Efficacy and Safety of RC48-ADC, a Her2-Targeting Antibody-Drug Conjugate, in Patients with Locally Advanced or Metastatic Urothelial Carcinoma: A Phase 2, Open-Label, Multi-Centre, Single-Arm Study

Abstract

Background: Platinum-containing chemotherapy is the standard first-line treatment of advanced urothelial carcinoma (UC). After the failure of the first-line treatment, emerging anti-PD-1/L1 therapies yield rather low response rates. RC48-ADC is a novel HER2-targeting antibody-drug conjugate (ADC). We aimed to evaluate the efficacy and safety of RC48-ADC in patients with HER2-positive locally advanced or metastatic UC. Methods: This is a phase 2, open-label, multi-centre, single-arm study of RC48-ADC at 2·0 mg/kg intravenously once every two weeks in patients with HER2-positive (immunohistochemical status 3+ or 2+ by central lab) locally advanced or metastatic UC who had failed with at least one line systemic chemotherapy. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC)- per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1·1. The secondary endpoint included progression-free survival, duration of response, disease control rate, overall survival and safety. Findings: From 28 December 2017 to 28 November 2018, 43 patients were enrolled and treated with RC48-ADC. The median follow-up was 11·8 months. The confirmed ORR as assessed by BIRC was 51·2% (95% CI: 35·5%, 66·7%). Similar responses were observed in prespecified subgroups, such as those with liver metastasis and those previously treated with anti-PD-1/L1 therapies. Median progression-free survival was 6·9 months (95% CI: 5·3, 8·3). Median overall survival was 13·9 months (95% CI: 9·0, NE). The most commonly treatment-related adverse events (TRAEs) were hypoaesthesia (60·5%), alopecia (55·.8%), and leukopenia (55·8%). No Grade 4 or Grade 5 TRAE had occurred. Twenty-four (55·8%) patients experienced Grade 3 TRAEs, including hypoaesthesia (18·6%) and neutropenia (14·0%). Interpretation RC48-ADC manifested clinically meaningful efficacy and a manageable safety profile in patients with HER2-positive locally advanced or metastatic UC who were previously treated with platinum-containing chemotherapy and/or anti-PD-1/L1 therapies. Clinical Trial Registration: This study is registered with ClinicalTrials.gov, number NCT03507166. Funding Statement: RemeGen, Ltd., funded the study and provided the study drug. This work was also supported by grants from Natural Science Foundation of China (81672696) and Beijing Municipal Administration of Hospitals' Ascent Plan (DFL20181101). Declaration of Interests: JG is the member of the advisory board/consultant of MSD, Roche, Pfizer, Bayer, Novartis, Simcere, Shanghai Junshi Bioscience, Oriengene. JF are employees and shareholders of RemeGen, Ltd. All the other authors declare no conflict of interest. Ethical Approval Statement: All the patients provided written informed consent before joining the study. The study protocol was approved by a relevant institutional review board or ethics committee of each study centre. The study was compliant with the Declaration of Helsinki and Good Clinical Practice guidelines.