Agenus Publishes Promising Phase 1b Data for Botensilimab and Balstilimab Combination in Advanced Liver Cancer
Agenus has announced the publication of new clinical data highlighting the potential of its investigational immunotherapy combination of botensilimab and balstilimab in patients with advanced hepatocellular carcinoma (HCC) who had previously progressed after immunotherapy treatment. The findings were published in the peer-reviewed journal Liver Cancer and represent another important milestone in the company’s ongoing efforts to develop next-generation immuno-oncology therapies for difficult-to-treat cancers.
The manuscript, titled “A phase 1b study of botensilimab and balstilimab in treatment-refractory hepatocellular carcinoma,” detailed results from an expansion cohort of the Phase 1b C-800-01 clinical study. The trial evaluated the investigational combination of botensilimab, an Fc-enhanced anti-CTLA-4 antibody, together with balstilimab, an anti-PD-1 antibody, in patients with advanced liver cancer who had already received and progressed on prior immunotherapy treatments.
The published data focused on a particularly challenging patient population. All participants had previously received anti-PD-(L)1 therapy, many had undergone treatment with tyrosine kinase inhibitors, and more than half had previously been treated with the widely used immunotherapy combination of atezolizumab and bevacizumab. Additionally, nearly half of the patients had albumin-bilirubin grade 2 liver function, an indicator associated with significantly poorer liver reserve and reduced survival outcomes in hepatocellular carcinoma.
Hepatocellular carcinoma remains one of the most difficult cancers to treat, especially in later treatment settings after frontline therapies fail. While recent advances in immune checkpoint inhibitors have improved outcomes for some patients, treatment options remain extremely limited for individuals whose disease progresses following immunotherapy.
Researchers involved in the study emphasized that patients with impaired liver function generally experience substantially worse outcomes than patients with healthier liver reserve. Published literature has linked albumin-bilirubin grade 2 liver function with reductions in median overall survival ranging from four to ten months compared with patients classified as grade 1. This makes the reported results from the Agenus study particularly notable because many patients enrolled in the cohort carried adverse prognostic features typically associated with lower response rates and shorter survival.
Among the 18 patients considered evaluable for efficacy, the combination of botensilimab and balstilimab produced an objective response rate of 17%. Responses included one complete response and two partial responses. Researchers also reported an 18-week clinical benefit rate of 50%, suggesting that a substantial portion of patients achieved either tumor reduction or durable disease stabilization.
Importantly, the median duration of response was not reached at the time of analysis, indicating that several patients continued to derive ongoing clinical benefit from treatment. Median progression-free survival was reported at 4.4 months, while median overall survival reached 12.3 months.
The study also highlighted evidence of prolonged disease control beyond conventional response metrics. One patient maintained stable disease for 66 weeks, demonstrating that clinical benefit from the regimen was not limited solely to patients achieving measurable tumor shrinkage under RECIST response criteria.
The results are viewed as encouraging given the historically limited effectiveness of available therapies after progression on immune checkpoint inhibitors in advanced liver cancer.
Published studies evaluating currently available later-line therapies such as lenvatinib, cabozantinib, and regorafenib following immunotherapy have generally demonstrated modest clinical activity. These therapies have shown objective response rates ranging from approximately 6% to 14%, median progression-free survival of roughly four to five months, and median overall survival of approximately 10.5 months or less in similar patient populations.
Against this backdrop, Agenus believes the new findings provide early prospective evidence supporting the activity of the botensilimab and balstilimab combination in patients with advanced hepatocellular carcinoma who have limited remaining treatment options.
Steven O’Day stated that the publication contributes to a growing body of evidence demonstrating activity of the BOT plus BAL combination across multiple difficult-to-treat, late-line solid tumors.
According to O’Day, hepatocellular carcinoma presents unique challenges because both tumor biology and underlying liver function significantly influence treatment outcomes. He noted that the study findings support the scientific rationale behind botensilimab’s Fc-enhanced CTLA-4 design and its potential ability to stimulate immune activity in settings where traditional checkpoint inhibitor approaches have shown only limited success.
Botensilimab has attracted attention within the oncology community because of its differentiated design compared with earlier CTLA-4 antibodies. The Fc-enhanced structure is intended to improve immune activation and potentially enhance anti-tumor responses, particularly in tumors that have become resistant to conventional checkpoint inhibition strategies.
Balstilimab, meanwhile, functions as an anti-PD-1 antibody designed to restore immune recognition of tumor cells by blocking inhibitory signaling pathways that suppress T-cell activity.
The combination strategy aims to leverage complementary mechanisms of immune activation in order to overcome resistance in heavily pretreated cancers.
Anthony B. El-Khoueiry described the results as encouraging for patients with advanced liver cancer who face poor outcomes after immunotherapy failure.
El-Khoueiry explained that patients whose disease progresses following immunotherapy often have very limited treatment alternatives, particularly when liver function is already compromised. He stated that observing objective responses, prolonged disease control, and a median overall survival exceeding 12 months in this exploratory cohort supports continued investigation of the combination in the post-immunotherapy setting.
The safety profile reported in the study was generally consistent with prior observations across the broader Phase 1b development program involving botensilimab and balstilimab.
