A phase II, randomized study of JMT101 in combination with irinotecan and SG001 versus regorafenib in patients with metastatic colorectal adenocarcinoma (mCRC).

TPS314 Background: Epidermal growth factor receptor (EGFR) inhibitorcombined withchemotherapy based on5-FU with oxaliplatin and irinotecanis the first-line treatment of wild-type RAS mCRC.JMT101 is a humanized monoclonal IgG1 antibody targeting EGFR. Previous trials showed that JMT101 monotherapy or in combination with chemotherapy had demonstrated a promising anti-tumor activity in advanced solid tumors with good safety profiles. EGFR inhibitor might have a synergetic effect with immunocheckpoint inhibitor (ICI) by activating innate and adaptive immune response. SG001 is a fully humanized and high-affinity immunoglobulin G4 monoclonal antibody that targets programmed death-1 (PD-1), which also had encouraging efficacy in advanced solid tumors. Therefore, EGFR antibody in combination with chemotherapy plus ICI is worthy exploration in patients with mCRC. Methods: This is a phase II, multicenter, open-label, two-part study. Part I is a safety run-in, followed by part II randomized treatment. Eligible patients are histologically confirmed mCRC without MSI-H/dMMR, wild-type RAS and BRAF, who progressed on at least 2 prior systemic therapy with chemotherapy based on 5-FU with oxaliplatin and irinotecan, with or without cetuximab and bevacizumab (both parts); no prior treatment with regorafenib, fruquintinib, or TAS-102 (part II). Safety run-in data will be analyzed after 3-6 patients have received JMT101 6 mg/kg plus irinotecan 180 mg/m 2 plus SG001 240 mg Q2W. Upon dose confirmation, 90 patients with mCRC will be randomized into three arms (1:1:1) to receive JMT101 plus irinotecan plus SG001, or JMT101 plus irinotecan, or regorafenib monotherapy. Primary endpoints include incidence of dose limiting toxicities (DLT) and adverse events (part I) and objective response rate (ORR) as per RECIST v1.1 by investigator (part II). Secondary endpoints include JMT101 and SG001 pharmacokinetic profile, antidrug antibodies (ADA) (both parts), disease control rate (DCR), duration of response (DOR), progression free survival (PFS), and overall survival (OS), as well as safety (part II). Prespecified goal for safety run-in part was met; randomized treatment part accrual began in February 2024. Clinical trial information: NCT06089330 .