Balstilimab

LEXINGTON, Mass.--(BUSINESS WIRE)--Agenus Inc. (Nasdaq: AGEN), a leader in immuno-oncology innovation, today announced the peer-reviewed publication of mature Phase 1b results from the fully enrolled C-800-01 cohort evaluating botensilimab (BOT), a multifunctional Fc-enhanced anti–CTLA-4 antibody, plus balstilimab (BAL), an anti–PD-1 antibody, in 123 heavily pre-treated patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) without active liver metastases. The manuscript, titled "Extended Follow-Up of Botensilimab Plus Balstilimab in an Expanded Cohort of Microsatellite-Stable Metastatic Colorectal Cancer Without Active Liver Metastases," was published in Clinical Cancer Research. The publication builds on three-year efficacy data presented at the European Society for Medical Oncology Gastrointestinal Cancers (ESMO GI) Congress 2026 and provides additional biomarker analyses offering insight into the biology underlying BOT+BAL activity. MSS tumors account for the vast majority of mCRC cases and have historically derived little or no benefit from conventional checkpoint immunotherapy. In this fully enrolled cohort, patients received a median of three prior lines of therapy. BOT+BAL demonstrated a median overall survival of 21.2 months and a three-year overall survival rate of 33%. In this treatment setting, available later-line standard treatments have reported median overall survival of approximately 10-14 months in patients with refractory MSS, without active liver metastases.i Durable clinical activity was observed in the context of limited drug exposure, with patients receiving a median of two BOT doses and six BAL doses. In exploratory analyses, responses were observed in tumors lacking the conventional markers of checkpoint sensitivity including low tumor mutational burden (TMB) and no detectable PD-L1 expression, and neither biomarker was associated with response. These findings are consistent with BOT's Fc-enhanced design, intended role in promoting immune priming in immunologically "cold" tumors. “These mature results are important because they show a pattern of durable activity in MSS colorectal cancer that is not limited to tumors with the conventional features associated with checkpoint sensitivity,” said Benjamin L. Schlechter, M.D., of Dana-Farber Cancer Institute and lead author of the publication. “In a heavily pretreated setting where patients have few remaining options, BOT+BAL compares favorably with what is typically expected from available later-line standard therapies in terms of tolerability, depth of response and duration of response. That is a meaningful clinical difference and provides important evidence that antitumor immunity can be generated even in tumors traditionally considered immunologically cold.” "BOT was specifically engineered to add Fc-mediated immune engagement to CTLA-4 blockade, with the goal of priming antitumor immunity in cancers that have historically been resistant to conventional checkpoint inhibition," said Steven O'Day, M.D., Chief Medical Officer of Agenus. “This peer-reviewed publication connects the durable clinical activity observed in refractory MSS colorectal cancer with biomarker findings consistent with that biology. When considered alongside our emerging neoadjuvant data, these findings strengthen the rationale for evaluating BOT+BAL earlier in the disease course, where immune priming before surgery may offer the greatest opportunity to alter the trajectory of MSS colorectal cancer.” Mature Clinical Outcomes The Phase 1b cohort included 123 patients with MSS mCRC without active liver metastases who had received a median of three prior lines of therapy. Key findings reported in the publication include: Overall survival: Median overall survival was 21.2 months, with 24-month and 36-month overall survival rates of 41% and 33%, respectively Objective response: Confirmed objective response rate was 21%, including three complete responses and 23 partial responses Duration of response: Median duration of response was not reached, with responses extending to at least 37.4 months Disease control: Disease control rate was 69% at six weeks, and clinical benefit rate was 28% at 24 weeks Treatment-free