Dr Rosenberg on Efforts to Enhance Urothelial Cancer Treatment

Jonathan E. Rosenberg, MD, chief, Genitourinary Oncology Service, Division of Solid Tumor Oncology; Enno W. Ercklentz, Jr. Chair, Memorial Sloan Kettering Cancer Center, discusses ongoing and planned research efforts to enhance the treatment landscape for patients with advanced urothelial cancer.

Rosenberg states that there are several areas of opportunity for enhancing current treatment approaches in metastatic urothelial cancer, particularly for patients who experience disease progression after receiving enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) in the first-line setting. The combination received FDA approval for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma in December 2023, and has become the standard of care in this setting, Rosenberg says.

Despite the efficacy of enfortumab vedotin and pembrolizumab, questions have risen regarding the viability of Nectin-4 as a target for drug development in urothelial cancer, Rosenberg states. Numerous trials are currently exploring novel Nectin-4–directed antibody-drug conjugates (ADCs), which consist of varying linkers and payloads, he details, adding that these trials aim to develop more tolerable agents with potent activity for patients with refractory disease, as well as potential activity for previously untreated patients.

In addition to investigating alternative Nectin-4–directed therapies, research initiatives in urothelial cancer are focused on elucidating the role of HER2-targeted therapy in urothelial cancer now that fam-trastuzumab deruxtecan-nxki (Enhertu) is approved by the FDA for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.

Furthermore, the ADC tisotumab vedotin-tftv (Tivdak), which has monomethyl auristatin E payload, has shown high activity and synergy when administered alongside immune checkpoint blockade, he says. The agent is undergoing evaluation in global phase 3 trials following encouraging data from China, Rosenberg reports.

Moreover, there is a growing need for improved FGFR inhibitors, Rosenberg continues. The FGFR inhibitor erdafitinib (Balversa) gained full FDA approval in January 2024 for patients with FGFR3-altered locally advanced or metastatic urothelial cancer who previously received a checkpoint inhibitor. These patients may have also received prior enfortumab vedotin and/or chemotherapy, Rosenberg notes. However, the agent's toxicity profile remains a concern, he says. Although treatment-related toxicities are not necessarily life-threatening, they are known to negatively impact patients' quality of life. Efforts are underway to develop next-generation FGFR inhibitors, including FGFR3-selective agents, that could address the limitations of current treatments and improve therapeutic outcomes, Rosenberg concludes.