Agenus Reports Landmark Three-Year Phase 1b Data Showing Durable Survival with Botensilimab Plus Balstilimab in Refractory MSS Metastatic Colorectal Cancer
Agenus Inc., a biotechnology company focused on advancing next-generation immuno-oncology therapies, has announced encouraging three-year follow-up data from its fully enrolled Phase 1b C-800-01 clinical trial evaluating the combination of botensilimab (BOT) and balstilimab (BAL) in patients with refractory microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) without active liver metastases. The findings were presented during the European Society for Medical Oncology Gastrointestinal (ESMO GI) Congress 2026, held in Munich, Germany, highlighting what the company believes could represent an important advancement for a patient population that has historically derived limited benefit from immunotherapy.
The updated results demonstrate sustained long-term survival, durable tumor responses, prolonged treatment-free intervals, and a manageable safety profile following three years of follow-up. According to Agenus, the findings further strengthen the scientific rationale for its ongoing Phase 3 BATTMAN clinical trial, which is evaluating the combination in patients with refractory MSS/proficient mismatch repair (pMMR) metastatic colorectal cancer.
Addressing a Major Unmet Need in Colorectal Cancer
Metastatic colorectal cancer remains one of the leading causes of cancer-related mortality worldwide. Although immune checkpoint inhibitors have transformed the treatment landscape for several cancers, their benefit has largely been confined to tumors characterized by microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR).
Unfortunately, approximately 95% of metastatic colorectal cancers are microsatellite stable (MSS) or proficient mismatch repair (pMMR), making them considerably less responsive to currently available immunotherapies.
Patients whose disease progresses after standard chemotherapy and targeted therapies have relatively few treatment options. Approved later-line treatments—including regorafenib, trifluridine/tipiracil with or without bevacizumab, and more recently fruquintinib—have demonstrated modest improvements in survival, with median overall survival generally ranging from approximately 10 to 14 months.
Durable responses and long-term survival have historically been uncommon in this heavily pretreated population.
Against this backdrop, the three-year survival data reported by Agenus provide encouraging evidence that its investigational immunotherapy combination may be capable of overcoming some of the resistance mechanisms that have limited the effectiveness of conventional checkpoint inhibitors in MSS colorectal cancer.
Three-Year Survival Demonstrates Sustained Clinical Benefit
The updated analysis represents an additional year of follow-up beyond the two-year survival data previously presented at ESMO GI 2025.
With extended observation, investigators reported a median overall survival of 21.2 months among patients treated with botensilimab and balstilimab.
The Kaplan-Meier survival analysis demonstrated a plateau beyond two years, suggesting that a meaningful proportion of patients experienced sustained long-term benefit following treatment.
Overall survival rates reached 41% at 24 months and remained 33% at the three-year landmark.
In heavily pretreated MSS metastatic colorectal cancer, where durable survival has historically been uncommon, these results compare favorably with previously reported outcomes from available later-line therapies.
The persistence of the survival curve beyond two years also suggests that some patients continue to derive long-lasting benefit even after completing treatment.
Durable Responses Continue to Mature
In addition to improved survival, the updated analysis demonstrated durable objective tumor responses.
Investigators confirmed an objective response rate of 21%, including three complete responses and 23 partial responses.
Importantly, the median duration of response had not yet been reached after three years of follow-up.
Observed responses ranged from approximately two months to at least 37.4 months, indicating that many responding patients continued to benefit long after initiating therapy.
Tumor shrinkage was observed in more than 40% of treated patients.
The disease control rate reached 69% at the six-week assessment, while the clinical benefit rate at 24 weeks reached 28%.
These findings suggest that the combination not only induces measurable tumor regression in a subset of patients but also provides durable disease stabilization in many others.
Long-Term Treatment-Free Survival
Among the most noteworthy findings presented at ESMO GI was the observation that numerous patients remained alive without requiring additional systemic anticancer therapy.
At the most recent follow-up, 21 patients—representing 17% of the study population—remained alive and had not required any subsequent systemic cancer treatment.
Of these individuals, 13 had achieved confirmed objective responses.
Several patients remained free from additional therapy or disease-related death for more than two years.
Treatment-free survival has become an increasingly important measure in oncology because it reflects not only prolonged disease control but also periods during which patients may experience improved quality of life without ongoing treatment-related toxicities.
