Agenus’ BOT/BAL Combo Delivers 42% Two-Year Survival in MSS Colorectal Cancer: Phase 3 Trial Aligned with FDA
Agenus Inc., a pioneer in immuno-oncology, announced compelling new clinical results and regulatory progress for its combination therapy of botensilimab and balstilimab (BOT/BAL). At the 2025 ESMO Gastrointestinal Cancers Congress (ESMO-GI) in Barcelona, the company presented updated data showing a 42% two-year overall survival (OS) rate in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC)—a particularly treatment-resistant form of cancer. In parallel, Agenus shared outcomes from its July 1, 2025 End-of-Phase 2 (EoP2) meeting with the U.S. Food and Drug Administration (FDA), which outlined a clear regulatory path forward.
Durable Responses in a Refractory Cancer Population
The new data represent a substantial expansion over previous findings. In a cohort of 123 heavily pretreated MSS mCRC patients—up nearly 40% from the earlier 90-patient dataset published in Nature Medicine in 2024—BOT/BAL continues to demonstrate promising activity in a population where most therapies fail. These patients, who had no active liver metastases, had exhausted at least two prior lines of therapy, a group with historically dismal outcomes.
Key clinical findings include:
- Objective Response Rate (ORR): 20%
- Median Duration of Response (DOR): 16.6 months
- Disease Control Rate (DCR): 69%
- Median Overall Survival (OS): 20.9 months
- Two-Year Survival Rate: 42%
Notably, even in the most heavily pretreated subgroup—patients in the fourth-line or beyond (n=37)—the BOT/BAL combo delivered an ORR of 19% and a two-year survival rate of 43%. These results are particularly encouraging given that standard therapies offer only 5–8 months median OS in this setting.
“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,” said Dr. Benjamin Schlechter of Dana-Farber Cancer Institute, who presented the findings.
Safety Profile Remains Favorable
Crucially, the safety profile of BOT/BAL continues to hold steady as the dataset matures. There were no new safety signals, and no treatment-related deaths were observed. Immune-related side effects, a common concern with checkpoint inhibitors, were considered manageable across all dose levels.
“These deep, durable responses and emerging survival plateaus are rarely observed in MSS colorectal cancer,” said Dr. Steven O’Day, Chief Medical Officer at Agenus. “They are typically associated only with highly immunogenic tumors. These findings support the possibility of a chemotherapy-free treatment option for a patient population with limited alternatives.”
FDA Meeting Ushers in a Clear Path to Registration
At the July 1, 2025 End-of-Phase 2 meeting, Agenus reached a significant milestone: alignment with the FDA on the design of its global Phase 3 registrational trial, known as BATTMAN (CCTG CO.33).
Key Outcomes of the FDA Meeting:
- No Monotherapy Arm Required: The FDA acknowledged balstilimab’s role in the combination’s efficacy, waiving the requirement for a BOT monotherapy control arm.
- Two-Arm Randomized Design Approved: This simplifies the trial structure and enables faster initiation and execution.
- Phase 3 Launch Timing: Agenus plans to initiate BATTMAN in Q4 2025.
- FDA Feedback: While the FDA stated that the data may not currently meet the threshold of “reasonably likely to predict clinical benefit” under Subpart E, the Agency supported progression to a registrational trial given the urgent unmet need and positive early results.
“We are encouraged by the FDA’s recognition of balstilimab’s contribution to BOT/BAL’s clinical activity,” said Jennifer Buell, Ph.D., Executive Chairwoman of Agenus. “With the FDA’s constructive guidance, we are advancing BATTMAN and preparing to utilize every available expedited pathway to deliver this therapy to patients.”
BOT/BAL as a Potential Paradigm Shift in CRC Treatment
The potential for BOT/BAL to reshape the treatment landscape in colorectal cancer is underscored by growing urgency in the field. Colorectal cancer is projected to become the leading cause of cancer-related death in individuals under age 50 by 2030, with survival rates stagnating in late-line settings.
“Current treatment options offer little hope to patients in later lines of therapy,” said Dr. Richard Goldberg, Chief Development Officer at Agenus. “BOT/BAL offers the kind of durable response we simply haven’t seen before in this setting. Rapid registration and access are no longer just goals—they’re necessities.”
