botensilimab (AGEN1181) / Agenus, Zydus Lifesci - LARVOL DELTA

Botensilimab plus balstilimab in an expanded cohort of 123 patients with metastatic microsatellite-stable colorectal cancer and no active liver metastases (ESMO-GI 2025) - P1 | "This is the first presentation of a fully enrolled expanded cohort of pts with MSS mCRC NLM from the phase 1b trial. As of Mar 13, 2025, 123 pts with NLM were enrolled / treated with BOT every 6 wks (62 pts – 1 mg/kg, 61 pts – 2 mg/kg) plus BAL every 2 wks (3 mg/kg). Median age, 56 yrs (range 25–82); median prior lines, 3 (range 1–10); 58% ≥1 metastatic site, 16% treated liver metastases; 16% prior I-O, 30% prior regorafenib, trifluridine/tipiracil ± bevacizumab or fruquitinib; and 67% RAS mutant. BOT / BAL, a novel I-O only combination, demonstrates unprecedented clinical benefit with deep, durable responses, and for the first time, meaningful treatment free survival in refractory MSS mCRC NLM, with a manageable safety profile."

Clinical • IO biomarker • Metastases • Colorectal Cancer • Oncology • Solid Tumor

Evaluating efficacy of Fc-enhanced CTLA-4 inhibitor botensilimab, bastilimab with or without CXCR4 inhibitor (BL-8040) in an orthotopic murine model (ESMO-GI 2025) - "We evaluated the efficacy of using CXCR4 inhibitor (CXCR4i) BL-8040 in combination with Fc enhanced cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor Botensilimab (BOT) and Balstilimab (BAL) in an orthotopic murine PDAC model. We generated orthotopic pancreatic cancer models with KPC cells in C57BL/6 mice. Treatment with BOT/BAL or BOT/BAL/CXCR4i increased CD8+ T-Cells expressing GranzymeB, decreased CD4+ cells, and decreased F4-80+ macrophages that correspond with decreased tumor size."

IO biomarker • Preclinical • Gastrointestinal Cancer • Pancreatic Adenocarcinoma • Pancreatic Cancer • CD4 • CD8 • CXCL12 • CXCR4 • GZMB • PD-1

ESMO‑GI Clinical Highlights (Agenus Inc. Press Release) - P1 | N=499 | NCT03860272 | Sponsor: Agenus Inc. | "The new data presented at ESMO-GI represent an approximate 40% increase in number of patients (n=123) compared to earlier reports published in Nature Medicine in 2024. The expanded dataset demonstrates continued durability of tumor responses and median overall survival approaching two years in an immunotherapy-resistant treatment setting. Among these 123 heavily pretreated MSS mCRC patients (third-line or later) treated with BOT/BAL, the confirmed objective response rate (ORR) was 20%, with a median duration of response (DOR) of 16.6 months. The disease control rate (DCR, responses plus stable disease) was 69%. Notably, median overall survival (OS) reached 20.9 months, with 42% of patients still alive at two years in this refractory population. Patients in fourth-line or later (n=37), having exhausted all standard therapies, saw similar benefits, with a ~19% ORR and 43% two-year survival."

P1 data • Colorectal Cancer

FDA Meeting Outcomes (Agenus Inc. Press Release) - "Official minutes from the July 1, 2025 End-of-Phase 2 (EoP2) meeting reflect a meaningful shift in FDA alignment since July 2024, establishing two new areas of agreement: Contribution of components – FDA wrote that the current data 'appears to support' balstilimab’s contribution to the combination’s clinical activity and therefore a registrational Phase 3 trial may proceed without a BOT monotherapy arm; Phase 3 registrational trial – BATTMAN (CCTG CO.33): FDA and Agenus aligned on the core design of this global registration study for BOT/BAL. Agenus is incorporating the Agency’s feedback and will initiate BATTMAN in Q4 2025....During the discussion on July 1, 2025, the FDA stated that it continues to recommend Agenus conduct a randomized controlled trial to support the approval of BOT/BAL in the metastatic setting and the demonstrated magnitude of treatment effect 'does not appear to meet the standard of reasonably likely to predict benefit.'"

