641P - Phase I/II study of the EP4 antagonist CR6086 combined with the anti-PD-1 balstilimab in mismatch-repair-proficient and microsatellite stable (pMMR/MSS) chemorefractory metastatic colorectal cancer (mCRC)

Background

Approved immune checkpoint inhibitors (ICI) have little to no benefit in patients (pts) with pMMR/MSS mCRC. Several combination strategies to overcome intrinsic resistance have failed. Prostaglandin E2, through its receptor 4 (EP4), is a major contributor to immunosuppression in the tumor microenvironment and blockade of this pathway may sensitize cold tumors to ICI. In preclinical models, the EP4 antagonist CR6086 significantly enhanced the activity of PD-1 blockade, prompting this ongoing phase I/II study of CR6086 added to the anti-PD-1 balstilimab in pMMR/MSS chemorefractory mCRC.

Methods

Adult pts with pMMR/MSS mCRC, ECOG PS ≤1 and previous exposure to fluoropyrimidines, oxaliplatin and irinotecan, received oral CR6086 (30, 90 or 180 mg twice daily) plus balstilimab (3 mg/kg every 2 weeks) until disease progression, unacceptable toxicity or death. Primary endpoints are safety and disease control rate (DCR) per RECIST 1.1. Secondary endpoints include objective response rate (ORR), duration of response, progression-free and overall survival (PFS, OS). Exploratory endpoints include tissue and blood biomarkers.

Results

Twenty-eight pts were treated and 8 are still ongoing. Median age was 59 (interquartile range [IQR]: 54-68) years and 54% were men; median prior treatment lines was 4 (IQR: 3-5). No dose-limiting toxicities were observed. CR6086-related AEs were grade 1 (G1), except for a serious G4 duodenal ulcer which led to consideration of proton pump inhibitors prophylaxis in all pts. Balstilimab-related AEs were ≤G2 and one was serious (pneumonitis). Three pts had partial response (all ongoing at 15, 8, and 6 months) and 11 had stable disease, with an ORR of 11% and a DCR of 50% (8% and 25% in the 12 pts with liver metastases). At a median follow-up of 6.4 months (IQR 5.3-8.4), median PFS and OS were 2 (95% CI, 1.7–3.6) and 11.3 (95% CI, 8.8–not reached) months, respectively. Translational analyses are ongoing.

Conclusions

CR6086 combined with balstilimab was well tolerated and achieved durable responses in pMMR/MSS mCRC. Expansion in other gastrointestinal tumours and further clinical development in pMMR/MSS mCRC are ongoing.

Clinical trial identification

NCT05205330.

Editorial acknowledgement

Legal entity responsible for the study

Rottapharm Biotech Srl, Italy.

Funding

Rottapharm Biotech Srl, Italy.

Disclosure

F. Pietrantonio: Financial Interests, Personal, Advisory Board: Amgen, Merck Serono, MSD, Bayer, Organon, Astellas; Financial Interests, Personal, Invited Speaker: Amgen, Merck-Serono, Bristol Myers Squibb, Lilly, Servier, Bayer, Pierre Fabre, AstraZeneca, Astellas; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, AstraZeneca, Incyte, Agenus. F. Morano: Financial Interests, Personal, Invited Speaker: Servier, Pierre Fabre, Lilly; Financial Interests, Institutional, Research Grant: Incyte. M. Niger: Financial Interests, Personal, Other, consultant: EMD Serono, Incyte, MSD Italia; Financial Interests, Personal, Advisory Board, consultant: Basilea Pharmaceutica; Financial Interests, Personal, Advisory Board: AstraZeneca, Taiho; Financial Interests, Personal, Writing Engagement: Sandoz, Medpoint SRL, Incyte, Servier; Financial Interests, Personal, Invited Speaker: Incyte, Accademia della Medicina; Financial Interests, Personal, Other, travel expences for meetings: AstraZeneca. F. Ghelardi: Non-Financial Interests, Member: AIOM. All other authors have declared no conflicts of interest.