Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Medical Oncology 3, Istituto Oncologico Veneto IOV-IRCSS, Padua, Italy.
J Clin Oncol. 2022 May 10;40(14):1562-1573. doi: 10.1200/JCO.21.02583. Epub 2022 Mar 8.
This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O-methylguanine-DNA methyltransferase (MGMT)-silenced metastatic colorectal cancer (mCRC).
Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule.
Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported.
The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.
这是一项多中心、单臂 II 期临床试验，旨在评估替莫唑胺诱导免疫致敏策略联合低剂量伊匹单抗和纳武单抗在微卫星稳定（MSS）和 O-甲基鸟嘌呤-DNA 甲基转移酶（MGMT）沉默型转移性结直肠癌（mCRC）患者中的疗效和安全性。
经过预处理的 mCRC 患者接受中心预筛选，以确定 MSS 状态和 MGMT 沉默（即免疫组化检测无 MGMT 表达，焦磷酸测序检测甲基化）。符合条件的患者接受两个周期的口服替莫唑胺 150mg/sqm，每日一次，第 1-5 天，每 4 周一次（第一治疗部分），在没有进展的情况下，随后联合伊匹单抗 1mg/kg，每 8 周一次和纳武单抗 480mg，每 4 周一次（第二治疗部分）。主要终点是从开始第二治疗部分的患者中计算的 8 个月无进展生存率（PFS）率，在 8 个月时间点时，≥4/27 名患者无进展作为决策规则。
在 716 名经过预筛选的患者中，有 204 名（29%）具有分子学资格，135 名开始了第一治疗部分。其中，有 102 名（76%）因替莫唑胺诱导免疫致敏期间死亡或疾病进展而停药，而 33 名（24%）疾病控制的患者开始了第二治疗部分，成为最终研究人群。在中位随访 23.1 个月（四分位距，14.9-24.6 个月）后，8 个月的 PFS 率为 36%。中位 PFS 和总生存期分别为 7.0 和 18.4 个月，总缓解率为 45%。3-4 级免疫相关不良事件为皮疹（6%）、结肠炎（3%）和垂体炎（3%）。未报告任何意外的不良事件或治疗相关死亡。
MAYA 研究提供了概念验证，表明替莫唑胺诱导免疫致敏序贯低剂量伊匹单抗和纳武单抗联合治疗可能在 MSS 和 MGMT 沉默型 mCRC 中诱导持久的临床获益。
