128TiP - A phase II study of cadonilimab + FOLFOXIRI and bevacizumab as initial therapy for unresectable proficient mismatch repair/microsatellite stable (pMMR/MSS) metastatic colorectal cancer (mCRC)

Background

Immune-checkpoint inhibitors (ICI) show modest activity and efficacy in patients with MSS mCRC and pMMR. A recent trial of botensilimab (next-generation anti–CTLA-4 antibody) + balstilimab (anti-PD-1 antibody) for heavily pretreated pMMR/MSS mCRC reported promising results. Cadonilimab is a humanized bi-specific antibody that targets both PD-1 and CTLA-4. Its higher binding avidity in a tumor-like setting and Fc-null design may increase drug retention in tumors and improve safety. A more intensive chemotherapy, FOLFOXIRI + bevacizumab, can enhance the antitumor effect of ICI by increasing tumor immunogenicity. AtezoTRIBE, a phase II study, showed that adding atezolizumab to first-line FOLFOXIRI + bevacizumab might improve progression-free survival (PFS) in patients with mCRC. Therefore, in this study we aim to investigate the efficacy and safety of cadonilimab + FOLFOXIRI and bevacizumab as initial therapy for patients with unresectable pMMR/MSS mCRC.

Trial design

This is a multicenter single arm phase II study. Eligibility criteria include: histologically or cytologically confirmed pMMR/MSS mCRC; age 18-75 years; naive to systemic treatment in the metastatic setting; at least 1 measurable lesion according to RECIST 1.1; ECOG PS 0-1; and adequate organ function. Patients with high microsatellite instability (MSI-H) tumors and those who previously received immunotherapy are excluded. Twenty eligible participants will receive FOLFOXIRI (intravenous [i.v.] irinotecan 165 mg/m², oxaliplatin 85 mg/m², leucovorin 200 mg/m², and fluorouracil 2400 mg/m² as a 48-h infusion) + bevacizumab 5 mg/kg i.v. and cadonilimab 6 mg/kg i.v. Treatment is administered for up to twelve 14-day cycles followed by maintenance with fluorouracil and leucovorin (or capecitabine) + bevacizumab and cadonilimab for a total of 52 weeks or until disease progression, unacceptable adverse events, or consent withdrawal. The primary endpoint is objective response rate per RECIST 1.1. Secondary endpoints are PFS, overall survival, and safety. Enrollment is ongoing.

Clinical trial identification

NCT05839470.

Legal entity responsible for the study

The authors.

Funding

Akeso, Inc.

Disclosure

All authors have declared no conflicts of interest.