Conventional immunotherapy is largely ineffective in treating microsatellite stable metastatic colorectal cancer (MSS mCRC), and options remain limited for patients who progress on prior chemotherapy.
In clincal studies, botensilimab (BOT; AGEN1181; Agenus), a Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody that blocks designed to expand therapy by leveraging novel mechanisms of action that enhance T-cell priming, regulatory T-cell depletion, and macrophage and dendritic cell activation to overcome the immunologically cold or poorly immunogenic solid tumors, including MSS mCRC, with or without balstilimab (BAL; AGEN2034; Agenus), has shown great promise.
Balstilimab is a fully human monoclonal IgG4 antibody that blocks PD-1 (programmed cell death-1) from interacting with its ligands PD-L1 and PD-L2. By inhibiting the PD-1 checkpoint pathway, balstilimab aims to restore T-cell activity against tumors and sustains the activated immune response and has demonstrated durable clinical responses across multiple treatment-refractory solid tumors including 3L+ MSS mCRC with no active liver metastases (NLM). [1]
To date, approximately 1,200 patients have been treated with botensilimab and/or balstilimab in Phase 1 and 2 trials.
Results the combination of botensilimab and balstilimab achieved a two-year survival rate of 42% along with a now more mature 21-month median overall survival (OS) in an expanded cohort of 123 patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) without active liver metastases (NLM).
The new botensilimab + balstilimab data were presented at the 2025 European Society for Medical Oncology Gastrointestinal Cancers Congress (ESMO-GI) held in Barcelona, Spain, July 2 to 5, 2025, along with regulatory updates from its July 1, 2025 End-of-Phase 2 (EoP2) meeting with the U.S. Food and Drug Administration (FDA).
ESMO‑GI Highlights
The new data presented at ESMO-GI represent an approximate 40% increase in number of patients (n=123) compared to earlier reports published in Nature Medicine in 2024.
The expanded dataset demonstrates continued durability of tumor responses and median overall survival approaching two years in an immunotherapy-resistant treatment setting. Among these 123 heavily pretreated MSS mCRC patients (third-line or later) treated with BOT/BAL, the confirmed objective response rate (ORR) was 20%, with a median duration of response (DOR) of 16.6 months.
The disease control rate (DCR, responses plus stable disease) was 69%.
Notably, median overall survival (OS) reached 20.9 months, with 42% of patients still alive at two years in this refractory population.
Patients in fourth-line or later (n=37), having exhausted all standard therapies, saw similar benefits, with a ~19% ORR and 43% two-year survival. These findings are particularly meaningful in this refractory population for which best supportive care has been historically limited to roughly 5-8 months median overall survival.
No new safety signals were observed. Immune-related side effects were manageable and no treatment-related deaths occurred. The combination was tolerated across dose levels.
“These results reinforce the consistency and durability of the botensilimab plus balstilimab combination in a population that has historically seen minimal benefit from immune checkpoint blockade,” noted Benjamin L. Schlechter, MD, of Dana-Farber Cancer Institute, who presented the data.
“For patients with MSS colorectal cancer who have exhausted standard therapies, this combination is showing the kind of meaningful, long-lasting benefit we rarely see in this setting. It has the potential to fundamentally shift how we treat this disease,” Schlechter added.
“Deep, durable responses and survival plateaus emerging at two years and beyond are rarely seen in microsatellite stable refractory colorectal cancer – they are usually only seen in highly immunogenic tumors,” explained Steven O’Day, MD, Chief Medical Officer of Agenus.
“These data reinforce the potential for a chemo‑free option in a population with limited alternatives,” O’Day further noted.
Clinical Urgency
The FDA reviewed the data presented at ESMO GI and, based on the outcomes of the study, approved the therapy for phase 3 trials and ‘expanded access’ use. As a result, colon cancer patients in the most dire need can receive the new therapy.
“Colorectal cancer is rising fastest in people under 50 and is projected to become the leading cause of cancer death in that age group by 2030,” said Richard Goldberg, M.D., Chief Development Officer, Agenus.
“Given the dismal five‑to‑eight‑month median survival with current late‑line therapies, making the combination od botensilimab plus balstilimab available quickly is not just prudent—it is imperative,” Goldberg further noted.
Clinical trials
Fc-Engineered Anti-CTLA-4 Monoclonal Antibody in Advanced Cancer – ClinicalTrials.gov ID NCT03860272
Reference
[1] Bullock AJ, Schlechter BL, Fakih MG, Tsimberidou AM, Grossman JE, Gordon MS, Wilky BA, Pimentel A, Mahadevan D, Balmanoukian AS, Sanborn RE, Schwartz GK, Abou-Alfa GK, Segal NH, Bockorny B, Moser JC, Sharma S, Patel JM, Wu W, Chand D, Rosenthal K, Mednick G, Delepine C, Curiel TJ, Stebbing J, Lenz HJ, O’Day SJ, El-Khoueiry AB. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. 2024 Sep;30(9):2558-2567. doi: 10.1038/s41591-024-03083-7. Epub 2024 Jun 13. PMID: 38871975; PMCID: PMC11405281.
[2] Kasi PM, Hidalgo M, Jafari MD, Yeo H, Lowenfeld L, Khan U, Nguyen ATH, Siolas D, Swed B, Hyun J, Khan S, Wood M, Samstein B, Rocca JP, Ocean AJ, Popa EC, Hunt DH, Uppal NP, Garrett KA, Pigazzi A, Zhou XK, Shah MA, Hissong E. Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer. Oncogene. 2023 Oct;42(44):3252-3259. doi: 10.1038/s41388-023-02835-y. Epub 2023 Sep 21. PMID: 37731056; PMCID: PMC10611560.
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