Botensilimab Plus Balstilimab Produces Durable Responses and 33% Three-Year Survival in Refractory, Microsatellite-Stable Colorectal Cancer

Why This Study Matters

Microsatellite-stable (MSS) tumors account for roughly 95–96% of metastatic colorectal cancer (mCRC) cases and are largely resistant to checkpoint immunotherapy, in sharp contrast to the smaller microsatellite-instability-high (MSI-H) population, where checkpoint inhibition is already standard of care. Patients whose disease progresses after standard chemotherapy and later-line options such as regorafenib or trifluridine/tipiracil have historically faced modest survival prospects, which is the unmet need this botensilimab plus balstilimab combination — an Fc-enhanced anti-CTLA-4 antibody paired with an anti-PD-1 antibody — was designed to address.

This article reports extended follow-up of an expanded phase 1b cohort of the combination in patients with MSS mCRC who do not have active liver metastases, including a post hoc analysis of patients already exposed to later-line standard therapies.

Study Design

This is an open-label, single-arm phase 1b expansion cohort conducted within a larger phase 1 basket study of botensilimab with and without balstilimab in advanced cancers (ClinicalTrials.gov NCT03860272). The primary objective of the cohort was safety and tolerability; efficacy (objective response rate, duration of response, progression-free survival) was assessed as secondary endpoints, with overall survival tracked as an exploratory endpoint. A post hoc analysis separately examined patients who had already received later-line therapies — regorafenib, trifluridine/tipiracil with or without bevacizumab, or fruquintinib ("late-line exposed").

Patient Population and Dosing

Enrolled patients had MSS mCRC without active liver metastases and had received a median of 3 prior lines of therapy (67% had received 3 or more prior lines). Treatment consisted of intravenous botensilimab 1 or 2 mg/kg every 6 weeks plus balstilimab 3 mg/kg every 2 weeks, continued for up to 2 years or until disease progression or unacceptable toxicity. As of the data cutoff, 123 patients had been treated, with a median follow-up of 20.2 months.

Efficacy Results

The objective response rate was 21% (95% CI, 14–29). Median duration of response was not reached (95% CI, 7.3 months–not reached), indicating that responses have been durable over the follow-up period. Median progression-free survival was 4.0 months (95% CI, 2.8–4.1). Median overall survival — tracked as an exploratory endpoint — was 21.2 months (95% CI, 16.2–23.8), with a 36-month overall survival rate of 33% (95% CI, 24–43).

Subgroup Analysis: Prior Later-Line Exposure

A post hoc analysis compared the overall cohort with a subgroup of 37 patients already exposed to later-line standard therapies (regorafenib, trifluridine/tipiracil with or without bevacizumab, or fruquintinib) before enrolling. The abstract characterizes efficacy in the late-line-exposed subgroup as consistent with the overall cohort.

Safety Profile

The most frequently reported treatment-related adverse events in the abstract were diarrhea (39% any grade, 8% grade 3 or higher) and fatigue (37% any grade, 2% grade 3 or higher). Other adverse event categories and their grade breakdowns were not specified in the available abstract.

Interpretation and Broader Context

For context, standard later-line therapies have historically produced modest survival gains in unselected refractory mCRC populations. In the phase 3 CORRECT trial, regorafenib improved median overall survival to 6.4 months versus 5.0 months with placebo (HR 0.77, 95% CI 0.64–0.94). In the phase 3 RECOURSE trial, trifluridine/tipiracil improved median overall survival to 7.1 months versus 5.3 months with placebo (HR 0.68, 95% CI 0.58–0.81, P < .001). These are historical, cross-study benchmarks from unselected refractory mCRC populations — not head-to-head comparisons against the botensilimab-balstilimab cohort described here, which enrolled a distinct population (MSS mCRC without active liver metastases) under different trial conditions.

Within that context, a 21.2-month median overall survival and 33% three-year survival rate in a heavily pretreated MSS mCRC population without active liver metastases represents a notably longer survival tail than those historical benchmarks, though cross-trial comparisons should be interpreted cautiously given differences in patient selection and trial design.

Limitations

This is a single-arm, non-randomized, open-label phase 1b expansion cohort with no concurrent control arm; its primary objective was safety, and efficacy measures, including overall survival, were secondary or exploratory endpoints rather than the trial's statistical basis. The late-line-exposed comparison is a post hoc subgroup analysis of only 37 patients and was not a prespecified, powered comparison. The historical benchmarks from the CORRECT and RECOURSE trials are cross-study comparisons rather than a concurrent randomized control, and differences in patient selection — notably, this cohort excluded patients with active liver metastases — limit how directly survival figures can be compared. The manuscript is based on a conference abstract rather than a full peer-reviewed publication, and sponsor-disclosed figures beyond the abstract (such as additional survival and safety rates from the ESMO GI 2026 presentation) have not yet undergone peer review.