Phase 2 COMBAT tests botensilimab plus balstilimab for ctDNA-positive molecular residual disease in MSS colorectal cancer

This open-label Phase 2 NCI/ETCTN study evaluates botensilimab, an Fc-enhanced CTLA-4-directed antibody, with balstilimab, a PD-1-blocking antibody, in MSS stage II/III colorectal cancer with ctDNA-positive molecular residual disease after definitive treatment and no radiographically detectable recurrence. Both drugs originate from Agenus. Treatment uses 42-day cycles: balstilimab is administered during up to 4 cycles, while botensilimab is limited to the first 2 cycles under the protocol.

The study examines ctDNA clearance at approximately 6 months, with imaging and longer-term clinical follow-up. Clearance is a biologic activity signal, not a validated stand-alone demonstration of improved survival from this treatment. The scientific question is whether Fc-enhanced CTLA-4 activity plus PD-1 blockade can affect low-volume residual MSS disease even though checkpoint therapy has generally been ineffective in unselected advanced MSS colorectal cancer. Safety is especially consequential when patients have no visible cancer and may already have been cured by prior treatment.