713MO - Nivolumab and ipilimumab combination treatment in advanced gynaecological clear cell cancers: Results from the phase II MoST-CIRCUIT trial

Background

Clear cell carcinoma (CCC) represents a rare subtype of ovarian (OCCC) and uterine cancers (UCCC). Patients (pts) with advanced disease respond poorly to chemotherapy regimens used for high grade serous ovarian or endometrial ca leading to an overall poor prognosis. There have been conflicting results regarding the benefit of immunotherapy using anti-PD-1/PD-L1 blockade and minimal data on the activity of combined anti-PD-1/CTLA-4 blockade. The MoST-CIRCUIT trial evaluated nivolumab (nivo) and ipilimumab (ipi) combination treatment in this patient population.

Methods

Pts with advanced OCCC/UCCC 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, 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 has been performed by NGS using the TSO500 assay.

Results

28 pts (24 OCCC and 4 UCCC) were enrolled with 75% being pre-treated with one line of therapy. ORR was 50% in the overall population (13%CR, 37%PR) and 50% in the OCCC and UCCC subgroups respectively, median duration of response has not been reached, with all responses ongoing at 6 months. The 6-month-PFS was 52% with the median OS being 9.9 months. The median TMB for the population was 2.4/MB (range 1-13.9) and although being overall low, correlated with response (3.1/MB versus 1.15/MB, Mann-Whitney p=0.03). Tumour mutational analysis (N=18) revealed frequent mutations in ARID1A (44%), PIK3CA (39%), SPOP (22%), TERT promoter (22%), KRAS (17%) with responses being predominately seen in ARID1A WT tumours. 7 pts (25%) experienced a grade 3/4 immune–related adverse event and grade 5 myocarditis occurred in one patient.

Conclusions

Immunotherapy using combined anti-CTLA-4/PD-1 blockade demonstrated encouraging activity with a high rate of durable responses in pts with advanced gynaecological CCC. This regimen should be further investigated in this patient population of unmet medical need. Tumour genomic analysis and TMB may be helpful in predicting response.

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

M.S. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre-Fabre, Eisai, Nektar, Regeneron. C.R. Underhill: Financial Interests, Personal, Advisory Board: Merck Serono, AstraZeneca, Bayer. 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. Y. Antill: Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, GSK, Eisai, Pfizer; Financial Interests, Personal, Speaker’s Bureau: Lilly. W. Lam: Financial Interests, Personal, Advisory Board: Amgen, Janssen; Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, MSD, Roche, Pfizer, Novartis, AstraZeneca. All other authors have declared no conflicts of interest.