Extended follow-up from the phase Ib C-800-01 trial showed durable responses and long-term survival with botensilimab plus balstilimab (BOT/BAL) in patients with microsatellite-stable metastatic colorectal cancer (MSS mCRC) without active liver metastases.
The results were published on September 21, 2026, in Clinical Cancer Research in the article, “Extended Follow-up of Botensilimab plus Balstilimab in an Expanded Cohort of Microsatellite-Stable Metastatic Colorectal Cancer without Active Liver Metastases.”
Authors: Benjamin L. Schlechter, Marwan G. Fakih, Apostolia M. Tsimberidou, Andrea J. Bullock, Agustin Pimentel, Sunil Sharma, Heinz-Josef Lenz, Michael S. Gordon, Ghassan K. Abou-Alfa, Thomas U. Marron, Robert W. Lentz, Wells Messersmith, Ian Chau, Bruno Bockorny, Dhan Chand, Manushak Avagyan, Wei Wu, Benny Johnson, Joseph E. Grossman, Steven J. O’Day, Anthony B. El-Khoueiry, and Neil H. Segal.
Why the Study Was Conducted
Most patients with advanced colorectal cancer have microsatellite-stable or mismatch repair–proficient disease. This subtype has historically responded poorly to immune checkpoint inhibitors and remains an area of high unmet need, particularly after progression on standard systemic therapies.
The study focused on patients without active liver metastases. In this report, this group included patients with either definitively treated liver metastases or no history of liver metastases. The authors noted that active liver metastases may be associated with an immunosuppressive tumor microenvironment that can reduce systemic antitumor immunity.
Botensilimab is an Fc-enhanced anti–CTLA-4 antibody designed to support antigen-presenting cell activation, T-cell priming and memory, and reduction of intratumoral regulatory T cells. Balstilimab is an anti–PD-1 antibody. The rationale for combining the two agents was to test whether this immune approach could produce activity in MSS colorectal cancer, a disease usually considered immunologically “cold.”
Study Design
C-800-01 was an open-label, multicenter phase Ib trial evaluating botensilimab with or without balstilimab. This report included the fully enrolled cohort of 123 patients with MSS metastatic colorectal cancer without active liver metastases. Patients were enrolled and treated between May 11, 2020, and September 29, 2023, at 15 sites in the United States and the United Kingdom. The current data cutoff was December 13, 2025.
Eligible patients were at least 18 years old, had measurable disease by RECIST v1.1, ECOG performance status 0 or 1, adequate organ function, and confirmed metastatic or locally advanced disease. Prior anti–PD-(L)1 with or without anti–CTLA-4 therapy was permitted, and there was no limit on the number of previous treatment lines.
Patients received botensilimab 1 mg/kg or 2 mg/kg intravenously every 6 weeks plus balstilimab 3 mg/kg intravenously every 2 weeks. Treatment continued for up to 2 years or until disease progression or unacceptable toxicity.
The primary objective was safety and tolerability. Efficacy endpoints included objective response rate, duration of response, disease control rate, and progression-free survival; clinical benefit rate was also assessed, and overall survival was exploratory. The study also included an exploratory post hoc analysis of patients previously exposed to later-line therapies, defined as prior regorafenib, trifluridine/tipiracil with or without bevacizumab, or fruquintinib.
Patient Population
A total of 123 patients were treated. The median follow-up was 20.2 months, with a range of 0.7 to 62.3 months. The reverse Kaplan–Meier median follow-up estimate was 34.8 months. The median age was 56 years. All patients had MSS/pMMR disease and no active liver metastases. Sixteen percent had definitively treated liver metastases, while 84% had no history of liver metastases.
The study population was heavily pretreated. Patients had received a median of 3 prior lines of therapy, with 67% having received at least 3 prior lines. Thirty percent had previously received at least 1 regimen of regorafenib, trifluridine/tipiracil with or without bevacizumab, or fruquintinib. Fifteen percent had prior exposure to anti–PD-(L)1 with or without anti–CTLA-4 therapy.
Metastatic burden was also substantial. Sixty-nine percent of patients had metastases in at least 2 sites. The most common metastatic sites were lung, lymph nodes, and peritoneum.
Efficacy Results
In the overall population, the confirmed objective response rate was 21%, with 26 responses among 123 patients. Responses included 3 complete responses and 23 partial responses. The response rate was consistent across the two botensilimab dose groups. The objective response rate was 21% with botensilimab 1 mg/kg plus balstilimab and 21% with botensilimab 2 mg/kg plus balstilimab.
The median duration of response was not reached. Duration of response ranged from 1.9 months to at least 37.4 months, and 10 responses were ongoing at the data cutoff. The disease control rate at 6 weeks or later was 69%, and the clinical benefit rate at 24 weeks or later was 28%.
