The combination of balstilimab and botensilimab has demonstrated a promising objective response rate (ORR) in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) without liver metastases. Preliminary data from a phase 2 study (NCT05608044), presented at the 2025 Gastrointestinal Cancers Symposium, indicate that this dual anti-TIGIT/PD-1 blockade could offer a clinically meaningful benefit for this specific subset of mCRC patients.
At a median follow-up of 12.7 months, botensilimab at 75 mg every 6 weeks (Q6W) plus balstilimab (n = 62) resulted in a confirmed objective response rate (cORR) of 19% (95% CI, 10%-31%) and a disease control rate (DCR) of 55% (95% CI, 42%-68%). In contrast, when botensilimab was administered at a higher dose of 150 mg Q6W plus balstilimab (n = 61), the cORR was 8% (95% CI, 3%-18%), with a DCR of 54% (95% CI, 41%-67%) at a median follow-up of 12.9 months.
Monotherapy Outcomes
Botensilimab monotherapy at 75 mg Q6W (n = 38) showed a cORR of 0% (95% CI, 0%-9%) and a DCR of 37% (95% CI, 22%-54%). Botensilimab monotherapy at 150 mg Q6W (n = 40) resulted in a cORR of 8% (95% CI, 2%-20%) and a DCR of 38% (95% CI, 23%-54%). The median follow-up for these monotherapy arms was 9.8 months and 13.4 months, respectively.
Durability of Response
The median duration of response (DOR) has not been reached, and 70% of responses are ongoing, suggesting a durable effect of the combination therapy.
Expert Commentary
Marwan G. Fakih, MD, of the Department of Medical Oncology and Therapeutics Research at City of Hope Comprehensive Cancer Center, emphasized the importance of these findings. "This is proof that botensilimab monotherapy is not as effective at 75 mg and that we do need the combination of balstilimab/botensilimab, so we did meet the primary end point of identifying contribution of component," Dr. Fakih stated during the presentation of the data. He also noted the "unprecedented confirmed response rates with an IO-only combination in chemo-refractory mCRC" and the "impressive" durability of responses. Based on the safety and efficacy data, the recommended dose for a phase 3 trial is botensilimab 75 mg in combination with balstilimab 240 mg.
Unmet Needs in MSS mCRC
Colorectal cancer remains a leading cause of death worldwide, with increasing incidence in younger individuals. There is a significant unmet need for safe and effective treatments for patients with MSS mCRC, particularly those who have progressed on two prior lines of treatment. Immunotherapy has historically been ineffective in this population due to poor immunogenicity.
Trial Design and Patient Population
The global phase 2 study aimed to determine the optimal dose of botensilimab and the contribution of balstilimab. The trial enrolled patients with MSS CRC without active liver metastasis who had previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, as well as anti-VEGF and/or anti-EGFR agents, if appropriate.
Patients were randomized to one of five arms: botensilimab monotherapy at 75 mg Q6W (n = 38), botensilimab at 75 mg Q6W plus balstilimab at 240 mg every 2 weeks (Q2W; n = 62), botensilimab monotherapy at 150 mg Q6W (n = 40), botensilimab at 150 mg Q6W plus balstilimab at 240 mg Q2W (n = 61), or standard-of-care (SOC) trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga; n = 33).
The primary endpoint was investigator-assessed ORR by RECIST v1.1 criteria. Secondary endpoints included DOR, progression-free survival (PFS), overall survival (OS), safety, pharmacokinetics, and immunogenicity. A total of 234 patients were enrolled, and 219 were dosed.
Safety Profile
Botensilimab at 75 mg plus balstilimab (n = 62) demonstrated the best risk-benefit profile. Treatment-related adverse effects (AEs) occurred in 87% of patients, with grade 3 or higher AEs in 35%. Common immune-mediated AEs included diarrhea/colitis (35%), hypothyroidism (13%), and skin toxicities (6%). The most common grade 3 or higher AEs were diarrhea/colitis (18%), pneumonitis (3%), and hepatitis (2%). No treatment-related deaths occurred, and no new safety signals were observed.
Future Directions
Time-to-event secondary endpoints of DOR, PFS, and OS will be presented at a future meeting as the data continue to mature.