The ability to discontinue therapy while maintaining durable disease control remains a key objective of modern immuno-oncology.
Encouraging Results Despite Extensive Prior Treatment
The Phase 1b study enrolled patients whose disease had already progressed despite multiple prior therapies.
Overall, the fully enrolled cohort included 123 patients with MSS metastatic colorectal cancer lacking active liver metastases.
Participants had received a median of three previous lines of systemic therapy.
Approximately 67% had undergone at least three prior treatment regimens before entering the study.
Fifteen percent had previously received anti-PD-(L)1 therapy, with or without anti-CTLA-4 treatment, indicating that some patients had already experienced prior immunotherapy exposure.
Additionally, 30% had previously received one or more approved later-line agents, including regorafenib, trifluridine/tipiracil with or without bevacizumab, or fruquintinib.
These characteristics underscore the advanced nature of the study population and highlight the limited therapeutic options available to these patients.
Performance in Later-Line Treatment Subgroup
Investigators also performed a post hoc analysis focusing on 37 patients who had previously received one or more approved later-line therapies.
Within this particularly difficult-to-treat subgroup, the combination continued to demonstrate clinically meaningful activity.
The confirmed objective response rate reached 22%.
Median overall survival measured 16.2 months.
The three-year overall survival rate remained 30%.
Median duration of response reached 16.6 months.
The disease control rate was 70%, while the clinical benefit rate at 24 weeks reached 27%.
Although exploratory, these findings suggest that botensilimab plus balstilimab may retain activity even among patients whose disease has progressed after currently available later-line treatments.
Novel Checkpoint Combination Designed for Resistant Tumors
Botensilimab is an investigational Fc-enhanced multifunctional anti-CTLA-4 antibody engineered to stimulate broader antitumor immune activation than conventional CTLA-4 inhibitors.
Balstilimab is an investigational anti-PD-1 antibody designed to restore T-cell activity by blocking inhibitory immune checkpoint signaling.
According to Agenus, the combination was specifically designed to activate immune responses within tumors that have historically demonstrated resistance to traditional checkpoint inhibition.
Unlike standard checkpoint inhibitor combinations primarily developed for immunologically active tumors, botensilimab incorporates Fc-enhancement intended to improve activation of both innate and adaptive immune responses.
The company believes this broader immune activation may help overcome the immunologically “cold” tumor microenvironment commonly observed in MSS colorectal cancer.
Investigators Highlight Clinical Significance
Benjamin L. Schlechter, M.D., of Dana-Farber Cancer Institute and presenting author of the study, emphasized the importance of the three-year findings.
He noted that patients enrolled in the trial had already exhausted multiple prior treatment options and generally faced poor prognoses.
According to Dr. Schlechter, observing a subset of patients who remain alive and free from systemic anticancer therapy several years after treatment is not typically expected in refractory MSS colorectal cancer.
He stated that the durability of benefit demonstrated in the study suggests the combination may have the potential to redefine expectations regarding immunotherapy for this challenging disease.
Agenus Sees Foundation for Phase 3 Development
Steven O’Day, M.D., Chief Medical Officer of Agenus, described the combination as more than simply another checkpoint inhibitor regimen.
He explained that botensilimab and balstilimab were intentionally designed to activate antitumor immunity within cancers that have remained largely inaccessible to conventional immunotherapy.
According to O’Day, the longer follow-up continues to reveal the characteristics expected from a differentiated immunotherapy approach, including durable survival, sustained objective responses, treatment-free intervals, and an acceptable safety profile.
He added that these mature data strengthen the scientific foundation supporting the ongoing BATTMAN Phase 3 development program.
Favorable Long-Term Safety Profile
Safety findings remained generally consistent with previous analyses.
Importantly, investigators reported no new safety signals during the additional year of follow-up.
No treatment-related deaths occurred throughout the study.
Immune-mediated diarrhea and colitis represented the most frequently observed immune-related adverse event.
Overall, diarrhea or colitis occurred in 42% of patients, with grade 3 or higher events reported in 15%.
Encouragingly, 98% of affected patients experienced complete resolution of these events.
The median time to resolution measured approximately 14 days from symptom onset.
Investigators also reported improved tolerability with the Phase 3 dosing regimen of botensilimab administered at 1 mg/kg together with balstilimab.
Compared with the higher 2 mg/kg dose evaluated earlier in development, the selected regimen demonstrated lower rates of immune-mediated diarrhea and colitis.
