An open-label, phase 2 study of patritumab deruxtecan in patients with previously treated advanced/metastatic colorectal cancer

Background Patritumab deruxtecan (HER3-DXd) is a novel, investigational antibody-drug conjugate comprising an anti-HER3 monoclonal antibody, a tetrapeptide-based linker, and a topoisomerase I inhibitor payload. Ongoing clinical trials of HER3-DXd in patients with metastatic breast cancer or non-small cell lung cancer have shown promising clinical activity and acceptable safety. HER3 (human epidermal growth receptor 3), a member of the tyrosine kinase receptor family, is overexpressed in most colorectal cancer tumors (≈50%-90%) and associated with an adverse prognosis. Significant tumor regression with HER3-DXd has been observed in colorectal cancer murine xenograft models, regardless of KRAS mutation status. Here, we introduce the design of a phase 2 study (U31402-A-U202) that is evaluating HER3-DXd in previously treated patients with advanced/metastatic colorectal cancer. Trial design U31402-A-U202 (NCT04479436) is an open-label, multicenter phase 2 study that will enroll approximately 80 patients in the USA, Europe, and Asia. Patients are enrolled who are aged ≥ 18 years with advanced/metastatic colorectal adenocarcinoma that is resistant/refractory/intolerant to ≥ 2 prior lines of therapy, including a fluoropyrimidine, irinotecan, a platinum agent, an anti-EGFR agent (if clinically indicated), an anti-VEGF agent (if clinically indicated), a BRAF inhibitor (if clinically indicated), and an immune checkpoint inhibitor, if clinically indicated (eg, microsatellite instability-high status). Patients with current/previous interstitial lung disease or clinically severe pulmonary compromise are excluded. Archival tumor biopsy and pretreatment tumor biopsy are collected from all patients at screening, with HER3 protein expression measured by immunohistochemistry (IHC). In Part 1, results of the HER3 IHC assay from the pre-treatment tumor biopsy are used to assign patients into 1 of 2 cohorts. Cohort 1: HER3 high (IHC 3+, 2+), n=24; Cohort 2: HER3 low/negative (IHC 1+, 0), n=12. Patients receive 5.6 mg/kg HER3-DXd intravenously every 3 weeks. An interim futility analysis will be conducted separately for Cohort 1 and Cohort 2, and will determine enrollment in Part 2, with 2 potential scenarios: enrollment continues irrespective of HER3 IHC status, or enrollment continues in HER3 high patients only. The primary objective is the evaluation of the antitumor activity of HER3-DXd as measured by objective response rate (ORR) (assessed by blinded independent central review according to RECIST v1.1). ORR will be summarized with the 2-sided 95% confidence interval. Secondary objectives include the evaluation of efficacy as measured by ORR (assessed by investigator according to RECIST v1.1), duration of response, time to tumor response, disease control rate, progression-free survival (assessed by investigator and blinded independent central review according to RECIST v1.1), overall survival, safety and tolerability, HER3 protein expression in tumor tissue and relationship with efficacy, and pharmacokinetic properties. The trial initiated on September 14, 2020, and enrollment for Part 1 is now closed. Forty patients were enrolled in Part 1. Encore statement: © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 Gastrointestinal Cancers Symposium. Clinical trial identification NCT04479436. Editorial acknowledgement Medical writing and editorial support was provided by Gráinne Faherty, MPharm, and Frederique H. Evans, MBS, both of Ashfield MedComms, an Ashfield Health company, and was funded by Daiichi Sankyo, Inc. Legal entity responsible for the study TC. Funding This study is sponsored by Daiichi Sankyo, Inc. Disclosure T. Yoshino: Honoraria (self): Bayer, Chugai, Taiho, Eli Lilly, Merck Biopharma; Research grant / Funding (institution): Daiichi Sankyo, MSD, Ono, Parexel International, Taiho, Amgen. H. Taniguchi: Honoraria (self): Ono; Research grant / Funding (institution): Daiichi-Sankyo, Sysmex, Taiho. A. Vogel: Honoraria (self): Daiichi Sankyo, AstraZeneca; Advisory / Consultancy: Daiichi Sankyo, AstraZeneca. Z. Wainberg: Advisory / Consultancy: Daiichi, Astra Zeneca, Merck. K. Yamaguchi: Honoraria (Institution): Daiichi Sankyo; Speaker Bureau / Expert testimony: Daiichi Sankyo. M. Fakih: Honoraria (self): Guardant Health, Amgen; Advisory / Consultancy: Taiho, Seattle Genetic, Pfizer; Research grant / Funding (institution): Novartis, Amgen, BMS. M. Kanai: Shareholder / Stockholder / Stock options: Daiichi Sankyo Inc; Full / Part-time employment: Daiichi Sankyo Inc. Y. Liu: Full / Part-time employment: Daiichi Sankyo Inc. S. Mekan: Full / Part-time employment: Daiichi Sankyo. G. Pudussery: Full / Part-time employment: Daiichi Sankyo. Y. Qiu: Full / Part-time employment: Daiichi. S. Kopetz: Advisory / Consultancy: Roche, Redx Pharma, Jacobio, Merck, Navire Pharma, Holy Stone, Biocartis, Natera, Karyopharm Therapeutics, Repare Therapeutics, Genentech, Lilly, AstraZeneca/MedImmune, EMD Serono, Daiichi Sankyo, Amal Therapeutics, Boehringer Ingelheim, Bayer Health, Lutris, Pfizer, Amgen, Pierre Fabre, Symphogen, Novartis, Boston Biomedical, Ipsen, HalioDx.