Agenus Reports Three-Year Phase 1b Results for Botensilimab Plus Balstilimab Showing Durable Survival 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 results 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 updated findings were presented during the European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress 2026, held in Munich, Germany.
The newly reported data demonstrate sustained long-term survival and durable clinical responses in a heavily pretreated patient population that historically has had very limited treatment options after progressing on standard therapies. The results reinforce the potential of the BOT+BAL combination to overcome one of the greatest challenges in immuno-oncology—treating MSS colorectal cancer, a disease that has traditionally shown poor responsiveness to conventional immune checkpoint inhibitors.
Addressing a Significant Unmet Need in Metastatic Colorectal Cancer
Colorectal cancer remains one of the leading causes of cancer-related deaths worldwide. While immunotherapy has dramatically improved outcomes for patients whose tumors exhibit microsatellite instability-high (MSI-H) characteristics, approximately 95% of metastatic colorectal cancers are microsatellite stable (MSS). These tumors are generally considered “immune cold,” meaning they generate limited immune responses and are largely resistant to currently approved checkpoint inhibitors.
Patients with refractory MSS metastatic colorectal cancer often receive several lines of chemotherapy, targeted therapies, and anti-angiogenic agents before exhausting available treatment options. Once standard therapies fail, median overall survival has historically ranged between 10 and 14 months, with very few patients achieving durable responses.
Against this challenging clinical backdrop, Agenus’ updated three-year results suggest that botensilimab combined with balstilimab may provide meaningful long-term clinical benefit for a subset of these patients.
Three-Year Follow-Up Demonstrates Durable Survival
The most notable finding from the updated analysis is the durability of survival observed following extended follow-up.
Among the 123 patients enrolled in the Phase 1b study, the combination therapy achieved:
- Median overall survival (OS): 21.2 months
- 24-month overall survival rate: 41%
- 36-month overall survival rate: 33%
Importantly, the Kaplan-Meier survival curve demonstrated a plateau beyond two years, suggesting that a meaningful proportion of patients continue to derive long-lasting benefit from treatment.
In oncology, a plateau in long-term survival curves often indicates the possibility of durable disease control among responders, a feature commonly associated with successful immunotherapy approaches.
Compared with historical outcomes for later-line MSS metastatic colorectal cancer, these results represent a substantial improvement in long-term survival.
Improvement Over Previously Reported Results
The newly released analysis builds upon the encouraging two-year survival data presented during the 2025 ESMO Gastrointestinal Congress.
An additional year of patient follow-up has allowed investigators to better understand the durability of clinical responses and long-term treatment outcomes.
With this extended observation period:
- Total confirmed responses increased to 26
- Median duration of response has not yet been reached
- Responses remain ongoing for as long as 37.4 months
- Seventeen percent of patients remain alive without requiring additional systemic anticancer therapy
These findings strengthen confidence that the clinical activity observed previously has remained durable over time.
Long-Term Treatment-Free Survival
One particularly encouraging aspect of the updated dataset involves treatment-free survival.
At the latest follow-up:
- 21 patients (17%) remained alive and had not required any additional systemic anticancer treatment.
- Among these individuals, 13 were confirmed responders.
Several patients remained free from subsequent therapy or death for more than two years after completing treatment.
Treatment-free intervals are increasingly recognized as an important measure of clinical benefit because they may reflect sustained immune control of disease while allowing patients to avoid the toxicities associated with continuous cancer therapy.
Investigator Highlights Clinical Significance
Dr. Benjamin L. Schlechter of Dana-Farber Cancer Institute, who presented the study findings, emphasized the importance of these long-term outcomes.
He noted that patients enrolled in the study had already received multiple prior treatment regimens and had very limited remaining therapeutic options.
According to Dr. Schlechter, observing patients who remain alive and off systemic therapy several years after treatment represents an outcome that is rarely seen in refractory MSS colorectal cancer.
He suggested that these findings could reshape expectations regarding what immunotherapy might achieve in this difficult-to-treat patient population.
Agenus Highlights Novel Mechanism
Steven O’Day, M.D., Chief Medical Officer of Agenus, explained that the BOT+BAL combination was specifically engineered to activate anti-tumor immune responses within tumors that have historically resisted conventional checkpoint inhibition.
Unlike traditional CTLA-4 antibodies, botensilimab incorporates Fc-enhanced technology intended to stimulate multiple components of the immune system.
Balstilimab complements this activity by targeting the PD-1 immune checkpoint pathway.
According to Agenus, the combination is designed to produce broader immune activation capable of overcoming the immune suppression characteristic of MSS colorectal tumors.
Dr. O’Day noted that the mature data now demonstrate several characteristics considered important for a differentiated immunotherapy regimen, including:
- Durable survival
- Sustained objective responses
- Extended treatment-free intervals
- Manageable long-term safety
He stated that these results provide additional support for the ongoing Phase 3 BATTMAN clinical trial.
