Preliminary results from a randomized, open-label, phase 2 study of botensilimab (BOT) with or without balstilimab (BAL) in refractory microsatellite stable metastatic colorectal cancer with no liver metastases (MSS mCRC NLM).
Authors: Marwan Fakih, Neil Howard Segal, Benjamin L. Schlechter, Thierry Andre, Filippo Pietrantonio, Benny Johnson, Alexander Vasilyev, Smitha S. Krishnamurthi, Salvatore Siena, Wells A. Messersmith, Virgilio Souza E Silva, Andrew Scott Paulson, Elena Elez, Cathy Eng, Sabine Tejpar, Michel Pierre Ducreux, Wei Wu, Joseph Elan Grossman, Eric Van Cutsem, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2025)

23 Background: BOT is an Fc-enhanced, multifunctional anti-CTLA−4 antibody designed to improve Fc gamma receptor-mediated effector functions and extend the reach of I-O to tumor types such as MSS mCRC. Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD−1; NCT05608044). The study aimed to inform dose and contribution of components based on the primary endpoint of objective response rate (ORR) by RECIST 1.1 per investigator, and safety, and was not powered for statistical comparisons between arms. Methods: A total of 234 pts (intent-to-treat [ITT]) were randomized to BOT (up to 4 doses) 75 or 150 mg every 6 wks (Q6W), BOT 75 or 150 mg Q6W plus BAL 240 mg Q2W (up to 2 years), or standard of care (SOC; regorafenib or trifluridine/tipiracil). Results: Median age was 58 yrs (range 23—90), 50% male, 39% rectal, 44% 3L+, 43% ECOG 1, 58% KRAS mutant, 4% NRAS mutant, 83% prior bev, all MSS and/or pMMR by local testing. Key characteristics were well balanced with some exceptions including median time from diagnosis of metastatic disease to study entry (30 mos across arms; 45 mos SOC) and presence of peritoneal metastases (34% across arms; 42% 75 mg BOT / 240 mg BAL; 27% SOC). As of July 29, 2024, median follow-up was 9.8 mos. Key efficacy and safety data are shown (Table). Image based endpoints by blinded independent review, as well as overall survival will be reported in the future. Grade ≥3 treatment-related adverse events (TRAEs) were highest with SOC followed by BOT + BAL combination, and then BOT monotherapy, with dose dependency. Treatment-related immune-mediated diarrhea/colitis (imDC) was manageable and highest with 150 mg BOT / 240 mg BAL. No new safety signals and no treatment-related deaths occurred. Conclusions: The study met the objectives of informing dose and contribution of components. Overall ORR was higher with BOT + BAL vs BOT monotherapy. ORR was highest with 75 mg BOT / 240 mg BAL with less toxicity as compared to 150 mg BOT / 240 mg BAL. Consistent with published data, there were no objective responses in SOC whereas most responses seen with BOT + BAL were ongoing, similar to the durable responses observed in the ph1 study. These responses are differentiated from previous I-O-only combinations and SOC, supporting further investigation of 75 mg BOT / 240 mg BAL vs SOC in a planned global ph3 trial. Clinical trial information: NCT05608044 . 75 mg BOT/240 mg BAL 150 mg BOT/240 mg BAL 75 mg BOT 150 mg BOT SOC ITT (Randomized) n=62 n=61 38 n=40 n=33 ORR, % (95% CI) 19%(10—31) 8%(3—18) 0%(0—10) 8%(2—20) 0%(0—11) Safety (Treated) n=62 n=60 n=37 n=39 n=21 Any Grade TRAEs, n (%) 54 (87) 59 (98) 28 (76) 31 (79) 19 (90) Grade ≥3 TRAEs, n (%) 22 (35) 25 (42) 8 (22) 9 (23) 12 (57) Any Grade Treatment-related IMDC, n (%) 19 (31) 28 (47) 13 (35) 12 (31) 0 (0)