Disitamab vedotin (RC48) for previously treated HER2-expressing metastatic breast cancer with abnormal activation of PAM pathway: Results from a single-arm, prospective phase II clinical trial

BackgroundDisitamab vedotin (RC48) is an antibody-drug conjugate targeting HER2, demonstrating promising efficacy and safety in HER2-positive and HER2-low metastatic breast cancer (MBC). This study aimed to explore the efficacy and safety of RC48 in HER2-expressing pretreated MBC patients with abnormal activation of the PI3k/Akt/mTOR (PAM) pathway.MethodsThis single-arm phase II clinical trial recruited HER2-positive and HER2-low MBC patients who had progressed on at least one line of systemic chemotherapy with confirmed PAM pathway activation from September 2022 to December 2023. Patients received RC48 treatment (2 mg/kg IV infusion, once every 2 weeks). The primary endpoint was objective response rate (ORR), and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.ResultsAs of Mar 15, 2024, a total of 62 patients with confirmed PAM pathway activation were enrolled, comprising 26 patients with HER2-positive MBC and 36 with HER2 low MBC. These patients had a median 2 prior lines of chemotherapy (range 1-9), with 79.0% receiving ≥2 lines of chemotherapy for metastatic disease. Prior treatments included taxane (98.4%), trastuzumab (96.2%) and CDK 4/6 inhibitors (61.5%). The median follow-up time was 13.2 months. The ORR for HER2-expressing MBC was 34.4% (21/61), with rates of 34.6% (9/26) in the HER2-positive patients and 34.3% (12/31) in the HER2 low-expression group. The median PFS with RC48 was 3.5 months (95%CI [confidence interval]: 2.4-4.6 months), with 4.5 months (95%CI: 2.9-6.1 months) in HER2-positive and 3.4 months (95%CI: 2.8-4.0 months) in HER2 low patients. In terms of safety, the most common grade 3 or higher treatment-related adverse events included neuropathy (11.3%), neutropenia (8.1%), aspartate aminotransferase elevation (3.2%), and leukopenia (3.2%), with no treatment-related deaths.ConclusionsRC48 showed promising efficacy and manageable safety in HER2-positive and HER2-low pretreated MBC patients with abnormal PAM pathway activation. It may serve as a therapeutic option for HER2-expressing MBC patients with PAM pathway abnormalities.Clinical trial identificationNCT05331326.Legal entity responsible for the studyThe authors.FundingRemeGen Co., Ltd.DisclosureAll authors have declared no conflicts of interest.