On January 22, 2025 Agenus Inc. (Nasdaq: AGEN ), a leader in immuno-oncology, reported new data on botensilimab (BOT) and balstilimab (BAL) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco (Press release, Agenus, JAN 22, 2025, View Source [SID1234649831]). Data from five presentations underscore the transformative potential of BOT/BAL across multiple lines of therapy in colorectal cancer, including neoadjuvant, first-line, and refractory settings. Data presented also highlight BOT/BAL’s potential in treating microsatellite stable (MSS) CRC tumors, which account for 85-95%1 of patients living with CRC that historically have been unresponsive to immuno-oncology (I/O) therapies. To date, BOT/BAL has been evaluated in approximately 1,100 patients across more than 60 centers worldwide.
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"Data presented at ASCO (Free ASCO Whitepaper) GI highlight botensilimab and balstilimab’s potential to redefine colorectal cancer treatment, delivering remarkable outcomes in neoadjuvant MSS CRC," said Dr. Steven O’Day, Chief Medical Officer of Agenus . "These findings set the stage for pivotal studies intended to create a new standard of care for colon and rectal cancer patients by reducing reliance on chemotherapy, radiation, and surgery, while improving survival."
Key Data Highlights
Neoadjuvant CRC: A Potential Path to Chemo-Free Treatment
Data presented from two independent studies, UNICORN and NEST, collectively include more than 80 patients treated with BOT/BAL:
UNICORN: Phase 2 Trial of Pre-Operative BOT/BAL Combination Treatment in Resectable Colon Cancer (Abstract 158):
This multicenter Phase 2 study enrolled 56 patients across 10 centers in Italy and France.
Pathological complete responses (pCR) and pathological major responses (pMR) were observed in both the pMMR/MSS and dMMR/MSI-H patient populations.
BOT/BAL achieved a 93% pCR rate and 100% pMR in dMMR/MSI-H tumors and 29% pCR rate and 36% pMR rate in pMMR/MSS tumors, highlighting the opportunity for a non-operative, organ sparing, approach in this disease setting.
Serious adverse events (AEs) occurred in 9 pts (16%) and were treatment-related in 3 pts (5%). Only 1 of 56 surgeries were delayed due to an AE.
NEST: Phase 2 Trial of Neoadjuvant Combination Treatment of BOT/BAL in Patients with Resectable Colon Cancer (Abstract 207):
This trial has currently enrolled 24 patients.
After median follow-up of 18 months (NEST-1 arm) and 9 months (NEST-2 arm), all patients (100%) remained ctDNA negative and no clinical recurrences were observed. The pMR improved in NEST-2 to 47% (7/15) in MSS tumors when the median time to surgery was extended.
The combination was well tolerated with no grade 4 events and no unresolved immune-mediated adverse events (imAEs). No delays in surgery occurred due to imAEs.
Dr. Filippo Pietrantonio, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori Milan comments on the UNICORN study stating, " These results further validate the transformative potential of botensilimab and balstilimab in colorectal cancer. The remarkable pathological response rates observed in both pMMR and dMMR tumors highlight the unique strength of this combination in addressing a critical unmet need and pave the way for non-operative management strategies."
First-Line and FOLFOX Rechallenged MSS CRC: Powerful Combination with Standard Therapies
Phase 1/2 Trial of BOT/BAL With FOLFOX-Bevacizumab in MSS mCRC (Abstract 180):
Preliminary findings showed activity of combination independent of liver metastases.
In the initial 14 patients, 12 which were previously treated with FOLFOX, a 71% overall response rate (ORR) was achieved. In the 9/14 patients with liver metastases, a 67% ORR was achieved.
The combination was well-tolerated with limited severe imAEs, supporting the opportunity for higher doses of BOT.
Refractory MSS CRC: Consistent Results Across Phase 1 and 2 Studies
Global Randomized Phase 2 Study of BOT/BAL in MSS mCRC NLM (Abstract 23):
This is a global Phase 2 trial (NCT05608044) of BOT/BAL versus standard-of-care treatments of regorafenib or trifluridine/tipiracil in patients with refractory metastatic colorectal cancer that had spread to either peritoneum, lymph nodes, lungs, bone or brain. 234 patients were enrolled across 40 centers worldwide.
These results reinforce the activity and safety seen in the Phase 1 study and confirm the contribution of BAL to BOT.
BOT75/BAL achieved a 19% ORR and 55% disease control rate (DCR) in this refractory population. Standard of care had no responses.
70% of responses were ongoing at the time of data cut-off, demonstrating durability as DOR continues to mature.
BOT/BAL showed a superior benefit-risk profile at 75 mg compared to BOT/BAL 150mg and has been selected for Phase 3 trials.
No new safety signals were observed, and no treatment related deaths occurred. The most common imAEs at BOT 75mg + BAL included diarrhea/colitis (35%) and hypothyroidism (13%).
"The Phase 2 results highlight the unique and consistent activity of the botensilimab and balstilimab combination, demonstrating a compelling objective response rate in microsatellite stable metastatic colorectal cancer, a disease where responses to immunotherapy have historically been absent," said Dr. Marwan Fakih, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center. "These findings underscore the potential of botensilimab and balstilimab combination treatment in addressing this critical unmet need, paving the way for further investigation."
Gastric Cancer
Phase 2 BOT/BAL/AgenT-797 in Combination with Ramucirumab and Paclitaxel in Patients with Previously Treated, Unresectable or Metastatic Gastroesophageal Cancers (Abstract TPS515):
The Phase 2 trial (NCT06251973) is investigating a novel combination approach, which leverages cellular therapy and immune modulation to address the unmet needs in gastroesophageal cancers. Gastroesophageal cancers continue to be a growing global burden responsible for nearly 1.3 million global deaths annually2.
The novel approach demonstrated early signals of activity and tolerability in the second-line treatment setting, with additional efficacy data anticipated in 2H 2025.
Future Development Plans
Agenus has developed registrational enabling trials in MSS CRC across neoadjuvant, first-line, and late-line settings. These trials will launch upon completion of strategic transactions. Upon the options being considered are, partnerships, licensing, or joint ventures. These initiatives aim to accelerate global access to BOT/BOL to deliver transformative patient outcomes and drive substantial value for stakeholders.
Botensilimab, balstilimab, and agenT-797 are investigational agents and are not approved for use as therapies in any jurisdiction worldwide.
For additional data and publications, visit agenusbio.com/publications.