Agenus BOT+BAL Shows 33% Three-Year Survival in Immunotherapy-Resistant Colorectal Cancer

Agenus Inc. announced today that updated three-year follow-up data from its phase 2 trial of botensilimab (BOT) plus balstilimab (BAL) in refractory microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) will be presented at the European Society for Medical Oncology Gastrointestinal Cancers Congress (ESMO GI 2026), demonstrating a 33% overall survival (OS) rate at three years — a result the company is characterizing as landmark in a population where immunotherapy has historically failed to produce meaningful benefit.¹ The findings extend a body of evidence that is reshaping how the biopharmaceutical field approaches immunologically resistant solid tumors, and position BOT+BAL as a potential first immunotherapy regimen to demonstrate durable, long-term survival in this setting.

Why has MSS colorectal cancer been such a difficult target for immunotherapy?

Approximately 95% of metastatic colorectal cancers are microsatellite-stable — characterized by an intact DNA mismatch repair system, low tumor mutational burden, and an immunosuppressive tumor microenvironment with minimal infiltrating T cells.² These features render MSS mCRC intrinsically resistant to conventional PD-1 and CTLA-4 checkpoint inhibitors, which depend on pre-existing immune activation to work. Large randomized trials of pembrolizumab, nivolumab, and ipilimumab in MSS mCRC have consistently shown overall response rates below 5% and no survival benefit compared with standard chemotherapy.³ Until recently, the field had largely concluded that MSS mCRC was immunotherapy-resistant by definition.

The only subset showing even modest checkpoint inhibitor activity has been patients without active liver metastases, a subgroup thought to be less profoundly immunosuppressed than those with hepatic disease — a distinction that has become central to BOT+BAL's clinical development strategy.

What makes botensilimab mechanistically different from standard anti-CTLA-4 antibodies?

Botensilimab is not a conventional anti-CTLA-4 antibody. It is a next-generation, Fc-enhanced anti-CTLA-4 monoclonal antibody engineered to activate both innate and adaptive arms of the immune system simultaneously — a dual mechanism designed to generate de novo immune responses even in tumors with cold, immunologically inert microenvironments.¹ The Fc enhancement drives superior engagement of innate immune cells (including macrophages and NK cells) via Fc gamma receptor binding, amplifying the immunostimulatory signal beyond what conventional CTLA-4 blockade produces. Balstilimab is a fully human IgG4 anti-PD-1 monoclonal antibody that complements botensilimab by blocking the PD-1/PD-L1 axis and sustaining T-cell activity once immune priming has occurred.¹

As Atul Mohindra, head of Biologics R&D at Lonza, noted in a recent BioPharm International feature on next-generation antibody engineering, biological pipelines are evolving from standard antibody formats to next-generation biologics such as bispecific and Fc-engineered antibodies "due to these molecules' increased potential for precision targeting and higher potency" — a principle directly embodied in botensilimab's Fc-optimized design.

What did the three-year data show?

The updated dataset reported today includes patients with refractory MSS mCRC without active liver metastases treated with BOT+BAL in the phase 2 trial (NCT05608044).¹ Key findings presented at ESMO GI 2026:

• 33% three-year overall survival rate — with a Kaplan-Meier curve plateau emerging beyond two years, indicative of a subset of patients achieving durable long-term benefit
• 17% of patients alive and off all systemic therapy at last follow-up — a finding with no precedent in third-line or later MSS mCRC
• Mature median OS of 21 months in this population, building on the 42% two-year OS rate reported in earlier interim analysis⁴
• Safety profile consistent with prior reporting, with no new signals emerging at extended follow-up¹

"These data reaffirm our conviction that BOT+BAL has created a unique immunological imprint in MSS colorectal cancer — not just delaying progression, but potentially curing a subset of patients who had no curative options available," said Steve O'Day, MD, Chief Medical Officer of Agenus. "A Kaplan-Meier plateau with 17% of patients off all therapy is not something we have seen in this population before."¹

The liver metastasis exclusion remains an important clinical qualifier — the immunosuppressive hepatic microenvironment appears to limit BOT+BAL's efficacy in patients with active liver disease, and the company's ongoing phase 3 confirmatory trial is designed accordingly.¹

What is the path to regulatory approval?

Agenus is advancing BOT+BAL toward a phase 3 confirmatory trial in MSS mCRC without active liver metastases, supported by the global development and manufacturing collaboration with Zydus Lifesciences announced in 2025 and closed in February 2026, which secured dedicated US biologics manufacturing capacity in California and provided $141 million in strategic capital.⁴ Under the agreement, Zydus holds exclusive rights to develop and commercialize BOT and BAL in India and Sri Lanka. The phase 3 design and regulatory pathway discussions with the FDA are ongoing.¹

BOT+BAL is also being evaluated in earlier lines of CRC and in other tumor types, including a pilot study of BOT+BAL combined with stereotactic body radiation therapy (SBRT) in non-MSI-H colorectal cancer with liver metastasis (NCT07128355) — a strategy aimed at using local ablation to overcome the hepatic immunosuppression barrier that has limited activity in liver-metastatic disease.⁵

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. (2026 Jul 6). Business Wire. https://www.businesswire.com/news/home/20260706344475/en/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
2. Ros J, Balconi F, Baraibar I, et al. (2023 Feb 2). Advances in immune checkpoint inhibitor combination strategies for microsatellite stable colorectal cancer. Front Oncol. https://pubmed.ncbi.nlm.nih.gov/36816981/
3. Gilson A, Tan V, Koessler T, et al. (2025 Jun 14). Immune checkpoint inhibitors for metastatic colorectal cancer: a systematic review. Cancers (Basel). https://pubmed.ncbi.nlm.nih.gov/40647424/
4. Jacobus, N. (2026 Jan 15). Agenus Closes $141 Million Immunotherapy Collaboration with Zydus Lifesciences. BioPharm International. https://www.biopharminternational.com/view/agenus-closes-141-million-immunotherapy-collaboration-zydus-lifesciences
5. Botensilimab, Balstilimab, and SBRT in Colorectal Cancer. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT07128355
6. Bullock AJ, Schlechter BL, Fakih MG, et al. (2024 Sep). Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. https://pubmed.ncbi.nlm.nih.gov/38871975/
7. A Study of Botensilimab and Balstilimab for the Treatment of Colorectal Cancer. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05608044