Median progression-free survival was 4.0 months. The 12-month progression-free survival rate was 23%, and the 18-month progression-free survival rate was 18%. Median overall survival was 21.2 months. The 12-month overall survival rate was 65%, the 24-month overall survival rate was 41%, and the 36-month overall survival rate was 33%. At last follow-up, 21 patients were alive and off all therapy, including 13 responders.
Late-Line Exposed Subgroup
The exploratory post hoc subgroup included 37 patients who had previously received at least 1 later-line regimen of regorafenib, trifluridine/tipiracil with or without bevacizumab, or fruquintinib.
In this subgroup, the confirmed objective response rate was 22%, with 8 responses among 37 patients. These included 1 complete response and 7 partial responses. The median duration of response was 16.6 months, with duration of response ranging from 1.9 months to at least 24.3 months. Two responses were ongoing at the data cutoff.
The disease control rate was 70%, and the clinical benefit rate was 27%. Median progression-free survival was 4.1 months. Median overall survival was 16.2 months, with 12-month, 24-month, and 36-month overall survival rates of 54%, 35%, and 30%, respectively.
Safety Findings
No new safety signals were observed with extended follow-up. All patients experienced a treatment-emergent adverse event, and 73% had grade 3 or higher treatment-emergent adverse events. Treatment-related adverse events occurred in 92% of patients, with grade 3 or higher events in 41%.
The most common treatment-related adverse events were diarrhea, reported in 39% of patients; fatigue, reported in 37%; and pyrexia, reported in 24%. Grade 3 or higher diarrhea occurred in 8%, grade 3 or higher fatigue in 2%, and grade 3 or higher pyrexia in 3%. Treatment-related adverse events led to discontinuation of both botensilimab and balstilimab in 17% of patients. No treatment-related deaths were reported.
Treatment-related immune-mediated adverse events occurred in 59% of patients. Grade 3 immune-mediated adverse events occurred in 29%, and grade 4 events occurred in 1%. No grade 5 immune-mediated adverse events were reported. The most common immune-mediated adverse event was immune-mediated diarrhea/colitis, reported in 41% of patients, with grade 3 or higher events in 15%. Other immune-mediated adverse events included thyroid disorders, pulmonary events, and hepatitis.
Immune-mediated adverse events were dose dependent, with lower rates of any-grade immune-mediated adverse events and immune-mediated diarrhea/colitis in patients receiving botensilimab 1 mg/kg plus balstilimab compared with botensilimab 2 mg/kg plus balstilimab. Among the 51 patients with immune-mediated diarrhea/colitis, 98% of events resolved. The median time to resolution from onset was 14 days.
Biomarker Findings
Exploratory biomarker analyses evaluated PD-L1 expression and tumor mutational burden. Responses were observed in tumors with low tumor mutational burden and in tumors with PD-L1 combined positive score of 0. Tumor mutational burden did not significantly differ between responders and nonresponders and did not correlate with best percent change in target lesions from baseline.
PD-L1 combined positive score also did not significantly differ between responders and nonresponders and did not correlate with best percent change in target lesions.
Among responders with clinical tissue-based next-generation sequencing data available, none had tumor mutational burden greater than 13 mutations per megabase, and none had a POLE mutation associated with hypermutation. The authors concluded that these conventional immunotherapy biomarkers did not reliably differentiate responders from nonresponders to botensilimab plus balstilimab.
Study Limitations
The authors noted several limitations. The study was a nonrandomized, open-label phase 1b cohort without a control arm, which limits cross-trial comparisons and prevents definitive efficacy conclusions.
The cohort was restricted to patients without active liver metastases. Although this was biologically justified, it may have enriched for patients with more favorable prognosis and limits generalizability to patients with active liver metastases. The late-line exposed subgroup analysis was exploratory, post hoc, and not powered for formal comparison. Biomarker analyses were also limited by data availability.
The authors stated that ongoing randomized studies are needed to confirm clinical benefit and better define which patients are most likely to derive durable benefit from botensilimab plus balstilimab.
Takeaway
With extended follow-up, botensilimab plus balstilimab demonstrated durable antitumor activity and long-term survival in heavily pretreated patients with MSS metastatic colorectal cancer without active liver metastases.
The regimen produced a confirmed objective response rate of 21%, a median overall survival of 21.2 months, and 24-month and 36-month overall survival rates of 41% and 33%. Safety remained manageable, with no treatment-related deaths and no new safety signals. These findings support further phase 3 evaluation of botensilimab plus balstilimab in MSS metastatic colorectal cancer without active liver metastases.