FDA event • New P3 trial • Colorectal Cancer

The Miami "EMPIRE" Trial - Eradication of Metastatic Pancreatic Cancer With Immuno-Radiation (clinicaltrials.gov) - P2 | N=20 | Recruiting | Sponsor: Benjamin Spieler | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor

Agenus and Noetik Enter Collaboration to Develop AI-Enabled Predictive Biomarkers for BOT/BAL Using Foundation Models of Virtual Cell Biology (Businesswire) - "Agenus...announced a research collaboration to develop predictive biomarkers of response to Agenus’ lead clinical stage immuno-oncology (IO) combination, botensilimab (BOT, multifunctional Fc-enhanced anti-CTLA-4) and balstilimab (BAL, anti-PD-1). The collaboration harnesses Noetik’s proprietary virtual cell foundation models and large-scale, multimodal tumor data to uncover novel insights into the biology of tumor immunology....Botensilimab, alone or in combination with BAL, has been evaluated in more than 1,200 patients across nine tumor types, including colorectal cancer, NSCLC, and sarcomas....The collaboration aims to uncover clear, actionable biomarkers that can help predict which patients are most likely to respond to BOT/BAL treatment....The goal is to identify patterns that can predict treatment outcomes and help classify patient groups who may benefit most."

Biomarker • Licensing / partnership • Colorectal Cancer • Non Small Cell Lung Cancer • Sarcoma

A phase 2 study of SR-8541A in combination with botensilimab and balstilimab in subjects with refractory metastatic microsatellite stable colorectal cancer (MSS-CRC). (ASCO 2025) - P1, P2 | "SR-8541A is administered orally twice daily (BID) in 28-day cycles. Blood samples are being collected for PK, target engagement, and biomarker assessment."

Clinical • Combination therapy • IO biomarker • Metastases • P2 data • Colorectal Cancer • Hepatology • Microsatellite Instability • Oncology • Solid Tumor • CTLA4 • ENPP1 • MSI

A phase 2 study of botensilimab and AGEN1423, an anti-CD73-TGFβ-trap bifunctional antibody, with or without chemotherapy in subjects with advanced pancreatic cancer. (ASCO 2025) - P2 | "In Cohort 2, 12 additional patients with disease progression on first-line fluorouracil-based chemotherapy will be enrolled to receive second-line gemcitabine and nab-paclitaxel in combination with AGEN1423 30mg/kg IV Q2W for 4 doses + BOT 150mg IV Q6W. Translational endpoints include the characterization of the transcriptional signatures in paired biopsies obtained before and on-treatment with BOT + AGEN1423, as well as the changes in cell composition of the TME following treatment using multiplexed immunofluorescence spatial technology. Enrolment has started and accrual is anticipated to complete in Q4 2025."

Clinical • Metastases • P2 data • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD73 • CTLA4 • TGFB1

An open-label, phase 1 trial with expansion cohort of botensilimab (AGEN1181) + balstilimab (AGEN2034) + nab-paclitaxel + gemcitabine + cisplatin + chloroquine + celecoxib in adult patients with previously untreated metastatic pancreatic cancer. (ASCO 2025) - P1 | "Key eligibility criteria include 1) histologically confirmed diagnosis of metastatic pancreatic ductal adenocarcinoma with measurable disease on baseline imaging, 2) life expectancy of at least 3 months, 3) no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease, and 4) no prior immune checkpoint inhibitor therapy. Enrollment began in January 2025 at the HonorHealth Research Institute."

Clinical • Metastases • P1 data • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PD-L2

Monitoring botensilimab- and balstilimab-induced T-cell dynamics in refractory mismatch repair proficient metastatic colorectal cancer. (ASCO 2025) - P2 | "In this trial patients were randomized into BOT (75mg or 150mg Q6W, 4x) monotherapy or in combination with BAL (240mg Q2W, for 2 years), versus standard of care (regorafenib or trifluridine/tipiracil). Deep T cell repertoire profiling detected dynamics of circulating T cells with quantitative and qualitative difference related to ICI response. Immune cell tracking from liquid biopsies is a powerful tool to quantify ICI efficacy in real time."

IO biomarker • Metastases • Mismatch repair • pMMR • Colorectal Cancer • Hepatology • Oncology • Solid Tumor

A phase Ib study of a pooled synthetic long peptide mutant KRAS vaccine combined with balstilimab/botensilimab in metastatic pancreatic cancer and metastatic MMR-proficient colorectal cancer in the maintenance setting. (ASCO 2025) - P1 | "In an ongoing pilot study in patients with resected PDAC and metastatic MMRp CRC (NCT04117087), we demonstrated that a pooled synthetic long peptide (SLP) mKRAS vaccine in combination with ipilimumab and nivolumab was safe and well tolerated...The vaccine consists of SLPs corresponding to six common mKRAS alleles: G12D, G12V, G12R, G12C, G12A, G13D admixed with poly-ICLC adjuvant...Study drug support provided by Agenus. Trial information: NCT06411691."

