BOT+BAL Yields Long-Term Survival in Patients With Refractory MSS mCRC

More than half of patients with refractory microsatellite-stable (MSS) metastatic colorectal cancer (CRC) without active liver metastases survived at least 18 months after starting botensilimab (BOT) plus balstilimab (BAL) in the phase 1b C-800-01 trial (NCT03860272), according to findings shared in a poster at the 2026 Society for Immunotherapy of Cancer (SITC) Annual Meeting and a news release from Agenus.^1,2

What did the long-term survivor analysis show?

Of 123 patients in the cohort, 63 (51%) were long-term survivors, defined as having an overall survival (OS) of at least 18 months from treatment initiation. The data cutoff was December 13, 2025. Among LTS, median OS was not reached (95% CI, 31.3 months-not reached [NR]), and 59% (95% CI, 43%-71%) were alive at 36 months. In the overall cohort, median OS was 21.2 months (95% CI, 16.2-23.8) and the 36-month OS rate was 33% (95% CI, 24%-43%).

The objective response rate among LTS was 35% (95% CI, 23%-48%), including 3 complete responses. Median duration of response was NR (95% CI, 12.1 months-NR), with responses ranging from 1.9 to at least 37.4 months and 10 ongoing at cutoff. At last follow-up, 15 of 63 LTS (24%) were alive and off all therapy, 13 of whom had responded.

What clinical features were associated with long-term survival?

Most baseline characteristics did not differ significantly between LTS and short-term survivors (n = 60), who were defined as having an OS of less than 18 months, including prior immunotherapy exposure, ECOG performance status, and prognostic biomarkers. Fewer prior lines of therapy were associated with long-term survival: 56% of LTS vs 78% of short-term survivors had received at least 3 prior lines (P = .008). The median number of BOT doses was 2 in both the overall cohort and LTS.

“For patients with metastatic MSS colorectal cancer without active liver metastases who have exhausted multiple therapies, living another year and a half or more is rare,” said presenting study author Thomas U. Marron, MD, PhD, of the Tisch Cancer Center at Mount Sinai.¹ “What is particularly interesting is that the long-term survivors did not fit a single favorable clinical profile. Durable benefit was seen even in patients previously treated with immunotherapy, and a subset remains alive without any further cancer treatment. These findings suggest the potential to meaningfully change the course of disease and provide a compelling rationale for evaluating this approach earlier in treatment.”

What was the design of the C-800-01 trial?

C-800-01 is a first-in-human phase 1b trial of BOT with or without BAL in patients with advanced solid tumors. The cohort analyzed included 123 patients with relapsed or refractory MSS metastatic CRC without active liver metastases, as determined by local assessment, with an ECOG performance status of 0 or 1. Prior immune checkpoint inhibitor therapy was allowed. Patients received BOT, an Fc-enhanced anti–CTLA-4 antibody, at 1 mg/kg or 2 mg/kg every 6 weeks plus BAL, an anti–PD-1 antibody, at 3 mg/kg every 2 weeks. Efficacy end points included objective response rate per RECIST 1.1 by investigator, duration of response, disease control rate, clinical benefit rate, progression-free survival, and OS. The safety end point was immune-mediated adverse effects (imAEs). LTS (OS of at least 18 months from treatment initiation) and short-term survivors were defined post hoc, and baseline characteristics were compared between the groups using Fisher’s exact test. The data cutoff was December 13, 2025.

What adverse effects occurred in long-term survivors?

imAEs of any grade occurred in 75% of LTS (grade 3 or higher, 38%) vs 59% (grade 3 or higher, 30%) in the overall cohort. Immune-mediated diarrhea/colitis was the most common, occurring in 54% of LTS (grade 3 or higher, 19%), and resolved in 33 of 34 LTS (97%), with a median time to resolution of 13 days (IQR, 8-22). The poster said immune-mediated diarrhea/colitis was managed with early mid-dose oral steroids followed by tumor necrosis factor-α therapy and a rapid steroid taper. No treatment-related deaths occurred.

What is the regulatory status of botensilimab and balstilimab?

BOT and BAL are investigational outside Armenia and are not approved by the FDA. Armenia granted the first marketing authorizations for eligible adults with MSS metastatic CRC without active liver metastases, according to the release.¹

Previously, Agenus decided in July 2026 to stop financial support for the phase 3 CO.33/BATTMAN trial (NCT07152821) of BOT plus BAL in late-line MSS metastatic CRC to focus on neoadjuvant development in the planned phase 3 ROBBIN trial.³

References

1. Agenus reports more than half of patients with refractory MSS metastatic colorectal cancer achieved long-term survival following BOT+BAL treatment at SITC 2026. News release. Agenus Inc. November 6, 2026. Accessed November 6, 2026. https://tinyurl.com/3czencn5
2. El-Khoueiry AB, Bullock AJ, Fakih MG, et al. Clinical features of long-term survivors treated with next-generation anti–CTLA-4 (botensilimab) plus anti–PD-1 (balstilimab) in refractory microsatellite-stable metastatic colorectal cancer. Poster presented at: Society for Immunotherapy of Cancer 2026; November 4-8, 2026; Phoenix, AZ. Poster 472.
3. Agenus announces oversubscribed private placement of up to $340 million to advance registrational ROBBIN trial of neoadjuvant BOT+BAL in MSS colon cancer. News release. Agenus Inc. July 13, 2026. Accessed November 6, 2026. https://tinyurl.com/stpux5au