status: At last follow-up, 17% were alive and off all systemic anticancer therapy, including 13 responders Activity Maintained in the Most Heavily Pretreated Patients In an exploratory subgroup of 37 patients who had already exhausted available later-line therapies, patients had received a median of five prior lines of therapy. In this subgroup, BOT+BAL demonstrated a 22% confirmed objective response rate, median overall survival of 16.2 months, and a three-year overall survival rate of 30%. Median duration of response was 16.6 months, disease control rate was 70%, and clinical benefit rate at 24 weeks was 27%, indicating that clinical benefit was preserved even in the most refractory setting. Biomarker Findings Support Fc-Enhanced Immune Priming Biology Exploratory biomarker analyses showed that responses were observed among patients with low tumor mutational burden (TMB) and no detectable PD-L1–expression, and neither biomarker was associated with response in the evaluable population. These findings suggest that activity was not confined to tumors with conventional markers of checkpoint sensitivity. These observations are consistent with BOT’s Fc-enhanced design, which is intended to engage activating Fc-gamma receptors on antigen-presenting and other myeloid cells, promote T-cell priming, reduce intratumoral regulatory T cells, and reshape the immunosuppressive tumor microenvironment rather than relying solely on pre-existing tumor immunogenicity. Extended Safety Follow-Up Supports Optimized Dosing No new safety signals were observed with extended follow-up, and there were no treatment-related deaths. Immune-mediated diarrhea/colitis, the most common immune-mediated adverse event, resolved in 98% of affected patients, with a median time to resolution of 14 days. Efficacy was consistent across the two BOT dose levels evaluated, with a 21% objective response rate at both 1 mg/kg and 2 mg/kg. Lower rates of immune-mediated adverse events were observed with BOT 1 mg/kg plus BAL compared with the higher BOT dose. From Durable Metastatic Activity to Curative Intent Neoadjuvant Setting The publication follows the recent peer-reviewed report of updated NEST Phase 2 data evaluating neoadjuvant BOT+BAL in resectable colon cancer. The NEST results provide direct clinical evidence in the neoadjuvant setting, while the C-800-01 manuscript adds metastatic durability and biomarker evidence consistent with Fc-enhanced immune priming. This body of evidence supports continued evaluation of BOT+BAL in neoadjuvant, curative-intent MSS colon cancer, including Agenus’ planned Phase 3 ROBBIN trial. About the C-800-01 Study C-800-01 (NCT03860272) 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 efficacy endpoints included objective response rate, duration of response, disease control rate and progression-free survival; overall survival was an exploratory endpoint. 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 multifunctional, Fc-enhanced 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, reducing intratumoral regulatory T cells, activating myeloid cells and inducing durable 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. Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding its botensilimab and balstilimab programs, expected regulatory timelines and filings, and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "forecasts," "estimates," "will," “establish,” “potential,” “superiority,” “best in class,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Annual Report on Form 10-K for 2025, and subsequent Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. ____________________ i Available later-line standards include regorafenib, trifluridine/tipiracil with or without bevacizumab, and fruquintinib in refractory metastatic colorectal cancer, including analyses in patients without active liver metastases. Cross-trial comparisons are descriptive; differences in study design, eligibility criteria, patient populations, assessments, follow-up and data cutoffs may confound comparisons. References: Garcia-Carbonero R, et al. Presented at ESMO 2024. Poster #520P; Tabernero J, et al. Presented at ASCO 2024. Poster #3584; Cohen R, et al. Eur J Cancer. 2024;207:114160.

