ASCO 2022: A Phase II Study of RC48-ADC in HER2-Negative Patients With Locally Advanced or Metastatic Urothelial Carcinoma

(UroToday.com) At the 2022 American Society of Clinical Oncology Annual Meeting held in Chicago and virtually, the poster discussion session focused on Kidney and Bladder cancers on Saturday evening included a presentation from Dr. Huayan Xu on the role of combined treatment of advanced urothelial carcinoma (UC) using a combination of a HER-2 targeted antibody-drug conjugate and immunotherapy.

For patients with metastatic urothelial carcinoma (UC), platinum-based chemotherapy remains the first-line treatment of choice for patients who are eligible. Despite being the guideline-recommended approach, most patients will have disease progression following platinum-based chemotherapy. Immunotherapy using single agent immune checkpoint inhibitors is a standard, guideline-recommended second line treatment. However, the anti-HER-2 antibody-drug conjugate RC48-ADC (Disitamab Vedotin) has shown promising data in HER2-positive patients with locally advanced or metastatic UC who have progression following treatment with platinum-based chemotherapy. Interestingly, in these trials, some patients with evidence of HER2-positive immunohistochemistry (IHC 2+) but negative FISH test still benefited from the treatment of RC48-ADC. Thus, the authors sought to assess the efficacy and safety of RC48-ADC in HER2-negative patients with locally advanced or metastatic urothelial carcinoma (UC).

To do so, they performed an open-label, single-center, single-arm, phase II trial (NCT04073602). The authors enrolled patients with histologically confirmed urothelial carcinoma who received at least one prior systemic treatment. Patients further had to have evidence of HER2-negative disease (IHC 0 or 1+) and ECOG performance status of 0 or 1. Patients received RC48-ADC 2mg/kg every two weeks until disease progression, unacceptable toxicity, withdrawal of consent, or study termination.

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The primary objectives were activity (ORR) and safety with additional second objectives including progression-free survival, disease control rate and overall survival.

With a data cutoff of February 2022, 19 patients had been enrolled. The median age was 64 years (range 36 to 77 years). The majority (n=15; 79%) of patients had received two or more lines of treatment and 13 had visceral metastases. At baseline, 6 patients had HER2(IHC 0) and 13 had HER2(IHC 1+).

All patients (n=19) patients were assessable for response: the objective response rate was 26.3% (95% CI 9.1% to 51.2%) and the DCR was 94.7% (18/19). All six patients with HER2(0) had evidence of stable disease whereas the ORR was 38% (5/13) in patients with HER2(IHC 1+). Further, when stratified by clinical characteristics, the ORR was 31% (4/13) in patients with visceral metastasis, 17% (1/6) in those with liver metastasis, and 27% (4/15) in patients who had received at least 2 prior lines of treatment.

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The median progression-free and overall survival were 5.5 months (95% CI 3.9 to 6.8) and 16.4 months (95% CI 7.1 to 21.7), respectively.

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 though a grade 3 neutropenia event was noted in two patients (10.5%). A single serious adverse event was seen with CPK increase (5.3%).

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Thus, the authors conclude that this phase II trial demonstrates that RC-48-ADC is safe and has evidence of activity in HER-negative patients with locally advanced or metastatic urothelial carcinoma.

Presented by: Huayan Xu, MD, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Department of Genitourinary Oncology, Peking University Cancer Hospital & Institute, Beijing, China