On February 26, 2025 Agenus Inc. (Nasdaq: AGEN), a leader in immuno-oncology innovation, reported key scientific contributions in 2024-2025 that are shaping the future of cancer immunotherapy (Press release, Agenus, FEB 26, 2025, View Source [SID1234650647]).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
Agenus is advancing a robust clinical pipeline targeting complementary mechanisms to fight cancer, including checkpoint inhibitors, immune activators, tumor microenvironment conditioning agents and cell therapies (via MiNK Therapeutics). Our most advanced antibody candidates, botensilimab (BOT) an Fc-enhanced CTLA-4 blocking antibody, and balstilimab (BAL), a novel, PD-1 inhibitor, are central to our efforts.
Driving Innovation of Cancer Immunotherapy
BOT has demonstrated differentiated mechanisms to enhance T cell priming, activation, and memory to drive a more effective immune response and was intentionally designed to mitigate toxicities associated with first-generation anti-CTLA-4 therapies.
BOT is currently being investigated as a monotherapy and in combination with widely used standard of care anti-PD-1, chemotherapy, and allogeneic cell therapy across multiple indications:
MSS colorectal cancer (CRC), pancreatic cancer (in combination with chemotherapy), and gastroesophageal (in combination with BAL and agent-797).
To date, BOT, either alone or in combination with BAL, has been evaluated in approximately 1,100 patients across more than 60 centers worldwide.
The combination targets complementary pathways and has demonstrated clinical responses across nine tumor types, including those historically considered immuno-oncology (IO) "cold" tumors or resistant to prior IO treatments.
Recent data presented at leading international conferences (ASCO, ESMO (Free ESMO Whitepaper), ASCO (Free ASCO Whitepaper) GI, AACR (Free AACR Whitepaper) IO) and featured in prestigious journals (Nature Medicine, Journal of Clinical Oncology, Cancer Discovery), showcase Agenus’ pivotal role in advancing IO research and expanding the reach of IO therapies to new patient populations.
Agenus’ Commitment to Advancing Immuno-Oncology Therapies
"The breadth and consistency of data we have presented over the past year reinforce the transformative potential of botensilimab and balstilimab in redefining treatment paradigms for patients battling historically treatment-resistance cancers. Decades of immuno-oncology research have set the stage for next-generation breakthroughs, and these latest findings with botensilimab and balstilimab represent a major advancement," said Dr. Steven O’Day, Chief Medical Officer, Agenus.
Dr. O’Day continues, "By leveraging our deep expertise in immune activation, we are unlocking responses in tumors previously resistant to immunotherapy. The results are even more promising as we move from treatment refractory metastatic disease to the neoadjuvant setting where we have the potential to reduce the need for adjuvant chemotherapy, preserve organs, and improve long-term survival. These results highlight an opportunity to reshape treatment paradigms and address the greatest unmet needs in oncology."
Breakthrough Findings Across Multiple Cancers
1. Colorectal Cancer:
Neoadjuvant Botensilimab Plus Balstilimab in Resectable Mismatch Repair Proficient (pMMR) and Deficient (dMMR) Colorectal Cancer (CRC) – NEST Study1 link
Conference: ASCO (Free ASCO Whitepaper) GI 2025
Lead Author: Dr. Erika Hissong, Weill Cornell Medicine
Key Findings: This investigator-initiated Phase 2 trial assessed BOT/BAL as neoadjuvant therapy in localized pMMR/MSS and dMMR/MSI-H CRC patients. The combination achieved high major pathological response (MPR) rates, and after median follow-up of 18 months (NEST-1) and 9 months (NEST-2) no recurrences were observed. Extended time to surgery correlated with improved pathological response. The study underscores the potential of dual checkpoint inhibition in neoadjuvant settings for CRC and the potential for non-surgical approaches for some patients.
Neoadjuvant Botensilimab Plus Balstilimab in Resectable Mismatch Repair Proficient (pMMR) and Deficient (dMMR) Colorectal Cancer (NEST-1 Trial)2 link
Conference: ESMO (Free ESMO Whitepaper) GI 2024
Lead Author: Dr. Pashtoon Kasi (presented by Dr. Mehraneh Jafari), Weill Cornell Medicine
Key Findings: This investigator-initiated Phase 2 trial assessed BOT/BAL as neoadjuvant therapy in resectable pMMR and dMMR colorectal cancer (CRC). A major pathological response (MPR) rate was observed across both cohorts, with no recurrences reported to date. Notably, extended time to surgery was associated with improved responses. Updated data was presented in 2025.
Preoperative Botensilimab (BOT) with or without Balstilimab (BAL) in Resectable, Locally Advanced pMMR or dMMR Colon Cancer – UNICORN Trial3 link
Conference: ASCO (Free ASCO Whitepaper) GI 2025
Lead Author: Dr. Filippo Ghelardi, Fondazione IRCCS Istituto Nazionale dei Tumori Milan
Key Findings: The Investigator-initiated Phase 2 UNICORN trial, explored short-course neoadjuvant BOT ± BAL in non-metastatic CRC patients. Results showed that the addition of BAL significantly enhanced response rates compared to BOT monotherapy, particularly in pMMR tumors. The pCR rate for the combination was 29% and 93% for pMMR and dMMR status, respectively, supporting the potential for non-operative management strategies in CRC.