Overall incidence declined to 27%, while grade 3 or higher events decreased to 10%.
These findings support continued clinical development using the lower-dose regimen selected for Phase 3 evaluation.
Supporting the Ongoing BATTMAN Trial
The mature efficacy and safety findings provide important support for Agenus’ ongoing randomized Phase 3 BATTMAN clinical trial.
The study is evaluating botensilimab plus balstilimab in patients with refractory MSS/proficient mismatch repair metastatic colorectal cancer.
If the encouraging Phase 1b findings are confirmed in the larger randomized trial, the combination could potentially represent a significant advancement for patients who currently have limited treatment options after progression on standard therapies.
The Phase 3 study will provide more definitive evidence regarding overall survival, response durability, and safety while helping determine the potential role of the regimen within future treatment paradigms.
Presentation at ESMO GI 2026
The updated data were presented during the European Society for Medical Oncology Gastrointestinal Cancers Congress 2026 in Munich, Germany.
The scientific presentation, titled “Botensilimab + Balstilimab in Microsatellite-Stable Metastatic Colorectal Cancer Without Active Liver Metastases: Extended Follow-Up and 3-Year Survival,” was delivered by Benjamin L. Schlechter, M.D., of Dana-Farber Cancer Institute.
The presentation summarized the final three-year follow-up from the fully enrolled Phase 1b cohort and highlighted both the clinical efficacy and long-term safety profile of the investigational combination.
The three-year Phase 1b findings represent one of the longest follow-up analyses reported for an investigational checkpoint inhibitor combination in refractory MSS metastatic colorectal cancer. With a median overall survival exceeding 21 months, a one-third three-year survival rate, durable objective responses, prolonged treatment-free intervals, and a manageable safety profile, botensilimab plus balstilimab continues to demonstrate encouraging potential in a disease setting where durable immunotherapy benefit has historically been rare.
While confirmation in the ongoing randomized Phase 3 BATTMAN trial will be essential before any regulatory decisions can be considered, the mature data presented at ESMO GI 2026 provide growing evidence that this novel immunotherapy combination may help redefine expectations for long-term outcomes in patients with MSS metastatic colorectal cancer, an area that has remained one of the greatest challenges in gastrointestinal oncology.
About the C-800-01 Study (NCT03860272)
C-800-01 is a first-in-human Phase 1b clinical trial evaluating botensilimab with or without balstilimab in patients with advanced solid tumors. The MSS mCRC without active liver metastases cohort enrolled 123 patients who received BOT 1 mg/kg or 2 mg/kg every six weeks plus BAL 3 mg/kg every two weeks. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate, duration of response, disease control rate, and progression-free survival. Exploratory endpoints included overall survival and clinical benefit rate.
About Agenus
Agenus is a leading immuno-oncology company targeting cancer with a comprehensive pipeline of immunological agents. The company was founded in 1994 with a mission to expand patient populations benefiting from cancer immunotherapy through combination approaches, using a broad repertoire of antibody therapeutics, adoptive cell therapies (through MiNK Therapeutics) and adjuvants.
Agenus has robust end-to-end development capabilities, across commercial and clinical cGMP manufacturing facilities, research and discovery, and a global clinical operations footprint. Agenus is headquartered in Lexington, MA. For more information, visit www.agenusbio.com or @agenus_bio. Information that may be important to investors will be routinely posted on our website and social media channels.
About Botensilimab (BOT)
Botensilimab (BOT) is a human Fc enhanced multifunctional anti-CTLA-4 antibody designed to boost both innate and adaptive anti-tumor immune responses. Its novel design leverages mechanisms of action to extend immunotherapy benefits to “cold” tumors which generally respond poorly to standard of care or are refractory to conventional PD-1/CTLA-4 therapies and investigational therapies.
Botensilimab augments immune responses across a wide range of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells and inducing long-term memory responses.
Approximately 1,300 patients have been treated with botensilimab and/or balstilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ investigational PD-1 antibody, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit www.clinicaltrials.gov.
About Balstilimab (BAL)
Balstilimab is a novel, fully human monoclonal immunoglobulin G4 (IgG4) designed to block PD-1 (programmed cell death protein 1) from interacting with its ligands PD-L1 and PD-L2. It has been evaluated in more than 900 patients to date and has demonstrated clinical activity and a favorable tolerability profile in several tumor types.