免疫失调情况，免疫检查点阻断（ICB）已作为一种治疗机制进行探索，包括单药治疗以及与细胞毒性化疗、其他免疫疗法或靶向药物联合使用。在MSI-H或dMMR晚期子宫内膜癌中，PD-1抑制剂多斯塔利单抗和帕博利珠单抗的缓解率分别为49%和57%，而PD-L1抑制剂阿维鲁单抗和度伐鲁单抗的缓解率分别为27%和43%。在微卫星稳定（MSS）或PD-L1阳性的晚期子宫内膜癌中，已观察到PD-1抑制剂纳武利尤单抗和多斯塔利单抗以及PD-L1抑制剂阿特珠单抗、阿维鲁单抗和度伐鲁单抗有一定活性，缓解率在3%至23%之间。基于一项Ib/II期研究中的显著活性，美国食品药品监督管理局（FDA）于2019年批准乐伐替尼和帕博利珠单抗联合疗法加速批准用于治疗非MSI-H或dMMR且在先前治疗后进展的晚期子宫内膜癌。尽管这些进展影响重大，但更深入地了解反应和耐药的分子及免疫驱动因素对于优化子宫内膜癌的下一代研究至关重要。