Patient Population Reflects Advanced Disease
The Phase 1b study enrolled 123 patients with refractory MSS metastatic colorectal cancer who did not have active liver metastases.
Participants represented a heavily pretreated population.
Study characteristics included:
- Median of three prior treatment lines
- 67% received three or more previous therapies
- 15% previously treated with PD-1 or PD-L1 inhibitors, with or without CTLA-4 therapy
- 30% previously received later-line agents including:
- Regorafenib
- Trifluridine/tipiracil (with or without bevacizumab)
- Fruquintinib
This population closely reflects patients commonly encountered in later-line clinical practice after standard therapeutic options have been exhausted.
Objective Responses Remain Durable
Updated efficacy analyses demonstrated encouraging tumor responses.
Key efficacy findings included:
- Confirmed objective response rate (ORR): 21%
- Three complete responses
- Twenty-three partial responses
Importantly, the median duration of response has not yet been reached.
Observed responses ranged from approximately two months to more than 37 months, indicating remarkable durability among responders.
Long-lasting responses remain uncommon in refractory MSS colorectal cancer, further highlighting the significance of these findings.
Disease Control Beyond Tumor Shrinkage
Beyond objective responses, investigators reported favorable disease control metrics.
These included:
- Disease control rate at six weeks: 69%
- Clinical benefit rate at 24 weeks: 28%
- Tumor regression observed in more than 40% of patients
Tumor regression—even when insufficient to meet formal response criteria—may still translate into symptom improvement and delayed disease progression for many patients.
Results in Later-Line Treatment Subgroup
Researchers also evaluated outcomes within a post hoc subgroup consisting of patients previously exposed to later-line standard therapies.
This subgroup included 37 patients who had received regorafenib, trifluridine/tipiracil (with or without bevacizumab), or fruquintinib before enrollment.
Within this heavily pretreated population:
- Objective response rate: 22%
- Median overall survival: 16.2 months
- Three-year overall survival: 30%
- Median duration of response: 16.6 months
- Disease control rate: 70%
- Clinical benefit rate at 24 weeks: 27%
These findings suggest that the BOT+BAL combination may retain meaningful clinical activity even after patients have exhausted currently available later-line therapies.
Favorable Long-Term Safety Profile
Safety remains a critical consideration for immunotherapy combinations involving CTLA-4 blockade.
Encouragingly, extended follow-up identified no new safety signals.
Investigators also reported:
- No treatment-related deaths
- Consistent safety profile compared with earlier analyses
The most common immune-mediated adverse event remained diarrhea/colitis.
Overall incidence included:
- Any grade: 42%
- Grade 3 or higher: 15%
Importantly, 98% of affected patients experienced complete resolution of diarrhea or colitis.
Median time to resolution was 14 days following symptom onset.
Optimized Phase 3 Dose Improves Tolerability
Agenus also highlighted improved tolerability associated with the dose selected for Phase 3 development.
The chosen regimen consists of:
- Botensilimab 1 mg/kg
- Balstilimab standard dosing
Compared with the earlier 2 mg/kg botensilimab regimen, investigators observed lower rates of immune-mediated diarrhea and colitis.
Specifically:
- Any grade diarrhea/colitis decreased from 42% to 27%
- Grade 3 or higher events decreased from 15% to 10%
These improvements support continued evaluation of the optimized dosing strategy in larger randomized studies.
Supporting the Ongoing BATTMAN Phase 3 Trial
The mature efficacy and safety findings provide the scientific rationale for Agenus’ ongoing BATTMAN Phase 3 clinical trial.
BATTMAN is evaluating botensilimab plus balstilimab in patients with refractory MSS/proficient mismatch repair (pMMR) metastatic colorectal cancer.
The randomized Phase 3 study aims to determine whether the encouraging survival improvements observed in the Phase 1b trial can be confirmed in a larger patient population.
If successful, BATTMAN could establish BOT+BAL as a new immunotherapy option for one of oncology’s largest unmet needs.
The updated three-year results from the C-800-01 study further strengthen the clinical profile of botensilimab plus balstilimab in refractory MSS metastatic colorectal cancer. Durable overall survival, sustained objective responses, prolonged treatment-free intervals, and a manageable long-term safety profile distinguish the regimen in a disease setting where immunotherapy has historically delivered limited benefit.
Although these findings originate from an early-phase study and will require confirmation in randomized Phase 3 trials, they provide compelling evidence that next-generation immune checkpoint strategies may be capable of overcoming resistance mechanisms in MSS colorectal cancer. As the BATTMAN Phase 3 program continues enrollment and evaluation, Agenus hopes to determine whether this innovative combination can establish a new standard of care for patients with advanced colorectal cancer who currently have few effective therapeutic options.
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.