Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer
Phase II Study of Avelumab in Patients With Mismatch Repair Deficient and Mismatch Repair Proficient Recurrent/Persistent Endometrial Cancer
复制标题
DOI：
10.1200/jco.19.01021
复制
发表时间：
2019-10-20
影响因子：
45.3
通讯作者：
Matulonis, Ursula A.
中科院分区：
文献类型：
--
作者：
Konstantinopoulos, Panagiotis A.;Luo, Weixiu;Matulonis, Ursula A.
尽管派姆单抗在错配修复缺陷（MMRD）实体瘤中的组织不可知性批准，但关于免疫检查点阻断在错配修复有效（MMRP）和缺陷型子宫内膜癌（EC）中的作用的重要未回答的问题仍然存在。（1）MMRD/POLE（聚合酶III）组群，如通过一种或多种错配修复（MMR）蛋白的免疫组织化学（IHC）表达丧失和/或POLE的核酸外切酶结构域中记录的突变所定义的;和（2）所有MMR蛋白具有正常IHC表达的MMRP组群。共同主要终点为客观缓解（OR）和6个月无进展生存期（PFS 6）。Avelumab 10 mg/kg静脉给药，每2周一次，直到进展或不可接受的毒性。没有POLE突变肿瘤患者入组MMRD队列，所有MMRP肿瘤均未发生POLE突变。由于无效，MMRP队列在第一阶段关闭：16例患者中只有1例同时显示OR和PFS 6应答。MMRD队列在仅17例患者入组后达到预定义的主要终点4个OR;在15例开始avelumab治疗的患者中，4例显示OR（1例完全缓解，3例部分缓解; OR率，26.7%; 95% CI，7.8%-55.1%）和6例（包括所有4个OR）PFS 6缓解（PFS 6，40.0%; 95% CI，16.3%-66.7%），其中4个缓解截至数据截止日期仍在进行中。在不存在PD-L1表达的情况下观察到应答。IHC捕获所有MMRD病例，随后通过聚合酶链反应或基因组学通过靶向测序确定。结论Avelumab在MMRD EC中具有良好的活性，无论PD-L1状态如何。用于MMR评估的IHC是用于患者选择的有用工具。avelumab在MMRP/非POLE突变EC中的活性较低。(C)2019年美国临床肿瘤学会
PURPOSE Despite the tissue-agnostic approval of pembrolizumab in mismatch repair deficient (MMRD) solid tumors, important unanswered questions remain about the role of immune checkpoint blockade in mismatch repair-proficient (MMRP) and -deficient endometrial cancer (EC).METHODS This phase II study evaluated the PD-L1 inhibitor avelumab in two cohorts of patients with EC: (1) MMRD/POLE (polymerase epsilon) cohort, as defined by immunohistochemical (IHC) loss of expression of one or more mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE; and (2) MMRP cohort with normal IHC expression of all MMR proteins. Coprimary end points were objective response (OR) and progression-free survival at 6 months (PFS6). Avelumab 10 mg/kg intravenously was administered every 2 weeks until progression or unacceptable toxicity.RESULTS Thirty-three patients were enrolled. No patient with POLE-mutated tumor was enrolled in the MMRD cohort, and all MMRP tumors were not POLE-mutated. The MMRP cohort was closed at the first stage because of futility: Only one of 16 patients exhibited both OR and PFS6 responses. The MMRD cohort met the predefined primary end point of four ORs after accrual of only 17 patients; of 15 patients who initiated avelumab, four exhibited OR (one complete response, three partial responses; OR rate, 26.7%; 95% CI, 7.8% to 55.1%) and six (including all four ORs) PFS6 responses (PFS6, 40.0%; 95% CI, 16.3% to 66.7%), four of which are ongoing as of data cutoff date. Responses were observed in the absence of PD-L1 expression. IHC captured all cases of MMRD subsequently determined by polymerase chain reaction or genomically via targeted sequencing.CONCLUSION Avelumab exhibited promising activity in MMRD EC regardless of PD-L1 status. IHC for MMR assessment is a useful tool for patient selection. The activity of avelumab in MMRP/non-POLE-mutated ECs was low. (C) 2019 by American Society of Clinical Oncology