A phase II study of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma.

Abstract

4519 Background: RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). A phase II clinical study showed that RC48-ADC has a good effect on locally advanced or metastatic urothelial carcinoma with HER2-positive expression that failed standard chemotherapy. In the study, some patients with HER2-postive immunohistochemistry (IHC 2+) but negative FISH test still benefited from the treatment of RC48-ADC.This study was to evaluate the activity and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma. Methods: This study is an open-label, single-center, single-arm, phase II trial. Eligibility criteria include: histologically confirmed urothelial carcinoma, HER2-negasitive (IHC 0 or 1+), ECOG PS 0-1,and treated with ≥1 prior systemic treatment. Patients received RC48-ADC 2mg/kg q2w until disease progression, unacceptable toxicity, withdrawal of consent, or study termination. The primary objectives were activity (ORR) and safety. Second objectives included progress-free survival, disease control rate and overall survival. Results: As of February 2022(date cutoff),19 patients were enrolled. The median age was 64 years old(range:36-77). At baseline, there were 6 patients with HER2(IHC 0), and 13 patients with HER2(IHC 1+).Most patients (13/19) had visceral metastasis. 15(79%) patients had received≥2 lines treatment.At date cutoff, 19 patients were assessable for response. The objective response rate was 26.3% (95% CI:9.1%,51.2%) and the DCR was 94.7% (18/19). The mPFS was 5.5months (95% CI:3.9,6.8) and mOS was 16.4months (95% CI:7.1,21.7).All of the 6 patients with HER2(0) were SD in the study. The ORRs were 38% (5/13) in patients with HER2(IHC 1+),31% (4/13) in visceral metastasis,17% (1/6) in liver metastasis patients,27% (4/15) in patients post to ≥ 2 lines of treatment. Common treatment-related AEs were leukopenia (52.6%), hypoesthesia (47.4%),alopecia (47.4%), AST increase (42.1%), ALT increase (42.1%), and neutropenia (42.1%), fatigue (42.1%),nausea (26.3%), vomiting (15.8%).Most of these AEs were Grade 1 or 2. The AE of Grade 3 was neutropenia (10.5%). The SAE was CPK increased (5.3%). Conclusions: This study showed that RC48-ADC was safe and the ORR was 26.3% in HER-negative patients with locally advanced or metastatic urothelial carcinoma. The enrollment was completed and data will be updated later. Clinical trial information: NCT04073602.

Real‐world effectiveness and safety of RC48‐ADC alone or in combination with PD‐1 inhibitors for patients with locally advanced or metastatic urothelial carcinoma: A multicenter, retrospective clinical study

“…In this study, eight patients who received RC48 monotherapy presented an ORR of 50.0%, numerically in line with the combined outcomes of the RC48‐C005 and RC48‐C009 studies (50.5%) 17 and the RC48‐C011 study (26.3%) 16 . It exceeded the result presented by Chen et al.…”

“…The disease control rate (DCR) was 82.2% (95% CI: 73.7%, 89.0%), mPFS of 5.9 months (95% CI: 4.2, 7.2) and a median overall survival (mOS) of 14.2 months (95% CI: 9.7, 18.8) 17 . The RC48‐C011 study demonstrated that RC48‐ADC monotherapy achieved an ORR of 26.3% (95% CI: 9.1%, 51.2%) in la/mUC patients with low HER2 expression (IHC1+ and 0), a DCR of 94.7%, an mPFS of 5.5 months (95% CI: 3.9, 6.8), and an mOS of 16.4 months (95% CI: 7.1, 21.7) 16 . The RC48‐C014 study showed an ORR of 76.7% (95% CI: 57.7%–90.1%), an mPFS of 9.2 months, and an unreached mOS for RC48‐ADC combined with toripalimab in la/mUC patients 19 .…”

Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials

“…The preliminary result of the RC48-C011 study showed certain antitumor activity of DV in HER2-negative metastatic UC with a confirmed ORR of 26.3%, a mPFS of 5.6 months, and a mOS of 16.4 months. 27 EV and SG targets for nectin-4 and trop-2 were approved for use in the unselected patient population. In comparison, DV previously required HER2-positive patients.…”

Recent Advances in the Development of Antibody-Drug Conjugates in Urothelial Cancer

“…A total of 19 patients were enrolled with ORR of 26.3%. Median PFS was 5.5 months, and median OS was 16.4 months 39 . These promising results encouraged investigating the synergistic efficacy of the combination of RC48-ADC with CPIs.…”

“…Median PFS was 5.5 months, and median OS was 16.4 months. 39 These promising results encouraged investigating the synergistic efficacy of the combination of RC48-ADC with CPIs. In an open-label, multicenter, phase Ib/II trial (NCT04264936), the safety and the efficacy of RC48-ADC were evaluated in combination with toripalimab (anti-programmed cell death 1 antibody) in patients with metastatic UC.…”