No colorectal cancer recurrences observed at updated median follow-up of 32.2 months in NEST-1 and 23.5 months in NEST-2 In pMMR/MSS tumors, neoadjuvant BOT+BAL achieved 59% pathologic response, including 41% major pathologic response and 32% pathologic complete response 88% of evaluable patients cleared ctDNA before surgery, with no delays to planned surgical resection Longer follow-up and immune analysis provide clinical and biological support for Agenus’ planned global Phase 3 ROBBIN trial in curative-intent MSS/pMMR colon cancer LEXINGTON, Mass.--(BUSINESS WIRE)-- $AGEN #BOT -- Agenus Inc. (Nasdaq: AGEN) , a leader in immuno-oncology innovation, today announced the peer-reviewed publication of updated results from the investigator-sponsored Phase 2 NEST trial evaluating neoadjuvant botensilimab (BOT), Agenus’ multifunctional, Fc-enhanced anti-CTLA-4 antibody, and balstilimab (BAL), Agenus’ anti-PD-1 antibody, in patients with resectable colon cancer. The manuscript, titled “Neoadjuvant botensilimab/balstilimab for localized mismatch repair proficient and deficient colon cancer: Results of the NEST phase 2 clinical trial,” was published in Clinical Cancer Research and is available here . Earlier findings from NEST were presented at the 2025 ASCO Gastrointestinal Cancers Symposium. The publication provides longer follow-up and a fuller peer-reviewed analysis of tumor responses, circulating tumor DNA (ctDNA) dynamics, disease-free follow-up and immune changes in the tumor microenvironment. At the March 31, 2026 data cutoff, no colorectal cancer recurrences had been observed, with median follow-up of 32.2 months in NEST-1 and 23.5 months in NEST-2. Among 22 mismatch repair proficient/microsatellite stable (pMMR/MSS) tumors, 59% achieved a pathologic response, including 41% with a major pathologic response and 32% with a pathologic complete response. MSS/pMMR tumors represent approximately 85% of early-stage colorectal cancers and have historically derived limited benefit from conventional immunotherapy treatment, particularly in metastatic disease. i,ii In localized colon cancer, treatment remains centered on surgery and chemotherapy, creating a need for approaches that may deepen response and reduce recurrence risk. Administering immunotherapy before surgery offers a distinct biological opportunity to activate the immune system while the primary tumor, tumor-draining lymph nodes and surrounding immune microenvironment remain intact. The publication adds peer-reviewed clinical and biological support for Agenus’ previously announced decision to prioritize BOT+BAL in earlier-stage, curative-intent MSS colon cancer. Agenus is advancing ROBBIN, a planned global randomized Phase 3 trial evaluating neoadjuvant BOT+BAL followed by standard of care versus standard of care alone in previously untreated patients with high-risk Stage II or Stage III MSS colon cancer, with event-free survival as the primary endpoint. NEST’s deep tumor regression, pre-surgical ctDNA clearance, preserved surgical timing and no observed recurrences at longer follow-up supports the clinical hypothesis ROBBIN is designed to test. “NEST provides important context for Agenus’ strategic focus on neoadjuvant BOT+BAL in MSS colon cancer,” said Steven O’Day, M.D., Chief Medical Officer of Agenus. “With longer follow-up now extending beyond two years across both NEST cohorts, the findings show BOT+BAL can generate deep tumor responses and immune activation before surgery, without delaying surgery. These results strengthen the rationale for our phase 3 ROBBIN trial and for evaluating BOT+BAL in a curative-intent setting, where the goal is to reduce the risk of recurrence and improve long-term outcomes.” NEST was a single-center, open-label, single-arm Phase 2 study that enrolled 24 eligible patients with 26 resectable colorectal tumors, including 22 pMMR/MSS tumors and four dMMR/MSI-H tumors. The study evaluated two pre-surgical treatment intervals; approximately four weeks in NEST-1 and approximately eight weeks in NEST-2. Patients in both cohorts proceeded to planned surgical resection without treatment-related delays. NEST Results Tumor responses in pMMR/MSS disease Among 22 pMMR/MSS tumors, neoadjuvant BOT+BAL achieved: 59% pathologic response rate (pOR): defined as pathologic complete response, major pathologic response or partial response 41% major pathologic response rate (MPR) : 10% or less viable tumor remaining 32% pathologic complete response rate (pCR) : no viable tumor or adjacent lymph nodes found at surgery The manuscript cites previously reported MPR rates of approximately 19% to 20%, including pCR of approximately 10%, with first-generation CTLA-4/PD-1 combination therapy in pMMR colon cancer. Cross-trial comparisons should be interpreted cautiously because of differences in study design, patient population and follow-up. Tumor responses in dMMR/MSI-H disease All four dMMR/MSI-H tumors achieved an MPR, including two pCR and two additional tumors with near-complete tumor regression of 98% and 99%. ctDNA clearance before surgery Among patients with detectable circulating tumor DNA (ctDNA) at baseline and available pre-surgical samples, 88% cleared ctDNA prior to surgery. ctDNA remained undetectable following resection in all patients evaluated. No observed recurrences