Clinical • IO biomarker • Metastases • P1 data • Colorectal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • KRAS

FOLFOX, Botensilimab, and Balstilimab for the Treatment of Localized Rectal Cancer Before Surgery (clinicaltrials.gov) - P2 | N=26 | Recruiting | Sponsor: City of Hope Medical Center | Not yet recruiting ➔ Recruiting | Trial completion date: Dec 2026 ➔ Nov 2027 | Trial primary completion date: Dec 2026 ➔ Nov 2027

Enrollment open • Trial completion date • Trial primary completion date • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Rectal Cancer • Solid Tumor

Agenus and Zydus Lifesciences Enter $141M Strategic Collaboration to Advance BOT/BAL, Expand Zydus’ Biologics Manufacturing in the US (Businesswire) - "Agenus Inc...announced it has signed definitive partnership agreements with Zydus Lifesciences Ltd...including its subsidiaries/affiliates, hereafter referred to as 'Zydus,' designed to accelerate clinical development, scale global manufacturing, and expand patient access to botensilimab and balstilimab (BOT/BAL)...The strategic collaboration includes an exchange of Agenus’ state-of-the-art biologics CMC facilities in Emeryville, CA and Berkeley, CA for upfront consideration of $75M; Agenus to receive up to an additional $50M in contingent payments triggered by BOT/BAL production orders...Agenus will also grant Zydus an exclusive license to develop and commercialize BOT and BAL in India and Sri Lanka, capitalizing on Zydus’ established local market presence and infrastructure. Zydus will pay Agenus a 5 percent royalty on net sales in those countries....The parties aim to complete closing agreements within 60 days."

Licensing / partnership • Solid Tumor

Agenus Presents New Data at ASCO Highlighting Botensilimab’s Immune Activation in MSS Colorectal Cancer (Businesswire) - P2 | N=234 | NCT05608044 | Sponsor: Agenus Inc. | "Agenus Inc...presented new translational data at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. The study demonstrates that botensilimab-based therapy induces a robust and persistent T cell immune response in microsatellite stable (MSS), or mismatch repair proficient (pMMR), metastatic colorectal cancer (mCRC)....Data Highlights: Fast T cell priming and activation: T-cells begin activating within two weeks of starting botensilimab; Robustly expands and sustains T cell activity: Newly primed T cells persist and expand across treatment cycles, correlating with improved clinical responses; Immune activity detected before scans: Immune-profiling tests detect this activity even when standard imaging hasn’t yet caught a response; Blood signals predict benefit: A quick blood draw can reveal early immune markers that help doctors identify who is most likely to respond and live longer."

P2 data • pMMR • Colorectal Cancer

C-800-25: A Study of Botensilimab and Balstilimab for the Treatment of Colorectal Cancer (clinicaltrials.gov) - P2 | N=234 | Active, not recruiting | Sponsor: Agenus Inc. | Trial completion date: Jul 2025 ➔ Sep 2029 | Trial primary completion date: Feb 2025 ➔ Sep 2027

Monotherapy • Trial completion date • Trial primary completion date • Colorectal Cancer • Oncology • Solid Tumor • BRAF • EGFR • MSI

AGEN1423 and Botensilimab w/ or w/o Chemo in PDAC (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Bruno Bockorny | Recruiting ➔ Active, not recruiting

Enrollment closed • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor

Results from a phase 1 study of botensilimab and balstilimab in treatment refractory hepatocellular carcinoma (AACR 2025) - P1 | "Pts received a median of 2 prior lines of therapy (range 1–7); all had received prior PD-(L)1 as part of combination therapy (58% atezolizumab/bevacizumab [atezo/bev]) and 63% received prior receptor tyrosine kinase inhibitors...All 3 responders received prior atezo/bev; 1 also received lenvatinib; another also received sorafenib and a MER/AXL-targeted therapy (clinical trial)...The safety profile was manageable and consistent with other disease cohorts treated with BOT/BAL. These results support further investigation."

Late-breaking abstract • P1 data • Hepatocellular Cancer • Oncology • Solid Tumor • AXL

Agenus Announces New Data from Expanded MSS Metastatic Colorectal Cancer Cohort to be Presented at ESMO GI 2025 (Businesswire) - "Agenus Inc...today announced new data from its ongoing Phase 1 trial evaluating botensilimab and balstilimab (BOT/BAL) in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) at the 2025 European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress in Barcelona, Spain. A poster presentation will feature updated findings from an expanded cohort of 123 patients, incorporating additional participants and extended follow-up to further assess clinical activity of the combination, including durability of response and overall survival."

P1 data • Colorectal Cancer

Mutant KRAS peptide vaccine combined with ipilimumab/nivolumab in advanced mismatch repair proficient/microsatellite stable (MMRp/MSS) colorectal cancer: Preliminary analysis from a phase I study (AACR 2025) - P1 | "Key inclusion criteria included tumor expression of a KRAS mutation included in mKRAS-VAX and prior 5-fluorouracil, oxaliplatin, and irinotecan exposure. mKRAS-VAX and ipi/nivo is well-tolerated and induced mKRAS-specific T-cell responses. Moreover, this strategy resulted in meaningful clinical responses in chemorefractory metastatic mKRAS MMRp/MSS CRC with OS that was provocative. Ongoing studies of the T cell repertoire in blood and tumor tissue will be used to identify biomarkers that predict response to mKRAS-targeted immunotherapy."

