A phase 1 trial evaluated the safety and efficacy of botensilimab (BOT) combined with balstilimab (BAL) in patients with relapsed/refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC). The study enrolled 148 heavily pre-treated patients, with 101 being response-evaluable. The primary endpoint was safety and tolerability, with 89% of patients experiencing treatment-related adverse events (TRAEs), most commonly fatigue, diarrhea, and pyrexia. No grade 5 TRAEs were reported, and 12% of patients discontinued treatment due to TRAEs. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS). The ORR was 17% (17/101), and DCR was 61% (62/101). Median DOR was not reached, and median PFS was 3.5 months. The combination of BOT and BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity. The study also showed that patients with no liver metastases (NLM) had better outcomes compared to those with active liver metastases (LM). The combination of BOT and BAL showed promising efficacy in MSS mCRC, with an ORR of 17% and a DCR of 61%. The study highlights the potential of BOT and BAL in treating MSS mCRC, which has historically been resistant to immune checkpoint inhibitors. The findings suggest that the site of metastatic disease may be an important predictive biomarker for ICB efficacy, particularly in the context of MSS mCRC. A randomized phase 2 study is ongoing to confirm the comparative safety and efficacy of the BOT and BAL combination.A phase 1 trial evaluated the safety and efficacy of botensilimab (BOT) combined with balstilimab (BAL) in patients with relapsed/refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC). The study enrolled 148 heavily pre-treated patients, with 101 being response-evaluable. The primary endpoint was safety and tolerability, with 89% of patients experiencing treatment-related adverse events (TRAEs), most commonly fatigue, diarrhea, and pyrexia. No grade 5 TRAEs were reported, and 12% of patients discontinued treatment due to TRAEs. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS). The ORR was 17% (17/101), and DCR was 61% (62/101). Median DOR was not reached, and median PFS was 3.5 months. The combination of BOT and BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity. The study also showed that patients with no liver metastases (NLM) had better outcomes compared to those with active liver metastases (LM). The combination of BOT and BAL showed promising efficacy in MSS mCRC, with an ORR of 17% and a DCR of 61%. The study highlights the potential of BOT and BAL in treating MSS mCRC, which has historically been resistant to immune checkpoint inhibitors. The findings suggest that the site of metastatic disease may be an important predictive biomarker for ICB efficacy, particularly in the context of MSS mCRC. A randomized phase 2 study is ongoing to confirm the comparative safety and efficacy of the BOT and BAL combination.