Temozolomide followed by low-dose ipilimumab plus nivolumab for MSS and MGMT-silenced mCRC

Most patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) have immune-excluded tumors with intrinsic resistance to immune checkpoint inhibitors. The multicenter phase 2 MAYA trial in Italy was designed to prospectively provide clinical proof-of-concept of the role of temozolomide as an immune-sensitizing agent by induction of hypermutation in MSS, MGMT-silenced mCRC. Patients received two priming cycles of oral temozolomide followed, in absence of progression, by its combination with low-dose ipilimumab plus nivolumab. The overall response rate was 45%. After median follow-up of 23.1 months the 8-months PFS rate was 36%, while median progression-free survival and overall survival werd 7.0 and 18.4 months, respectively. The authors conclude that the MAYA study provided proof-of-concept that temozolomide priming followed by combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.