Novel HER2–Targeting Therapies in Urothelial Cancer
Key Points
- Anti–HER2 agents are gaining traction in advanced bladder cancers, including locally advanced or metastatic urothelial cancer.
- Multiple antibody-drug conjugates (ADCs) targeting HER2 are emerging as alternative options to standard enfortumab vedotin (EV)–based regimens.
- Outside of HER2–targeting regimens, novel combinations with FGFR3 inhibitors may improve upon the existing standard of care treatments.
Anti–HER2 Agents in Advanced Urothelial Cancer
In a brief interview at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU 2026), Miles Hsu, MD, of National Cancer Institute, and Brendan Guercio, MD, of University of Rochester Medical Center, discussed HER2–targeted therapies in locally advanced or metastatic urothelial cancer.
HER2–directed treatment is an exciting topic across bladder cancers, especially after trastuzumab deruxtecan (T-DXd), an anti–HER2 ADC, was approved by the FDA for all HER2–positive unresectable or metastatic solid tumors on April 5, 2024. Further studies showed T-DXd was effective even in patients with low or ultra-low HER2 expression, and it has been an effective option for patients with previously treated advanced urothelial cancer, said Dr. Guercio.
ASCO GU 2026 also featured promising data for a novel HER2–targeted ADC, disitamab vedotin (DV). Updated results from the phase 2 RC48-C017 trial showed DV plus a PD-1 inhibitor had comparable efficacy to the current standard of care, EV plus pembrolizumab. However, as DV and EV use the same payload component, there may be cross resistance or increased toxicity for EV–exposed patients. More data are needed to fit DV into the bladder cancer treatment landscape, including potential biomarkers to guide patient selection, said Dr. Guercio.
Looking forward, Dr. Guercio highlighted novel agents and combination regimens that may add new treatment options for patients with advanced bladder cancer. For instance, the DV-001 trial compares DV plus pembrolizumab with platinum-based chemotherapy in advanced urothelial cancer. In addition, the FORAGER-2 trial is evaluating vepugratinib, a novel FGFR3 inhibitor, in combination with EV plus pembrolizumab in advanced urothelial cancer. “Now that we have [EV plus pembrolizumab] as a really excellent first-line option for our patients, we need to start thinking about ways to make that regimen even better, potentially with triplets or other strategies,” Dr. Guercio said.