Patients with MSS and MGMT-depleted mCRC exhibited clinical benefit post–temozolomide and ICI treatment.

  • Major Finding: Patients with MSS and MGMT-depleted mCRC exhibited clinical benefit post–temozolomide and ICI treatment.

  • Concept: No treatment-related deaths or unexpected adverse events were observed.

  • Impact: This combination is effective in mCRC and could be translated to other temozolomide-sensitive cancers.

Use of immune checkpoint inhibitors (ICI) in patients with mismatch repair/microsatellite unstable colorectal cancer (CRC) has shown great benefit; however, those with proficient mismatch repair/microsatellite stable (pMMR/MSS) disease do not demonstrate this same response. Resistance to temozolomide, whose efficacy is related to O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, can lead to secondary mutations in MMR genes, as demonstrated in CRC models and patients with metastatic CRC (mCRC), which suggests that use of this drug in patients with pMMR/MSS and MGMT-silenced disease could promote ICI sensitization. Thus, Morano, Raimondi, and colleagues conducted a single-arm, phase II clinical trial that molecularly prescreened 716 patients with confirmed metastatic and inoperable MGMT-deficient and MSS CRC (MAYA trial). Treatment occurred in two stages: temozolomide alone for 2 monthly cycles followed by combination of temozolomide, nivolumab, and low-dose ipilimumab. The primary endpoint of this study was 8-month progression free survival (PFS), with secondary endpoints of PFS, death from any cause, overall survival (OS), overall response rate (ORR), and duration of response (DoR). Thirty-three out of 135 patients (24%) demonstrated disease control and were able to move on to the second treatment part, where the primary endpoint was met, with 12 patients achieving a PFS greater than 8 months. The median PFS and OS were 7 months and 18.4 months, respectively, while ORR for the whole treatment strategy was 45% and included 15 partial responses and 0 complete responses. The DoR was 4.8 months. Safety evaluation reported that 53% of patients had adverse events (AE) in the first part of treatment, with 3% being grade 3 or higher, while the second line reported that 91% of patients demonstrated AEs of any stage, with 21% being grade 3 or higher. The AEs across both treatment parts included skin rash, hypo/hyperthyroidism, hypophysitis, and adrenal insufficiency, with no treatment-related deaths being observed. Overall, this trial reported that priming with temozolomide followed by combination of ipilimumab and nivolumab provides clinical benefit to patients with pMMR/MSS and MGMT-silenced mCRC with no unexpected AEs, which supports further investigation into its optimal use.

Morano F, Raimondi A, Pagani F, Lonardi S, Salvatore L, Cremolini C, et al. Temozolomide followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite-stable, O6-methylguanine-DNA methyltransferase-silenced metastatic colorectal cancer: the MAYA trial. J Clin Oncol 2022 Mar 8 [Epub ahead of print].

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