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

Abstract

PURPOSE 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 O6-methylguanine–DNA methyltransferase (MGMT)–silenced metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus MGMT 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. RESULTS 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. CONCLUSION 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.

Dosing Regimens of Immune Checkpoint Inhibitors: Attempts at Lower Dose, Less Frequency, Shorter Course

“…In the CheckMate 920 study of renal cancer, Cohort 1 patients received 6 mg/kg Q8W nivolumab plus 1 mg/kg Q8W ipilimumab, alternating with nivolumab 480 mg Q8W, with an ORR of 34.4%, median PFS 4.8 months, which was not significantly different from the results of several other cohorts using N3I1 regimen followed by nivolumab 480 mg Q4W ( 51 , 52 ). The MAYA study evaluated the efficacy of temozolomide followed by nivolumab 480 mg Q4W plus ipilimumab 1 mg/kg Q8W in microsatellite-stable, O6-methylguanine–DNA methyltransferase–silenced metastatic colorectal cancer, with an ORR of 45% to the whole treatment strategy, median PFS of 7.1 months and median OS of 18.4 months ( 53 ). In CheckMate 012, nivolumab combined with ipilimumab 1 mg/kg Q6W or Q12W showed no significant differences in efficacy or safety in NSCLC patients ( 54 ).…”

Immunotherapies catering to the unmet medical need of cold colorectal cancer

“…This provides the rationale for inducing the immunosensitization of pMMR/MSS mCRC, which is MGMT silenced, by temozolomide initiation. A multicenter, single-arm phase II trial (NCT03832621), whose first phase of oral temozolomide 150 mg/sqm treatment in MSS mCRC, and a second phase of combination therapy with ipilimumab 1 mg/kg and nivolumab when no progression was observed, had the primary endpoint being the 8-month PFS rate calculated from the enrollment of patients starting the second treatment portion ( 49 ). 24% of the patients entering the second part of treatment showed a PFS rate of 36%.…”

MGMT inactivation as a new biomarker in patients with advanced biliary tract cancers

“…The primary aim was to investigate the frequency and percentage of MGMT promoter hypermethylation in advanced BTC patients. Secondary aims were: (a) to investigate the prognostic impact of MGMT promoter hypermethylation in terms of overall survival (OS); (b) to investigate the predictive role of MGMT promoter hypermethylation in first-line (1L) of standard chemotherapy in terms of 1L-progression-free survival (PFS); (c) to explore the potential effect on 1L-PFS of the interaction between MGMT promoter hypermethylation and use of platinum-based chemotherapy; (d) to evaluate the prognostic and predictive role of MGMT expression as evaluated by immunohistochemistry (IHC), given the growing evidence of the role of IHC as complementary assessment tool of MGMT status [18,19,21]; (e) to explore the association between MGMT promoter hypermethylation and the tumor molecular profile; and (f) to report safety and efficacy data of a case series of patients treated with TMZrelated regimens.…”