Botensilimab/Balstilimab Elicits Sustained Efficacy in MSS Metastatic CRC

The combination attained a 42% 2-year survival rate as well as a median overall survival of 20.9 months among 123 patients with MSS metastatic CRC.

The combination of botensilimab and balstilimab elicited sustained survival outcomes in patients with microsatellite-stable (MSS) metastatic colorectal cancer (CRC) without active liver metastases, according to findings from the phase 2 C-800-01 trial (NCT03860272) exhibited in a news release from the drug’s developer, Agenus Inc.1

Specifically, the combination attained a 42% 2-year survival rate as well as a median overall survival (OS) of 20.9 months among 123 patients with MSS metastatic CRC. Furthermore, data presented at the European Society for Medical Oncology Gastrointestinal Cancers Congress (ESMO-GI) 2025 revealed that the confirmed objective response rate (ORR) among these patients was 20% and the median duration of response (DOR) was 16.6 months.2 The disease control rate (DCR) was 69%.

Those treated in the fourth line or later saw a similar ORR of approximately 19% as well as a 43% 2-year survival rate. According to the developers, these findings are meaningful for a population historically limited to a maximum median OS of 8 months. Furthermore, no new safety signals were observed in the trial, with immune-related adverse effects (AEs) being manageable, no treatment-related deaths observed, and the combination exhibiting tolerability across dose levels.

“These results reinforce the consistency and durability of the botensilimab plus balstilimab combination in a population who has historically seen minimal benefit from immune checkpoint blockade,” Benjamin Schlechter, MD, senior physician at the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute and phase 1 C-800-01 trial presenter at ESMO-GI, said in the news release.1 “For patients with MSS colorectal cancer who have exhausted standard therapies, this combination is showing meaningful, long-lasting benefit we rarely see in this setting. It has the potential to fundamentally shift how we treat this disease.”

Patients with solid tumors in the multicenter phase 1 C-800-01 trial were randomly assigned to receive botensilimab alone or in combination with balstilimab. Patients in the monotherapy arm received botensilimab in a 3 + 3 dose-escalation design in 3-week or 6-week intervals.3 In the 3-week arm, patients received intravenous botensilimab starting at 0.1 mg/kg up to 4 mg/kg for up to 2 years, and in the 6-week monotherapy arm, patients started at 1 mg/kg up to 4 mg/kg for up to 2 years.

In the MSS metastatic CRC cohort, patients were treated with botensilimab at 1 mg/kg or 2 mg/kg every 6 weeks and balstilimab at 3 mg/kg every 2 weeks for a maximum of 2 years. Patients in the study were heavily pretreated, and none had active liver metastases.

The coprimary end points of the trial were the incidence of AEs, dose-limiting toxicities, and the recommended phase 2 dose of botensilimab. Secondary end points included ORR, DOR, DCR, progression-free survival, and OS.

According to minutes from an FDA clinical outcomes meeting held on July 1, 2025, the FDA wrote that the current data “appear to support” balstilimab’s contribution to the combination’s clinical activity, suggesting a phase 3 trial may proceed without a botensilimab monotherapy arm. Additionally, the FDA and the developers have aligned on the core design of the phase 3 BATTMAN trial, which will be initiated in Q4 2025.

“[The] FDA’s acknowledgment of balstilimab’s role and its constructive guidance on the phase 3 trial mark a pivotal step forward. We have incorporated the agency’s input and are moving swiftly to launch BATTMAN while continuing to mature our existing data set,” Jennifer Buell, PhD, executive chair of Agenus, stated in the news release.1 “We intend to use every expedited pathway…to bring this [chemotherapy]-free option to patients who have exhausted all other treatments.”

References

1. Agenus’ BOT/BAL achieves 42% two-year survival in refractory MSS CRC, advances toward registration with FDA alignment on phase 3. News release. Agenus Inc. July 7, 2025. Accessed July 9, 2025. https://tinyurl.com/yxkc3atd
2. Schlechter B. Botensilimab plus balstilimab achieves 42% two-year survival in refractory MSS mCRC without active liver metastases. Presented at: European Society for Medical Oncology Gastrointestinal Cancers Congress 2025; July 2-5, 2025; Barcelona, Spain.
3. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Updated February 6, 2025. Accessed July 9, 2025. https://tinyurl.com/576jmjbe