Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, O 6 -Methylguanine-DNA Methyltransferase-Silenced Metastatic Colorectal Cancer: The MAYA Trial.

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 O ⁶ -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.
Competing Interests: Federica MoranoHonoraria: ServierTravel, Accommodations, Expenses: Sanofi, Servier Sara LonardiConsulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, MSDSpeakers' Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, AmgenResearch Funding: Amgen, Merck Serono, Bayer (Inst), Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst) Lisa SalvatoreHonoraria: Roche, Merck Serono, Servier, Bayer, Amgen, Sanofi, AstraZeneca, Pierre Fabre, MSDConsulting or Advisory Role: Merck Serono, Servier, Bayer, Roche, Amgen, AstraZeneca, Sanofi, Pierre Fabre, MSDTravel, Accommodations, Expenses: Sanofi, Merck Serono, Bayer, Roche, Servier, Celgene Chiara CremoliniHonoraria: Roche, Amgen, Bayer, Servier, MSD, MerckConsulting or Advisory Role: Roche, Bayer, Amgen, MSDSpeakers' Bureau: ServierResearch Funding: Merck, Bayer, Roche, Servier Patrizia RaccaHonoraria: Merck Serono, Roche, Amgen, Servier Monica NigerConsulting or Advisory Role: Incyte, Basilea Pharmaceutical, EMD Serono, MSD/AstraZenecaTravel, Accommodations, Expenses: Celgene Francesca CortiTravel, Accommodations, Expenses: Advanced Accelerator Applications Alberto ZaniboniConsulting or Advisory Role: Amgen, Servier, Bayer, Merck Serono, MerckSpeakers' Bureau: servier, Astellas Pharma (Inst) Celeste CagnazzoSpeakers' Bureau: Boehringer Ingelheim, Novartis Massimo Di MaioHonoraria: Pfizer, Takeda, AstraZeneca, Janssen, Eisai, Novartis, Roche, Astellas Pharma, MSD OncologyConsulting or Advisory Role: AstraZeneca, Pfizer, Takeda, Janssen, Eisai, Novartis, Roche, MSD Oncology, AmgenResearch Funding: Tesaro (Inst), GlaxoSmithKline (Inst) Maria Di BartolomeoHonoraria: Lilly, MSD Oncology, ServierConsulting or Advisory Role: Lilly, MSD OncologyResearch Funding: LillyTravel, Accommodations, Expenses: Roche, Sanofi Filippo De BraudHonoraria: Roche, Pfizer, BMS, Merck, MSD, Servier, Sanofi, Amgen Astellas BioPharma, IncyteConsulting or Advisory Role: Roche, Incyte, EMD SERONO, Bristol Myers Squibb, Nerviano Medical Sciences, Sanofi, Novartis Italy, nms medical science, MenariniResearch Funding: Novartis (Inst), Roche (Inst), Merck Serono (Inst), Pfizer (Inst), Servier (Inst), Philogen (Inst), Loxo (Inst), Tesaro (Inst), Nerviano Medical Sciences (Inst), Kymab (Inst), Bristol Myers Squibb/Medarex, Merck KGaA, Ignyta, MedImmune, Exelixis, Bayer Health, Daiichi Sankyo Europe GmbH, Incyte, Basilea Pharmaceutical, Janssen Oncology Filippo PietrantonioHonoraria: Servier, Bayer, AstraZeneca/MedImmune, Lilly, Sanofi, MSD Oncology, AmgenConsulting or Advisory Role: Amgen, Servier, MSD Oncology, MerckResearch Funding: Bristol Myers Squibb (Inst), Astrazeneca (Inst)No other potential conflicts of interest were reported.