Looking Ahead: Key Catalysts in 2H2025
Agenus outlined an ambitious development and regulatory agenda for the second half of 2025, focused on maximizing the momentum of BOT/BAL and expanding its clinical reach:
1. Launch of BATTMAN Trial
- Global registration trial for BOT/BAL in refractory MSS mCRC.
- Designed to confirm overall survival benefits in a randomized setting.
2. Earlier-Line CRC Development
- Ongoing studies in first-line and neoadjuvant MSS colorectal cancer.
- Future discussions with regulators on expanding the treatment to earlier stages.
3. Global Expansion & Partnerships
- Leveraging clinical infrastructure in collaboration with Zydus and other strategic partners to ensure rapid patient enrollment and data collection.
4. Upcoming Scientific Presentations
- Additional data from BOT/BAL in colorectal and other tumor types to be presented at major oncology congresses in Q4 2025.
5. Regulatory Acceleration Pathways
- Pursuing expedited approval routes, including:
- Fast Track Designation
- Real-Time Oncology Review (RTOR)
- Commissioner’s National Priority Voucher Program
- Accelerated Approval Pathways for serious conditions with unmet needs
Commitment to Patient Access
Agenus reaffirmed its commitment to ensuring that patients with cancer—particularly those with few treatment options—can access its investigational therapies. Patients and physicians seeking more information can visit the company’s Medical Affairs portal at www.agenusbio.com/medical-affairs to learn more about expanded access programs and clinical trial opportunities.
About the C-800-01 Phase 1 Study
The C-800-01 Phase 1, open-label, multicenter trial (NCT03860272) evaluated botensilimab alone or in combination with balstilimab across multiple solid tumors, including an expansion cohort in microsatellite stable metastatic colorectal cancer. In the MSS CRC cohort, patients received botensilimab (1 or 2 mg/kg every six weeks) plus balstilimab (3 mg/kg every two weeks) for up to two years.
The study enrolled heavily pretreated patients, including those with no active liver metastases, and assessed safety, objective response rate, progression-free survival, and overall survival. No maximum tolerated dose was reached, and the safety profile was manageable across dose levels. The trial also included exploratory biomarker analyses to inform potential predictors of response. Preliminary findings from this study in refractory MSS CRC were published in Nature Medicine in September 2024.
About Agenus
Agenus is a leading immuno-oncology company targeting cancer with a comprehensive pipeline of immune-driven therapies. Founded in 1994, the company’s mission is to expand the patient populations benefiting from cancer immunotherapy through innovative combination approaches. Agenus’ portfolio includes a broad repertoire of antibody therapeutics, adoptive cell therapies (via its affiliate MiNK Therapeutics), and adjuvants (via SaponiQx).
The company has end-to-end capabilities spanning research, discovery, and GMP manufacturing, and it has a global clinical development footprint. Agenus is headquartered in Lexington, MA. For more information, visit www.agenusbio.comor follow @agenus_bio on social media. Important information for investors will be routinely posted on the company’s website and social channels.
About Botensilimab (BOT)
Botensilimab (AGEN1181) is a novel, multifunctional, Fc-enhanced CTLA-4 antibody engineered to boost both innate and adaptive anti-tumor immune responses. Its unique design aims to overcome the limitations of first-generation CTLA-4 inhibitors (like ipilimumab) and extend immunotherapy benefits to “cold” tumors that typically respond poorly or not at all to standard immune checkpoint blockade.
Botensilimab’s Fc-enhanced structure allows it to robustly engage activating Fc receptors on key immune cells, thereby priming and activating T cells, depleting immunosuppressive regulatory T cells in the tumor microenvironment, activating myeloid cells, and inducing long-term immune memory. Through these mechanisms, botensilimab has demonstrated the ability to ignite immune responses across a range of solid tumors, including those resistant to conventional PD-1 or CTLA-4 therapies.
To date, approximately 1,200 patients have been treated with botensilimab and/or balstilimab in Phase 1 and 2 trials. Botensilimab alone or in combination with Agenus’ investigational PD-1 antibody balstilimab has shown clinical responses in nine different metastatic cancers in late-line settings. For more information on ongoing botensilimab trials, please visit www.clinicaltrials.gov.
About Balstilimab (BAL)
Balstilimab (AGEN2034) is a novel, 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. It has been evaluated in over 900 patients to date and has demonstrated clinical activity with a favorable tolerability profile in several tumor types. Balstilimab is being studied both as a monotherapy and in combination with other agents (such as botensilimab) to expand its therapeutic impact.
