Trastuzumab Rezetecan in Human Epidermal Growth Factor Receptor 2–Expressing Advanced Gastric Cancer or Gastroesophageal Junction Adenocarcinoma and Colorectal Cancer: A Multicenter, Open-Label, Phase I Trial

PURPOSE: Antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) could be a promising strategy for HER2-expressing gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ) and colorectal cancer (CRC). We conducted a phase I trial to assess trastuzumab rezetecan, a novel HER2-targeted ADC, in HER2-expressing advanced GC/GEJ and CRC. METHODS: Patients with HER2-expressing advanced GC/GEJ and CRC whose disease progressed on and/or had no available/applicable standard treatment were enrolled. Patients were intravenously given trastuzumab rezetecan at 3.2, 4.8, 6.4, and 8.0 mg/kg (once every 3 weeks) in an i3+3 dose-escalation scheme, followed by pharmacokinetics expansion at selected doses and then clinical expansion. The primary end points were dose-limiting toxicity (DLT) and safety. RESULTS: Between March 30, 2021, and August 1, 2023, 100 patients were enrolled (57 with GC/GEJ and 43 with CRC). One DLT occurred in the 8.0 mg/kg dose cohort. Grade ≥3 treatment-related adverse events (TRAEs) were reported in 66 (66.0%) patients. Only 5 (5.0%) patients discontinued treatment because of TRAEs. In HER2-positive GC/GEJ (n = 40), trastuzumab rezetecan achieved an objective response rate (ORR) of 45.0%, a median progression-free survival (PFS) of 9.0 months (95% CI, 7.0 to 11.3), and a median overall survival (OS) of 16.3 months (95% CI, 12.4 to not reached [NR]). In GC/GEJ with HER2 immunohistochemical 2+ and in situ hybridization-negative (n = 12), trastuzumab rezetecan had an ORR of 25.0%, a median PFS of 12.2 months (95% CI, 2.8 to 14.0), and an immature median OS. In HER2-positive CRC (n = 37), trastuzumab rezetecan had an ORR of 40.5%, a median PFS of 9.5 months (95% CI, 7.3 to 11.2), and a median OS of 22.7 months (95% CI, 17.5 to NR). CONCLUSION: Trastuzumab rezetecan showed tolerable safety and preliminary efficacy in HER2-expressing advanced GC/GEJ and CRC.