998MO - Nivolumab and ipilimumab combination treatment in advanced dMMR/MSI-H noncolorectal cancers: Results from the phase II MoST-CIRCUIT study

Background

Mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) cancers (ca) are one of the most immunogenic ca. Anti-PD-1 monotherapy using Pembrolizumab has regulatory approval in advanced MSI-H colorectal ca (CRC) and non-CRCs leading to durable responses in a 1/3 of pts. Combined anti-PD-1/CTLA-4 blockade using nivolumab (nivo) and ipilimumab (ipi) has shown superiority to anti-PD-1 monotherapy in other immunogenic ca such as melanoma. MoST-CIRCUIT is the first trial that investigated combined anti-PD-1/CTLA-4 blockade in advanced dMMR/MSI-H non-CRCs.

Methods

Pts with advanced dMMR/MSI-H non-CRC ca were enrolled across 14 Australian sites. Pts received nivo 3mg/kg and ipi 1mg/kg q3 weekly for 4 doses, followed by nivo 480mg q4 weekly for 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. Co-primary endpoints were objective response rate (ORR) and 6 month-progression free survival (PFS). Tumour genomic profiling was undertaken by NGS using the TSO500 assay.

Results

52 pts representing 17 tumour types were enrolled; the most common tumour type being endometrial ca (43%). 27pts (52%) were pre-treated for metastatic disease. ORR was 66% with the median duration of response not being reached and 90% of responses ongoing at 6 months,11% of pts had stable disease with regression of target lesions. The 6-month-PFS is 80 %. The median TMB was 30.6/MB (range 0.8-99.5) and did not correlate with response. Tumour genomic profiling (N=37) revealed aberrations related to immunotherapy resistance (BM2, JAK1/2, IFNGR1, PTEN, CTNNB1) in 62% of pts and their presence had no impact on response. 21% of pts experienced a grade 3/4 immune –related adverse event.

Conclusions

Combined anti-PD-1/CTLA-4 blockade leads to a high rate of durable responses in dMMR/MSI-H non-CRC ca comparing favourably to published trials using anti-PD-1/PD-L1 monotherapy. Biomarkers of response and resistance identified in anti-PD-1 monotherapy treated MSI-H pts did not correlate with response in this cohort. Anti-PD-1/CTLA-4 blockade using nivo/ipi constitutes an alternative treatment option to monotherapy in this patient population.

Clinical trial identification

NCT04969887.

Editorial acknowledgement

Legal entity responsible for the study

Olivia Newton-John Cancer Research Institute.

Funding

Minderoo Foundation; Bristol Myers Squibb Ltd; Omico.

Disclosure

D. Kee: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp & Dohme; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board, Tebentafusp advisory board: Medison Pharma; Non-Financial Interests, Member: ASCO, COSA. W. Lam: Financial Interests, Personal, Invited Speaker: BMS, MSD, Roche, Pfizer, Novartis, AstraZeneca; Financial Interests, Personal, Advisory Board: Amgen, Janssen. C.R. Underhill: Financial Interests, Personal, Advisory Board: Merck Serono, Bayer, AstraZeneca. M. Brown: Financial Interests, Institutional, Invited Speaker: BMS. M.S. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre-Fabre, Eisai, Nektar, Regeneron. All other authors have declared no conflicts of interest.