NIVOLUMAB Plus IPILIMUMAB and TEMOZOLOMIDE in Microsatellite Stable, MGMT Silenced Metastatic Colorectal Cancer

This is a Phase II, multicenter, single-arm trial designed to evaluate the efficacy and safety of nivolumab (NIVO), ipilimumab (IPI) and temozolomide (TMZ) combination in 27 patients with MSS, MGMT-silenced mCRC with initial clinical benefit following lead-in treatment with single-agent TMZ.
Immune checkpoint inhibitors have been shown to trigger durable antitumor effects in a subset of patients. A high number of tumor mutations (so called ‘tumor mutational burden’) has recently been found associated with increased immunogenicity (due to a high number of neoantigens) and improved treatment efficacy across several different solid tumors. In mCRCs, only a small fraction of tumors (<5%) display a high mutational load and are usually associated with inactivation of mismatch repair genes such as MLH1, MSH2 and MSH6. Checkpoint inhibitors may have increased activity in dMMR/microsatellite instability-high (MSI-H) tumors, a hypothesis which was tested in various Phase II trials with positive results. On the opposite, mismatch repair proficient colorectal cancer is unresponsive to immune checkpoint inhibitors.
Previous reports indicate that acquired resistance to TMZ may emerge through the induction of a microsatellite-instability-positive phenotype and recent data showed that inactivation of MMR, driven by acquired resistance to the clinical agent temozolomide, increased mutational load, promoted continuous renewal of neoantigens in human colorectal cancers and triggered immune surveillance in mouse models.
On all of the above grounds, the investigators hypothesize that treatment of microsatellite stable MGMT hypermethylated CRCs with alkylating agents could reshape the tumor genetic landscape by increasing the tumor mutational burden, leading to achieve potential sensitization to immunotherapy.

本研究为一项II期多中心单臂临床试验，旨在评估纳武利尤单抗（nivolumab, NIVO）、伊匹木单抗（ipilimumab, IPI）联合替莫唑胺（temozolomide, TMZ）对27例微卫星稳定（microsatellite stable, MSS）、MGMT沉默型转移性结直肠癌（metastatic colorectal cancer, mCRC）患者的疗效与安全性，这些患者在接受单药替莫唑胺导入治疗后均获得初始临床获益。
免疫检查点抑制剂已被证实可在部分患者中引发持久的抗肿瘤效应。近期研究发现，高肿瘤突变负荷（tumor mutational burden, TMB）与肿瘤免疫原性增强（源于新抗原数量增多）及多种实体瘤的治疗获益提升相关。在转移性结直肠癌中，仅不足5%的肿瘤呈现高突变负荷，且通常与错配修复基因（如MLH1、MSH2、MSH6）的失活相关。免疫检查点抑制剂在错配修复缺陷型（mismatch repair deficient, dMMR）/微卫星高度不稳定型（microsatellite instability-high, MSI-H）肿瘤中可能具有更强的抗肿瘤活性，这一假说已在多项II期临床试验中得到验证并获得阳性结果。与之相反，错配修复完整型结直肠癌对免疫检查点抑制剂治疗无应答。
既往研究表明，对替莫唑胺的获得性耐药可能通过诱导微卫星不稳定阳性表型产生；最新数据显示，由替莫唑胺获得性耐药驱动的错配修复基因失活，可增加肿瘤突变负荷，促进结直肠癌中新抗原的持续产生，并在小鼠模型中触发免疫监视。
基于上述研究背景，本研究的研究者提出假说：使用烷基化药物治疗微卫星稳定、MGMT高甲基化结直肠癌，可通过提升肿瘤突变负荷重塑肿瘤的遗传特征，从而实现对免疫治疗的潜在增敏作用。