Botensilimab Plus Balstilimab Yields 33% OS Rate at 3 years in MSS mCRC

Botensilimab (BOT) plus balstilimab (BAL) produced durable survival in patients with refractory microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) without active liver metastases, according to extended follow-up data from the phase 1b C-800-01 trial (NCT03860272), presented at the 2026 European Society for Medical Oncology Gastrointestinal Cancers (ESMO GI) Congress 2026.¹

The median overall survival (OS) was 21.2 months and the three-year OS rate was 33%. The 24-month OS rate was 41%, with the Kaplan-Meier curve showing a plateau beyond two years. Among the 123 enrolled patients, a confirmed objective response rate (ORR) of 21% was achieved, comprising 3 complete responses and 23 partial responses. Median duration of response was not reached, with responses ranging from 1.9 months to at least 37.4 months.

The disease control rate at 6 weeks was 69%, clinical benefit rate at 24 weeks was 28%, and tumor regression was observed in more than 40% of patients. Seventeen percent of patients (n = 21) were alive and off all systemic anticancer therapy at last follow-up, including 13 responders, with a subset remaining free from subsequent therapy or death for more than two years.1

In a post hoc analysis of 37 patients with late-line exposure, defined as having received at least one prior regimen of regorafenib, trifluridine/tipiracil with or without bevacizumab, or fruquintinib, the combination produced a confirmed ORR of 22%, median OS of 16.2 months, a three-year OS rate of 30%, median duration of response of 16.6 months, disease control rate of 70%, and clinical benefit rate of 27% at 24 weeks.1

These results build on earlier phase 1 data from C-800-01 that had previously shown durable responses and a manageable safety profile in the same population, forming the clinical basis for the ongoing phase 3 BATTMAN trial.1

"These three-year data are important because they show a pattern of benefit that is not typically expected in refractory MSS colorectal cancer," said presenting author Benjamin L. Schlechter, MD, of Dana-Farber Cancer Institute. "These are patients who had received multiple prior lines of therapy and had few remaining options. Seeing a subset of patients remain alive and off systemic anticancer therapy after treatment speaks to the clinical relevance of these results and the potential for botensilimab plus balstilimab to change expectations for what immunotherapy may achieve in this setting."1

Safety of Botensilimab Plus Balstilimab

With extended follow-up, no new safety signals were identified and no treatment-related deaths occurred. Immune-mediated diarrhea/colitis resolved in 98% of affected patients, with a median time to resolution of 14 days from onset. Immune-mediated diarrhea/colitis was the most common immune-mediated adverse event, occurring in 42% of patients overall (grade 3 or higher, 15%). The phase 3-selected dose of BOT 1 mg/kg plus BAL showed improved tolerability relative to the 2 mg/kg regimen, with immune-mediated diarrhea/colitis rates of 27% (grade 3 or higher, 10%).¹

Study Design and Patient Population

C-800-01 is a first-in-human, phase 1b clinical trial evaluating botensilimab with or without balstilimab in adults with advanced solid tumors. The MSS mCRC without active liver metastases cohort enrolled 123 patients who received BOT at 1 mg/kg or 2 mg/kg every 6 weeks plus BAL 3 mg/kg every 2 weeks. The primary endpoint was safety and tolerability; secondary endpoints included ORR, duration of response, disease control rate, and progression-free survival, with OS as an exploratory endpoint. Patients had received a median of 3 prior lines of therapy; 67% had received at least 3 prior lines, 15% had received prior anti-PD-(L)1 with or without anti-CTLA-4 therapy, and 30% had received at least one prior late-line regimen.¹

Available later-line standards in refractory MSS mCRC without active liver metastases, including regorafenib, trifluridine/tipiracil with or without bevacizumab, and fruquintinib, have historically been associated with median OS of approximately 10 to 14 months in relevant analyses. Against this backdrop, the three-year OS rate and treatment-free survival observed with BOT plus BAL are notable, though the single-arm, phase 1b design and selected patient population (those without active liver metastases) limit direct cross-trial comparison.

Botensilimab is an Fc-enhanced anti-CTLA-4 antibody designed to augment both innate and adaptive antitumor immune responses in immunologically cold tumors, a population that includes MSS mCRC. Its Fc enhancement is intended to increase depletion of intratumoral regulatory T cells and activation of myeloid cells beyond what standard CTLA-4 blockade achieves.1 Balstilimab is a fully human anti-PD-1 monoclonal antibody that has been evaluated in more than 900 patients across multiple tumor types.¹

Next Steps and Regulatory Path for the Combination

A separate, randomized, open-label phase 2 study (NCT05608044) was conducted to build on the phase 1b findings, evaluating BOT monotherapy and BOT plus BAL in patients with refractory MSS mCRC without active liver metastases. Topline interim data from the phase 2 trial showed trends consistent with the phase 1b experience, with an ORR of 19.4% and a 6-month OS rate of 90% for the BOT 75 mg plus BAL combination. The safety profile was manageable with no new signals observed.²

Following an end-of-phase 2 meeting with the FDA in 2024, the agency advised against filing for accelerated approval of BOT plus BAL, concluding that the ORRs observed may not reliably translate to a survival benefit.² Accordingly, the FDA and Agenus reached agreement on the design of a phase 3 trial of the regimen. The ongoing phase 3 BATTMAN trial is now evaluating BOT/BAL plus best supportive care vs a control arm of best supportive care alone in patients with refractory MSS/proficient mismatch repair mCRC.¹

For expert insight on botensilimab plus balstilimab watch Targeted Oncology’s interview with Marwan G. Fakih, MD, professor in the Department of Medical Oncology & Therapeutics Research, who codirects the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center.

References

1. Agenus reports landmark BOT+BAL data showing 33% three-year overall survival in refractory MSS metastatic colorectal cancer without active liver metastases at ESMO GI 2026. News release. Agenus Inc. July 6, 2026. Accessed July 6, 2026. https://investor.agenusbio.com/news/news-details/2026/Agenus-Reports-Landmark-BOTBAL-Data-Showing-33-Three-Year-Overall-Survival-in-Refractory-MSS-Metastatic-Colorectal-Cancer-Without-Active-Liver-Metastases-at-ESMO-GI-2026/default.aspx

2. Agenus announces end-of-phase-2 meeting outcomes and topline interim phase 2 data for BOT/BAL in MSS colorectal cancer. News release. Agenus Inc. July 18, 2024. Accessed July 6, 2026. https://investor.agenusbio.com/news/news-details/2024/Agenus-Announces-End-of-Phase-2-Meeting-Outcomes-and-Topline-Interim-Phase-2-Data-for-BOTBAL-in-MSS-Colorectal-Cancer/default.aspx