IO biomarker • Metastases • Mismatch repair • P1 data • pMMR • Colorectal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • IFNG • KRAS

Agenus Reports Q1 2025 Financial Results and Key Business Updates (Agenus Inc. Press Release) - "Agenus is on track to reduce its annualized operating cash burn below $50 million starting in the second half of 2025, supported by recent cost optimization measures enabling the company to direct resources toward ensuring the potential of BOT/BAL is realized. The company is in final stages of an important collaboration which will result in substantial cash infusion."

Commercial • dMMR • MSI-H • Colorectal Cancer • Hepatocellular Cancer • Microsatellite Instability • Sarcoma • Triple Negative Breast Cancer

Botensilimab Plus Balstilimab Elicits Durable Responses in Treatment-Refractory HCC (OncLive) - "'Botensilimab/balstilimab demonstrated durable responses and prolonged stable disease in patients with treatment-refractory HCC, with a median of two prior lines of therapy and progressed on or after I-O, including patients who received prior atezolizumab [Tecentriq]/bevacizumab [Avastin],' Anthony B. El-Khoueiry, MD...and colleagues wrote in a poster of the data. 'The DCR and survival data provide early evidence of antitumor activity in the setting of prior I-O–based therapy.'"

Media quote

Agenus’ BOT/BAL Neoadjuvant Pan-Cancer Data from the NEOASIS Study Presented in an Oral Session at AACR (Businesswire) - P2/3 | N=92 | NEOASIS (NCT06279130) | "The safety run-in enrolled patients with non-metastatic solid tumors, divided into two cohorts of 10 patients each: dMMR/MSI-H and pMMR/MSS....Results: (i) dMMR/MSI-H Cohort (9 colorectal, 1 duodenal cancer): Pathological response rate: 90%; Major pathological response (MPR): 80%; Pathological complete response (pCR): 70%; (ii) pMMR/MSS Cohort (6 triple-negative breast cancer, 2 ER+ breast cancer, 1 merkel cell carcinoma, 1 sarcoma): Pathological response rate: 80%; Major pathological response (MPR): 70%; Pathological complete response (pCR): 20%; Triple-negative breast cancer subgroup (n=6): 63% achieved MPR."

dMMR • MSI-H • P2 data • Colorectal Cancer • Estrogen Receptor Positive Breast Cancer • Merkel Cell Carcinoma • Microsatellite Instability • Sarcoma • Triple Negative Breast Cancer

Agenus’ BOT/BAL Data in Pretreated Liver Cancer Presented at AACR 2025 (Businesswire) - P1 | N=499 | NCT03860272 | Sponsor: Agenus Inc. | "Phase 1 Study Overview: BOT/BAL in Treatment-Refractory Hepatocellular Carcinoma (NCT03860272)...The HCC cohort enrolled 19 patients (18 evaluable for efficacy) with treatment-refractory metastatic HCC. Patients received a median of two prior therapies, and progressed on or following anti-PD(L)-1. Patients were administered BOT (1 or 2 mg/kg) in combination with BAL (3 mg/kg)....Key Results: Overall response rate: 17%; Stable disease rate: 56%; Disease control rate: 72%; Median progression-free survival: 4.4 months; Median overall survival: 12.3 months....The safety profile of the BOT/BAL combination remained consistent with previous cohorts and was manageable."

P1 data • Hepatocellular Cancer

Study of AGEN1571 in Participants With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=22 | Completed | Sponsor: Agenus Inc. | Active, not recruiting ➔ Completed | Trial completion date: Jan 2027 ➔ Dec 2024 | Trial primary completion date: Jan 2027 ➔ Dec 2024

Trial completion • Trial completion date • Trial primary completion date • Solid Tumor

Agenus Announces Botensilimab and Balstilimab Presentations at ASCO 2025 (Businesswire) - "Agenus Inc...announced three upcoming presentations at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 30 – June 3 in Chicago, Illinois. A poster presentation will highlight new translational data monitoring induced T-cell dynamics from the botensilimab and balstilimab (BOT/BAL) program in mismatch repair–proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC). In addition, two trials-in-progress presentations will showcase the design and scientific rationale of ongoing clinical studies evaluating botensilimab-based combinations in advanced pancreatic cancer."

Clinical data • pMMR • Trial status • Colorectal Adenocarcinoma • Pancreatic Cancer