An open-label, single-arm, multicenter, phase II study of RC48-ADC to evaluate the efficacy and safety of subjects with HER2 overexpressing locally advanced or metastatic urothelial cancer (RC48-C009).

4584 Background: There is still urgent medical needs in the patients with locally advanced or metastatic urothelial cancer (mUC) post to the failure of at least one line chemotherapy. RC48-ADC, a novel humanized anti-HER2 antibody-drug conjugate (ADC), has proved its efficacy in these patients (RC48-C005, NCT03507166), most of whom had received gemcitabine and platinum. Taking into consideration that taxane is another possible active agent for mUC, this study aims to further evaluate the efficacy of RC48-ADC in HER2 overexpressing mUC post to the failure of platinum, gemcitabine and taxane. Methods: This study was an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria included: histologically confirmed UC, HER2 overexpressing (IHC 2+ or 3+), ECOG PS 0-1, failed platinum, gemcitabine and taxane. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, death or study termination. The primary endpoint was objective response rate (ORR) assessed by blinded independent review committee (BIRC) according to RECIST v1.1. Progress-free survival (PFS), duration of response (DOR), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study started in December 2018 and completed in September 2020. A total of 64 patients were enrolled, with a median age of 62.5 years. At baseline, most patients (82.8%) had visceral metastasis. Fifty-five patients (85.9%) had received ≥ 2 lines treatment and 19 (29.7%) patients had prior immune checkpoint inhibitor (CPI) therapy. As of Nov 30, 2020, the confirmed ORR assessed by BIRC was 46.9% (95% CI: 34.3%, 59.8%) and the median DOR was 8.3 months (95% CI: 4.3, NE), the median PFS was 4.3 months (95% CI: 4.0, 6.8). The median OS was 14.8 months (95% CI: 8.7, 21.1). The ORR was 60.0% (15/25) in patients with HER2 IHC3+ or FISH test positive, 45.3% (24/53) in patients with visceral metastasis, 42.1% (8/19) in patients post to CPI therapy. The ORR was 55.6% (5/9), 50.0% (21/20) and 30.8% (4/13), in patients who had received 1 line, 2 lines and ≥ 3 lines treatment, respectively. Most commonly reported TRAEs were leukopenia (45.3%), AST increase (43.8%), neutropenia (42.2%), hypoesthesia (42.2%), ALT increase (37.5%) and fatigue (35.9%); Most commonly reported ≥ grade 3 TRAEs were neutropenia (9.4%) and hypoesthesia (6.3%) Conclusions: In patients with HER2 overexpressing (IHC 2+ or 3+) mUC who had failed platinum, gemcitabine and taxane, and the great majority of whom had received ≥2 prior lines treatment, RC48-ADC has demonstrated consistently excellent efficacy and benefit-risk profile compared with the RC48-C005 study which enrolled patients with mUC who had received ≥1 line prior chemotherapy. Clinical trial information: NCT03809013.