The CO.33/BATTMAN trial: A phase 3 randomized study of botensilimab + balstilimab versus best supportive care in chemorefractory unresectable colorectal adenocarcinoma that is not dMMR/MSI-H.

TPS3676 Background: Despite significant progress and newly approved agents, metastatic colorectal cancer (mCRC) has limited prognosis after progressing on standard cytotoxic chemotherapies. Many patients remain well enough for treatment at the time when their cancer is refractory to all available therapy, creating a significant unmet need. Once refractory, patient management with best supportive care (BSC) results in a median overall survival (OS) of 4–6 months. To date, immune checkpoint inhibitors (ICIs) have shown limited activity in mCRC that is not mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H). Prior data from the CCTG CO.26 randomized phase 2 trial demonstrated doublet ICI with durvalumab + tremelimumab improved OS in refractory mCRC; however, a phase 3 trial was not undertaken. Botensilimab (BOT) is an Fc-enhanced multifunctional anti–CTLA-4 antibody designed to increase efficacy in poorly immunogenic cancers. The combination of BOT with the anti–PD-1 antibody balstilimab (BAL) has shown impressive objective response rates (ORRs), durations of response (DOR), and survival in heavily treated non–MSI-H/dMMR mCRC across phase 1 and 2 studies. The CO.33/BATTMAN trial will evaluate BOT + BAL + BSC versus BSC alone in patients with refractory mCRC that is not MSI-H/dMMR. Methods: BATTMAN (NCT07152821) is an international multi-centre, open-label randomized phase 3 trial that will be conducted in Canada (CCTG), Australia/New Zealand (AGITG) and France (Unicancer). Eligible patients will be ≥18 years old, have received and progressed on or been intolerant of all available therapies, have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0/1, have RECIST 1.1 measurable/evaluable disease, have a life expectancy of ≥12 weeks, and have adequate end organ function without concurrent illness contraindicating ICI. Exclusion criteria include: prior organ transplant or primary immunodeficiency, ongoing use of non-physiologic corticosteroid dosing, autoimmune disorders requiring ongoing management, and prior ICI exposure. The trial’s statistical plan will ascertain efficacy of BOT and BAL in all comers, as well as key subgroups based on the presence or absence of liver metastases. A planned 834 patients will be randomized 1:1 to BOT (75 mg IV every 6 weeks up to 4 doses) + BAL (450 mg IV every 3 weeks until progression) + BSC or BSC alone, with stratification for region of recruitment, ECOG PS, and presence of liver metastases. The primary endpoint is OS, with secondary endpoints including progression-free survival, ORR, clinical benefit rate, quality of life, safety, and toxicity, with correlative studies and economic evaluations planned. Support for this study is provided by: The Canadian Cancer Society and Agenus Inc. Clinical trial information: NCT07152821 .