Disitamab vedotin, a HER2-targeted antibody-drug conjugate, combined with pembrolizumab, a PD-1 inhibitor, has demonstrated encouraging preliminary results in patients with HER2-expressing metastatic urothelial cancer. The data, presented at ESMO, from Cohort C of the RC48G001 study, revealed a 75% response rate in treatment-naive patients, suggesting a potential new treatment option for this patient population.
RC48G001 Study: Key Findings
The RC48G001 study's Cohort C evaluated the safety and efficacy of disitamab vedotin plus pembrolizumab in 20 patients with metastatic urothelial cancer who had not previously received treatment. Patients were enrolled regardless of cisplatin eligibility. HER2 expression was defined as either positive (3+ by immunohistochemistry or 2+ with positive FISH) or low (2+ by IHC with FISH negative or 1+ expression).
According to Dr. Matthew Galsky, Professor of Medicine at the Icahn School of Medicine at Mount Sinai, "The response rate is 75%, and importantly, that response rate lines up almost exactly with what's been seen in the study in China with disitamab vedotin plus the PD-1 inhibitor toripalimab."
The study found that the combination was active in both HER2-positive and HER2-low expressing tumors. 70% of patients had HER2-low expressing tumors. The median follow-up was nine months, and the median duration of response had not yet been met. The complete response rate in this small cohort was 35%.
Safety Profile
The safety profile of disitamab vedotin plus pembrolizumab appears to differ from that of enfortumab vedotin plus pembrolizumab. While neuropathy was observed, the incidence of high-grade rashes and hyperglycemia, commonly associated with enfortumab vedotin, was not prominent in this study. Common side effects included neuropathy, rash, and gastrointestinal issues.
Clinical Implications and Future Directions
Urothelial cancer, where 60-80% of tumors express at least some amount of HER2, represents a significant target for therapeutic intervention. These findings underscore the importance of HER2 testing in all metastatic urothelial cancer patients, as highlighted by Dr. Galsky: "All patients with metastatic urothelial cancer should have testing for those two biomarkers [FGFR3 and HER2]."
An international phase III study is currently enrolling patients to compare disitamab vedotin plus pembrolizumab versus platinum-based chemotherapy. This trial aims to further define the role of this combination therapy in the treatment landscape of metastatic urothelial cancer.
Expert Commentary
Dr. Galsky emphasized the significance of HER2 as a target in urothelial cancer, particularly for the selective delivery of cytotoxic agents. He anticipates further developments in HER2-based strategies for this cancer type, noting that using HER2 as a target for selective delivery of cytotoxic agents is a completely different strategy, and now we have proof of concept that this is important."
