Agenus Inc. unveiled significant progress in its immuno-oncology pipeline during a virtual stakeholder briefing on August 27, 2025, highlighting breakthrough clinical results for its botensilimab (BOT) and balstilimab (BAL) combination therapy and announcing the launch of the pivotal BATTMAN Phase 3 trial for metastatic colorectal cancer.
The briefing, featuring presentations from senior management including CEO Garo H. Armen, PhD, and Jennifer Buell, PhD, alongside oncology experts Dr. Richard M. Goldberg and Dr. Nicholas C. DeVito, emphasized the transformative potential of the BOT/BAL combination in treating historically resistant cancers.
Mechanism of Action and Clinical Rationale
Botensilimab represents a next-generation CTLA-4 inhibitor engineered as an Fc-enhanced antibody designed to unleash powerful anti-tumor immune responses by targeting "cold tumors" that typically do not respond to traditional therapies. Unlike traditional CTLA-4 inhibitors such as ipilimumab and tremelimumab, botensilimab's Fc-enhanced design enables more robust engagement of activating Fc receptors on key immune cells, potentially leading to more potent antitumor effects and the ability to deplete immunosuppressive regulatory T cells within tumors.
Balstilimab, a fully human monoclonal IgG4 antibody, blocks PD-1 (programmed cell death protein 1), preventing cancer cells from exploiting this pathway to evade immune system attack. The combination strategy leverages botensilimab as a powerful "on switch" for immune activation while balstilimab acts as a "maintainer," ensuring newly activated T cells remain engaged to fight cancer.
Breakthrough Clinical Results in Colorectal Cancer
The most compelling data emerged from studies in microsatellite stable (MSS) colorectal cancer, a population that typically responds poorly to immunotherapies. In Phase 1 studies involving late-stage MSS colorectal cancer patients who had exhausted all approved treatment options, BOT demonstrated a remarkable 42% two-year survival rate with a median overall survival of 21 months, far exceeding the 10-14 months survival seen with traditional chemotherapy regimens.
"These patients had either exhausted all approved treatment options or were left with no therapeutic options. Despite this, we saw a remarkable median overall survival of 21 months, far outstripping the current best standard of care," stated Dr. Richard Goldberg, Chief Development Officer of Agenus.
Promising Neoadjuvant Therapy Results
Early-stage trials evaluating BOT/BAL as neoadjuvant therapy before chemotherapy showed even more dramatic responses. The NEOASIS trial demonstrated a 70% pathological complete response (pCR) in MSI-H tumors and 20% in MSS tumors. The NEST-1 and NEST-2 trials, evaluating neoadjuvant therapy in colorectal cancer, reported 100% ctDNA-negative status and 47% major pathological response in MSS tumors.
The UNICORN trial achieved 93% pCR in dMMR tumors and 29% in pMMR tumors with BOT/BAL treatment, suggesting the combination's efficacy extends across different molecular subtypes of early-stage colorectal cancer.
Efficacy Across Multiple Cancer Types
Clinical trials have enrolled approximately 1,200 patients across multiple tumor types for BOT studies, with over 900 patients treated with BAL across several cancer types. In hepatocellular carcinoma, BOT/BAL achieved a 17% overall response rate and 72% disease control rate, with a 12.3-month median overall survival, demonstrating promise for liver cancer patients previously unresponsive to first-line therapies.
BATTMAN Phase 3 Trial Design
The FDA-approved BATTMAN Phase 3 study will evaluate BOT/BAL combination against best supportive care in heavily pretreated patients with advanced MSS colorectal cancer. The trial design eliminates the need for a separate BOT monotherapy control arm, streamlining the path to approval. Agenus aims to expand enrollment through strategic collaborations and plans to launch the trial in Q4 2025.
Dr. Nicholas DeVito, assistant professor of medical oncology at Duke University, highlighted the urgent need: "The rise in colorectal cancer in younger patients is alarming, and the need for new therapies is clear. BOT and BAL offer hope where few options exist."
Regulatory Challenges and Call for Reform
Despite promising clinical data, company executives emphasized the urgent need for regulatory reform to accelerate patient access to innovative therapies. Dr. Goldberg stressed: "Patients are waiting, and every day that passes, lives are lost. The science is moving faster than the regulatory framework allows. It's time for the FDA and other regulatory agencies to adapt and reflect the rapid advancements in immuno-oncology."
The briefing highlighted challenges in navigating regulatory requirements that mandate large, randomized Phase 3 trials before approval, potentially delaying access to life-saving treatments for patients with aggressive cancers.
Quality of Life Considerations
Beyond survival benefits, the combination therapy offers improved tolerability compared to traditional chemotherapy. "Patients want more than just survival; they want quality of life. Chemotherapy often comes with debilitating side effects like neuropathy and cytopenias. BOT and BAL offer a path forward, with manageable side effects and the promise of longer, better lives," noted company representatives.
CEO Garo Armen concluded: "We believe that the regulators need to reflect upon and update the approval process. Science is moving fast, and regulatory processes need to move at the same pace as the science. We are committed to advancing immuno-oncology and accelerating access to therapies that can save lives today."
