Temozolomide Followed by Low-Dose Ipilimumab/Nivolumab in MSS and MGMT-Silenced Metastatic Colorectal Cancer

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In an Italian phase II study (MAYA) reported in the Journal of Clinical Oncology, Morano et al found that patients with microsatellite-stable (MSS) and O6-methylguanine–DNA methyltransferase (MGMT)-silenced metastatic colorectal cancer without disease progression on temozolomide derived benefit from subsequent low-dose ipilimumab/nivolumab.

In the multicenter trial, 716 patients with previously treated metastatic disease were prescreened for MSS status and MGMT silencing between March 2019 and November 2020. Patients who were molecularly eligible could begin temozolomide treatment; those without disease progression on temozolomide could begin ipilimumab/nivolumab. Initial treatment consisted of two priming cycles of temozolomide at 150 mg/m2 once daily on days 1 to 5 once every 4 weeks. Patients without disease progression on temozolomide received ipilimumab at 1 mg/kg once every 8 weeks and nivolumab at 480 mg once every 4 weeks. The primary outcome measure was 8-month progression-free survival among patients receiving ipilimumab/nivolumab, with the aim of increasing the rate to 20% from a historical benchmark of 5% with temozolomide alone.

Key Findings

Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started temozolomide treatment. Among these, 102 (76%) were discontinued due to death (n = 6) or disease progression (n = 95) on temozolomide (an additional patient withdrew from the trial), with 33 patients (24%) who achieved disease control on temozolomide beginning treatment with ipilimumab/nivolumab (final study population).

Median follow-up for the 33 patients was 23.1 months (interquartile range = 14.9–24.6 months). Progression-free survival at 8 months was achieved in 12 patients (36%, 95% confidence interval [CI] = 23%–57%). Median progression-free survival was 7.0 months (95% CI = 5.5–8.3 months), with 12- and 18-month rates of 24% and 20%. Median overall survival was 18.4 months (95% CI = 14.9 months–not assessable).

Objective responses (all partial) were observed in 15 patients (45%, 95% CI = 29%–62%). Of these, eight were observed after temozolomide treatment and seven during ipilimumab/nivolumab treatment. Median duration of response was 4.8 months (95% CI = 3.8–not assessable).

Grade 3 or 4 immune-related adverse events during ipilimumab/nivolumab treatment included skin rash in 6%, colitis in 3%, and hypophysitis in 3%. No unexpected adverse events or treatment-related deaths were reported.

The investigators concluded, “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 metastatic colorectal cancer.”

Filippo Pietrantonio, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Bristol Myers Squibb. For full disclosures of the study authors, visit


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