Investigators reported no treatment-related deaths and no newly identified class-related safety signals. Immune-mediated treatment-related adverse events occurred in approximately 68% of patients, while grade 3 immune-mediated adverse events occurred in 37% of participants.
The most frequently reported immune-mediated toxicities included diarrhea or colitis, hepatitis, and dermatologic adverse events. Notably, no grade 4 or higher immune-mediated treatment-related adverse events were observed in the study cohort.
Researchers also noted that all immune-mediated hepatitis events resolved to grade 1 or lower, suggesting that liver-related toxicities were manageable with appropriate monitoring and intervention.
The overall safety findings are particularly important in hepatocellular carcinoma because many patients already have compromised liver function due to underlying cirrhosis or chronic liver disease. This makes tolerability a major consideration when evaluating new systemic therapies in this patient population.
Hepatocellular carcinoma is the most common form of primary liver cancer and represents a major global health burden. The disease is frequently associated with chronic hepatitis infections, alcohol-related liver disease, nonalcoholic steatohepatitis, and cirrhosis. Because symptoms often emerge late in disease progression, many patients are diagnosed at advanced stages when curative surgical options are no longer feasible.
Over the past several years, frontline treatment for advanced hepatocellular carcinoma has evolved significantly with the introduction of immunotherapy combinations. Regimens such as atezolizumab plus bevacizumab have improved survival compared with older targeted therapies and have become standard frontline approaches in many regions.
However, despite these advances, many patients eventually experience disease progression. Once frontline immunotherapy fails, evidence guiding subsequent treatment decisions remains limited, creating an urgent need for additional therapies capable of improving outcomes in later treatment settings.
The publication of the botensilimab and balstilimab data contributes to broader industry efforts focused on next-generation immunotherapy combinations designed to improve efficacy beyond first-generation checkpoint inhibitors.
Agenus has been positioning botensilimab as a key component of its immuno-oncology pipeline across multiple tumor types. The company has previously reported encouraging signals involving the BOT plus BAL combination in colorectal cancer and other advanced solid tumors.
Researchers believe the Fc-enhanced design of botensilimab may offer important immunological advantages, potentially enhancing T-cell priming, activation, and tumor infiltration compared with earlier CTLA-4-directed therapies.
The findings in hepatocellular carcinoma may therefore have implications beyond liver cancer alone, particularly for understanding how optimized checkpoint inhibitor combinations could overcome resistance mechanisms in heavily pretreated cancers.
The study authors concluded in the published manuscript that the combination of botensilimab and balstilimab demonstrated promising efficacy together with manageable safety in previously treated hepatocellular carcinoma, including patients whose disease progressed after frontline immunotherapy.
They further stated that the findings support continued clinical investigation of the regimen in this difficult-to-treat patient population.
For Agenus, the publication represents another step in validating its broader immunotherapy platform strategy and advancing its pipeline of next-generation checkpoint inhibitor therapies. As competition intensifies across oncology drug development, the company hopes differentiated immunotherapy designs such as botensilimab may help address important unmet needs in cancers where conventional treatment approaches continue to provide limited benefit.
The oncology community will likely continue monitoring future studies involving the botensilimab and balstilimab combination as researchers seek to determine whether the encouraging early signals observed in Phase 1b development can translate into larger confirmatory studies and ultimately lead to expanded treatment options for patients with advanced hepatocellular carcinoma and other resistant cancers.
About the C-800-01 Study
C-800-01 (NCT03860272) is an open-label, multicenter Phase 1b clinical trial evaluating botensilimab in combination with or without balstilimab in patients with advanced solid tumors. The trial enrolled over 400 patients with refractory disease and included tumor types with limited or no responsiveness to prior checkpoint inhibitors.
The HCC expansion cohort enrolled 19 patients between March 2021 and September 2023 across six U.S. sites. Patients received botensilimab at 1 mg/kg or 2 mg/kg once every six weeks plus balstilimab 3 mg/kg once every two weeks. The safety analysis included all 19 patients who received at least one dose of study drug, and the efficacy-evaluable analysis included 18 patients with at least one post-baseline imaging scan.
About Agenus
Agenus is a clinical-stage immuno-oncology company advancing a pipeline of antibody-based programs designed to activate innate and adaptive immunity, overcome tumor immune evasion, and expand the population of patients who may benefit from immunotherapy. Founded in 1994, Agenus’ lead program is botensilimab plus balstilimab (BOT+BAL), a next-generation Fc-enhanced CTLA-4 plus PD-1 combination. BOT alone or in combination with BAL has been evaluated in approximately 1,300 patients across more than nine tumor types. The global Phase 3 BATTMAN trial, conducted with the Canadian Cancer Trials Group, is evaluating BOT+BAL in refractory MSS/pMMR metastatic colorectal cancer.
BOT/BAL is also available to eligible patients through regulatory-authorized access pathways in select countries, including France’s national Autorisation d’Accès Compassionnel framework. Agenus also holds an equity investment in MiNK Therapeutics, Inc. (Nasdaq: INKT), a clinical-stage developer of allogeneic invariant natural killer T cell therapies, and a majority interest in SaponiQx, Inc., a vaccine adjuvant business. Agenus is headquartered in Lexington, Massachusetts. For more information, visit www.agenusbio.com or @agenus_bio. Information that may be important to investors will be routinely posted on the Company’s 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.
