Immunotherapy Duo Shows 42% 2-Year Survival in MSS CRC Trial

At the 2025 European Society for Medical Oncology (ESMO) Gastrointestinal Cancers Congress in Barcelona, Spain, Agenus Inc unveiled new data showing that its combination immunotherapy botensilimab and balstilimab continues to demonstrate unprecedented survival benefits in patients with microsatellite-stable metastatic colorectal cancer (MSS mCRC), a population historically resistant to immunotherapies.¹

The updated results from the C-800-01 phase 1 trial (NCT03860272) include an expanded cohort of 123 patients without active liver metastases, showing a 2-year survival rate of 42% and a median overall survival (OS) of 20.9 months. These figures mark a significant improvement compared with the 5- to 8-month median OS typically observed with best supportive care in third-line or later MSS mCRC settings.

The combination therapy yielded a confirmed objective response rate (ORR) of 20% and a disease control rate of 69%. Among patients treated in the fourth-line setting or beyond (n = 37), the ORR was approximately 19%, and 2-year survival stood at 43%, reaffirming the regimen’s potential durability even in the most refractory cases. The median duration of response reached 16.6 months. Importantly, no new safety signals were reported, and immune-related adverse events remained manageable across dosing levels.

“These results reinforce the consistency and durability of the botensilimab plus balstilimab combination in a population that has historically seen minimal benefit from immune checkpoint blockade,” said Benjamin Schlechter, MD, Dana-Farber Cancer Institute, during the ESMO presentation.

The FDA has also shown increasing alignment with Agenus on the development path for this novel immunotherapy. In minutes released from a July 1, 2025, end-of-phase 2 meeting, the FDA acknowledged that current data support balstilimab’s contribution to the observed clinical benefit. As a result, the agency agreed to waive the requirement for a botensilimab monotherapy arm in the upcoming phase 3 BATTMAN trial (CCTG CO.33), streamlining it into a simpler 2-arm design. The global registration study is set to begin in the fourth quarter of 2025.

While the FDA continues to advocate for randomized controlled trials to support a potential approval, it noted that the magnitude of benefit observed “does not appear to meet the standard of reasonably likely to predict benefit” under current guidelines. However, Agenus and its clinical advisors argue that the combination's durable responses, meaningful survival outcomes, and the critical unmet need in this patient population justify consideration under subpart E regulatory provisions.

Jennifer Buell, PhD, executive chairwoman of Agenus, praised the FDA’s constructive guidance and reaffirmed the company’s commitment to expedited regulatory pathways. “We intend to use every expedited pathway—Fast Track, Real-Time Oncology Review, the new Commissioner’s National Priority Voucher Program—to bring this chemo-free option to patients who have exhausted all other treatments,” she stated in a press release.

Originally developed under the C-800-01 trial, botensilimab and balstilimab have emerged as potential game-changers for MSS CRC, tumor type historically unresponsive to checkpoint inhibitors. With the ongoing maturation of the dataset and upcoming data presentations in late 2025, this combination therapy may represent a paradigm shift in how clinicians’ approach late-line treatment in CRC.

REFERENCE:

Agenus’ BOT/BAL achieves 42% two-year survival in refractory MSS CRC, advances toward registration with FDA alignment on phase 3. News release. Agenus Inc. July 7, 2025. Accessed July 11, 2025. https://tinyurl.com/4ydpxdkk