Phase 2 Botensilimab Plus Balstilimab in Refractory Microsatellite Stable (MSS) Metastatic Colorectal Cancer with No Liver Metastases4 link
Conference: ASCO (Free ASCO Whitepaper) GI 2025
Lead Author: Dr. Marwan G. Fakih, City of Hope Comprehensive Cancer Center
Key Findings: A Phase 2 study demonstrated deep and durable responses in MSS mCRC patients, demonstrating reproducible response rates (19%) and disease control rate (DCR) of 55% in this refractory metastatic CRC patient population; the standard of care arm had no responses. Notably, some patients treated with BOT/BAL exhibited no active disease over two years after starting the trial.
Phase 1 Study of Botensilimab Plus Balstilimab in Relapsed/Refractory Microsatellite Stable (MSS) Metastatic Colorectal Cancer5 link
Publication: Nature Medicine (September 2024)
Lead Author: Dr. Andrea J. Bullock, Beth Israel Deaconess Medical Center
Key Findings: This study evaluated BOT/BAL in heavily pretreated MSS mCRC patients, a historically checkpoint inhibitor-resistant tumor type. The ORR was 17%, and DCR reached 61%. The combination demonstrated durable responses with a manageable safety profile. In patients with non-active liver metastases (NLM) (n = 77), the ORR was 22% and the DCR was 73% with a 12-month OS rate of 69%. Conversely, in patients with active LM (n=24), ORR was 0% and the DCR was 25% with a 12-month OS rate of 30%. Learnings from this study helped define the P2 study population in MSS mCRC NLM.
A Phase I Trial of FOLFOX-3B: A Combination of Chemotherapy, VEGF(R) Inhibitors, and Checkpoint Blockade in MSS Metastatic Colorectal Cancer6 link
Conference: ASCO (Free ASCO Whitepaper) GI 2025
Lead Author: Dr. Marwan G. Fakih, City of Hope Comprehensive Cancer Center
Key Findings: This Phase I study evaluated the combination of BOT, BAL, FOLFOX chemotherapy, and bevacizumab in MSS metastatic CRC. Preliminary findings showed activity of the combination independent of liver metastases. The regimen demonstrated a 71% objective response rate (ORR) overall. 12/14 patients were pre-treated (FOLFOX "rechallenge"). The combination was well tolerated with only 1/14 patients having immune mediated diarrhea/colitis. Findings suggest that checkpoint blockade plus chemotherapy may enhance immunogenicity in MSS CRC and extend benefit to patients with liver metastases, warranting further investigation in the first line metastatic setting.
2. Gastroesophageal Cancer:
Biomarker Analysis from Phase 2 Study of agenT-797, Botensilimab Plus Balstilimab in PD-1 Refractory Gastroesophageal Cancer link
Conference: AACR (Free AACR Whitepaper) IO 2025
Lead Author: Dr. Samuel L. Cytryn, Memorial Sloan Kettering Cancer Center
Key Findings: This investigator-initiated Phase 2 trial demonstrated significant immune modulation, including robust tumor T-cell infiltration and increased activation of effector-memory T cells, suggesting the potential for overcoming PD-1 resistance.7
3. Sarcoma:
Botensilimab Plus Balstilimab in Relapsed/Refractory (R/R) Metastatic Sarcomas8 link
Publication: Journal of Clinical Oncology (January 2025)
Lead Author: Dr. Breelyn A. Wilky, University of Colorado Cancer Center
Key Findings: This Phase 1 study demonstrated promising efficacy of BOT in combination with BAL, in heavily pretreated sarcoma patients, including soft tissue sarcoma subtypes considered immunologically "cold". Notably, the overall response rate (ORR) was 19.2%, with a 27.8% ORR among angiosarcoma patients. The disease control rate (DCR) reached 65.4%, with a median progression-free survival (PFS) of 4.4 months and a 12-month overall survival (OS) rate of 69%.
Updated Efficacy and Safety of Botensilimab Plus Balstilimab in Metastatic Sarcoma9 link
Conference: ESMO (Free ESMO Whitepaper) 2024
Lead Author: Dr. Breelyn A. Wilky, University of Colorado Cancer Center
Key Findings: Data from an expanded Phase 1 study reaffirmed the activity of BOT/BAL across refractory metastatic sarcomas, including angiosarcoma and leiomyosarcoma. ORR reached 19.2%, with durable responses beyond 21 months in some patients.
4. Mechanistic Insights
Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy10 link
Publication: Cancer Discovery (December 2024)
Lead Author: Dr. Dhan Chand, Agenus Inc.
Key Findings: This landmark study highlighted how botensilimab’s unique design and Fc-enhancement overcomes the limitations of conventional checkpoint inhibitors through multiple immune-activating mechanisms. The research demonstrates that botensilimab potentiates T-cell responsiveness, reduces regulatory T cells, and enhances antigen-presenting cell activation across both preclinical models and patient samples. Clinical data showed significant efficacy in multiple treatment-refractory cancers, including those that progressed on prior immunotherapies. The findings establish a new mechanistic paradigm for expanding immunotherapy benefits to patients with traditionally immunotherapy-resistant cancers.
AGEN1721 – a first-in-class Fc-enhanced Bifunctional Antibody Targeting FAP and TGFβ, Remodels the Tumor Microenvironment to Overcome Cancer-associated Fibroblast-mediated Immune Suppression11 link
Conference: SITC (Free SITC Whitepaper) 2024
Lead Author: Dr. Priya Iyer, Agenus Inc.
Key Findings: AGEN1721, a novel dual-targeting agent, demonstrated the ability to modulate the tumor stroma, enhancing T-cell infiltration and antitumor responses in preclinical models. These findings provide a strong rationale for clinical development.
Additional updates in mCRC, NSCLC, melanoma, ovarian and pancreatic cancer are anticipated in the second half of 2025.
For further details on these studies, please visit www.agenusbio.com, www.minktherapeutics.com or access the respective publications and conference presentations.