Disitamab vedotin

Recent approvals have led to the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda) becoming a dominant frontline therapy for bladder cancer. Zelenectide pevedotin, a Nectin-4–targeted bicycle toxin conjugate, shows promise with preliminary antitumor activity and fewer off-target toxicities. Ongoing phase 2/3 Duravelo-2 study investigates zelenectide pevedotin alone and in combination with pembrolizumab for advanced urothelial cancer patients.

Dr. Markus Eckstein discussed mechanisms of resistance to antibody-drug conjugates, including lack of target proteins, conventional resistance, and microenvironment remodeling. He highlighted cases of resistance in triple-negative breast cancer and urothelial carcinoma, emphasizing the importance of Nectin-4 expression in predicting response to enfortumab vedotin. Additionally, he mentioned other targets like HER2 and the potential of NECTIN4 amplifications as a biomarker for enfortumab vedotin response.

Preliminary results from the RC48G001 Study Cohort C show a 75% response rate with disitamab vedotin plus pembrolizumab in HER2-expressing metastatic urothelial cancer, with activity in both HER2-positive and HER2-low tumors. The safety profile differs from enfortumab vedotin plus pembrolizumab, potentially distinguishing it. Dr. Galsky emphasizes the importance of HER2 and FGFR3 biomarker testing in all metastatic urothelial cancer patients, noting 60-80% of tumors express HER2, and highlights the ongoing phase III study comparing this combination to platinum-based chemotherapy.

Dr. Begona Perez-Valderrama discussed novel agents and combinations in RCC and urothelial carcinoma at the 2024 ESMO meeting, highlighting belzutifan's potential in RCC therapy and ongoing trials assessing various combinations, including antibody-drug conjugates like disitamab vedotin and trastuzumab deruxtecan.

Dr. Bernadett E. Szabados discussed circulating vs. tissue-based biomarkers for urothelial and renal cell carcinomas at the 2024 ESMO meeting, highlighting established (FGFR3, PD-L1, ctDNA, HER2) and experimental biomarkers. FGFR3 expression varies by tumor stage, with erdafitinib targeting FGFR-positive metastatic urothelial carcinoma. PD-L1 testing shows mixed outcomes, while ctDNA correlates with disease burden and prognosis. For renal cell carcinoma, experimental biomarkers like PD-L1 and RNA-based molecular subtypes are under evaluation. Circulating biomarkers, particularly KIM-1, show promise in RCC.