Phase 1/2 study of the HER3-directed antibody-drug conjugate patritumab deruxtecan (MK-1022) as monotherapy in patients with gastrointestinal cancers.

TPS321 Background: A significant medical need exists for more effective and tolerable therapeutic options for patients with advanced gastrointestinal cancers (colorectal cancer [CRC], biliary tract cancer [BTC], and hepatocellular carcinoma [HCC]). Human epidermal growth factor receptor (HER3) expression is high in CRC and BTC, and low-to-intermediate in HCC. Patritumab deruxtecan (HER3-DXd; U3-1402/MK-1022) is a HER3-directed antibody-drug conjugate (ADC) comprising a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab), which includes a plasma-stable, selectively cleavable linker, and a potent topoisomerase I inhibitor payload (DXd; released payload) that leverages the clinically validated deruxtecan (a derivative of exatecan) technology. DXd is cell membrane permeable and enables a bystander antitumor effect after DXd ADC internalization and linker cleavage, resulting in elimination of both target and neighboring tumor cells. Patritumab deruxtecan has shown antitumor activity in phase 1 and 2 studies of EGFR-mutated advanced non–small cell lung cancer and advanced breast cancer and in preclinical studies of CRC. This nonrandomized, open-label, phase 1/2 study (NCT06596694) will examine the safety and efficacy of patritumab deruxtecan in select gastrointestinal cancers. Methods: Approximately 130 adults (aged ≥18 years) will be allocated to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n = 40) must have previously treated unresectable or metastatic colorectal adenocarcinoma. Patients in cohort 2 (BTC; n = 40) must have previously treated locally advanced or metastatic BTC. Patients in cohort 3 (HCC; n ≤50) must have previously treated advanced HCC. Prior topoisomerase I inhibitor therapy is not allowed. Patients in cohorts 1 and 2 will receive patritumab deruxtecan intravenously (IV) as monotherapy. Cohort 3 includes a dose-escalation phase to determine the recommended phase 2 dose of patritumab deruxtecan monotherapy and an efficacy phase. In the efficacy phase, patients will receive the recommended phase 2 dose of patritumab deruxtecan. The primary objectives are to evaluate safety and tolerability of patritumab deruxtecan and to evaluate the confirmed objective response rate per RECIST v1.1 assessed by blinded independent central review (BICR) for each cohort. Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival, and to characterize the pharmacokinetics of patritumab deruxtecan. Clinical trial information: NCT06596694 .