at longer follow-up At the March 31, 2026 data cutoff, no colorectal cancer recurrences had been observed. Median follow-up was 32.2 months in NEST-1 and 23.5 months in NEST-2. For external context, the FOxTROT study of neoadjuvant chemotherapy reported a two-year recurrence rate of 16.9%. Cross-trial comparisons should be interpreted cautiously. Immune remodeling and activation in the tumor microenvironment Analyses of paired tumor samples showed coordinated remodeling of the tumor immune microenvironment in responding tumors, characterized by increased CD8+ T-cell infiltration, reduced FOXP3+ regulatory T cells, increased CD8+/Treg ratios and spatial reorganization of immune cells within the tumor. These findings provide biological support for BOT’s multifunctional, Fc-enhanced mechanism, which extends beyond conventional checkpoint blockade to actively remodel the immunosuppressive tumor microenvironment, and establishes a mechanistic basis for activity in historically immunotherapy-resistant pMMR/MSS tumors. Surgical feasibility and safety Patients proceeded to planned surgery without treatment-related delays. No Grade 4 treatment-related adverse events, treatment-related deaths or study discontinuations were observed. “The NEST results reinforce a major opportunity in colorectal cancer to use immunotherapy earlier, before surgery, when the primary tumor and immune system are still positioned to generate a coordinated anti-tumor response,” said Pashtoon M. Kasi, M.D., M.S., Medical Director of GI Medical Oncology at City of Hope Orange County, Rad Family Chair in Gastrointestinal Oncology, and originator of the NEST study . “For pMMR/MSS disease, where immunotherapy has historically had limited impact, the combination of pathologic responses, ctDNA clearance, no observed colorectal cancer recurrences at longer follow-up and immune remodeling is highly encouraging, particularly when viewed against historical benchmarks. These findings provide a strong foundation for continued study of neoadjuvant BOT+BAL, including NEST3, our enrolling multicenter Phase 2 investigator-sponsored study.” About the NEST and NEST 3 Studies NEST (NCT05571293 ) was an investigator-initiated, single-center, open-label Phase 2 study evaluating neoadjuvant BOT+BAL in patients with resectable colorectal cancer. The study enrolled 24 eligible patients with 26 resectable colorectal tumors, including 22 with mismatch repair proficient/microsatellite stable and four mismatch repair deficient/microsatellite instability-high tumors. Patients received neoadjuvant BOT+BAL before planned surgical resection. The primary objectives were to assess safety, feasibility and anti-tumor activity, with exploratory analyses evaluating treatment-associated changes in the tumor immune microenvironment. Agenus supported the study and provided BOT and BAL. NEST3 (NCT07595874) is an open and actively enrolling multicenter Phase 2 investigator-sponsored study evaluating neoadjuvant BOT+BAL in advanced resectable colorectal cancer. The study is sponsored by City of Hope Medical Center, led by Pashtoon M. Kasi, M.D., M.S., as overall principal investigator, and designed to enroll approximately 100 patients across 11 U.S. sites. The first patient was dosed in July 2026. NEST3 is being conducted through City of Hope’s National Clinical Trials Model, a centralized research framework designed to expand patient access to clinical trials across multiple City of Hope locations. More information is available at ClinicalTrials.gov . 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, research and discovery. Agenus is headquartered in Lexington, MA. For more information, visit 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 multifunctional, Fc-enhanced 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, reducing intratumoral regulatory T cells, activating myeloid cells and inducing durable 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 . 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 pro several tumor types. Forward-Looking Statements This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the federal securities laws, including statements regarding its botensilimab and balstilimab programs, expected regulatory timelines and filings, and any other statements containing the words "may," "believes," "expects," "anticipates," "hopes," "intends," "plans," "forecasts," "estimates," "will," “establish,” “potential,” “superiority,” “best in class,” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include, among others, the factors described under the Risk Factors section of our most recent Annual Report on Form 10-K for 2025, and subsequent Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission. Agenus cautions investors not to place considerable reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this press release, and Agenus undertakes no obligation to update or revise the statements, other than to the extent required by law. All forward-looking statements are expressly qualified in their entirety by this cautionary statement. _________________________ References i Buchler T. Front Oncol. 2022;12:888181. ii Guven DC, et al. Oncologist. 2024;29(5):e580-e600. Contacts Investors 917-362-1370 | investor@agenusbio.com Media 781-674-4422 | communications@agenusbio.com