383O - MAYA trial: Temozolomide (TMZ) priming followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite stable (MSS), MGMT silenced metastatic colorectal cancer (mCRC)

Background

The activity of TMZ in patients with mCRC is modest, but restricted to those with MSS status and MGMT silencing (negative IHC + MGMT methylation). In this hyperselected population, acquired resistance to TMZ is linked to emergence of mutations in mismatch repair genes and hypermutation. Thus, TMZ may be used as priming agent for immune-sensitization of MSS CRCs.

Methods

MAYA was a multicenter, single-arm phase II trial enrolling patients with pretreated MSS mCRC and MGMT silencing as centrally assessed by IHC + pyrosequencing (NCT03832621). The trial was designed to evaluate the safety and efficacy of 2 priming cycles of TMZ 150 mg/sqm d1-5q4w followed in absence of disease progression by its combination with ipilimumab 1 mg/kg q8w/nivolumab 480 mg q4w. Primary endpoint: 8-month progression-free survival rate (8m PFS). Secondary endpoints: overall survival (OS), overall response rate (ORR), safety, patient-reported outcomes. According to a single-stage design, 27 patients were required to increase 8m PFS from 5% to 20% with α- and β-error of 5% and 20%.

Results

Among 703 patients prescreened from March 2019 to November 2020, 204 (29%) were molecularly eligible and 135 started the priming phase, of whom 33 (24%) reached the second treatment phase. For these, median age: 58 years, M/F 52/48%, RAS mutated/wild-type 76/24% (no BRAF mutated); 1/2/≥3 previous lines 6/45/49%. Overall, 10 were alive and progression free after 8 months, 21 had PFS <8 months (2 too early). The primary endpoint was met: 8m PFS was 32%; median PFS and OS: 7.1 and 18.5 months; ORR 39%, with delayed/gradual responses consistent with efficacy of immunotherapy. The rate of any grade/grade ≥3 immune-related adverse events was 48/6%, all easily manageable with protocol guidelines. On/post-therapy re-biopsies were analyzed in 9 cases with emergence of either TMB>10 mut/mb or MGMT expression, which predicted 8m PFS status.

Conclusions

MAYA study proved the immune-sensitizing role of TMZ in MSS/MGMT silenced mCRC. The safety and efficacy of TMZ priming followed by ipilimumab/nivolumab combo strategy is worthy of further development and extensive biomarker analyses are ongoing.

Clinical trial identification

NCT03832621.

Editorial acknowledgement

Legal entity responsible for the study

Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy.

Funding

Bristol-Myers Squibb.

Disclosure

F. Pietrantonio: Financial Interests, Invited Speaker: Merck Serono; Sanofi; Servier; Lilly; Amgen; Bayer HealthCare Pharmaceuticals; Financial Interests, Research Grant: Bristol-Myers Squibb; AstraZeneca. F. Morano: Financial Interests, Invited Speaker: Servier; Financial Interests, Other, Travel accomodations: Sanofi; Servier. S. Lonardi: Financial Interests, Invited Speaker: Merck Serono; Roche; Servier; Bristol Myers Squibb Foundation; Incyte; Daiichi Sankyo; Pierre Fabre; AstraZeneca; Amgen; Bayer HealthCare Pharmaceuticals; Financial Interests, Research Grant: AstraZeneca; Bristol Myers Squibb Foundation; Lilly; Merck Serono; Roche; Amgen. L. Salvatore: Financial Interests, Advisory Board: Merck Serono; Servier; Bayer; Roche; Amgen; AstraZeneca; Sanofi; Pierre Fabre; Financial Interests, Other, travel accomodations/expenses: Sanofi; Merck Serono; Bayer; Roche; Servier; Celgene; Financial Interests, Invited Speaker: Roche; Merck Serono; Servier; Bayer; Amgen; Sanofi; AstraZeneca; Pierre Fabre. A. Zaniboni: Financial Interests, Invited Speaker: Sanofi; Merck Serono; Roche; Amgen; Bayer HealthCare Pharmaceuticals. M. Di Bartolomeo: Financial Interests, Advisory Board: Lilly; MSD Oncology; Financial Interests, Other, Travel accomodations: Roche; Sanofi; Financial Interests, Invited Speaker: Lilly; MSD Oncology; Servier; Financial Interests, Research Grant: Lilly. F. de Braud: Financial Interests, Advisory Board: Roche; Incyte; Teofarma; EMD Serono; Bristol-Myers Squibb; Nerviano Medical Sciences; Sanofi; Novartis Italia; Financial Interests, Invited Speaker: Roche; Bristol-Myers Squibb; Merck; MSD; Servier; Sanofi; Financial Interests, Research Grant: Novartis; Roche; Merck Serono; Pfizer; Servier; Philogen; Loxo; Tesaro; Nerviano Medical Sciences; Kymab. All other authors have declared no conflicts of interest.