Novel agents and promising combinations in urothelial and renal cell carcinomas were a key focus at the 2024 ESMO annual meeting. Dr. Begona Perez-Valderrama discussed strategies to build on standard therapies by assessing new agents and combinations. The treatment landscape for both renal cell carcinoma (RCC) and urothelial carcinoma has seen significant advancements, yet challenges remain in overcoming resistance to existing therapies and addressing unmet needs.
Advancements in Renal Cell Carcinoma
While the metastatic RCC landscape has become increasingly crowded, resistance to immunotherapy and antiangiogenic treatments necessitates the development of novel therapies and combination regimens. Belzutifan, a novel agent, has emerged as a potential game-changer in RCC therapy.
The phase 3 LITESPARK-005 trial randomized previously treated patients to either belzutifan 120 mg or everolimus 10 mg daily. Belzutifan demonstrated a sustained progression-free survival benefit (median 5.6 months versus 5.6 months; HR 0.75; 95% CI 0.63–0.88). The estimated progression-free survival rate at 12 months was 33.7% for belzutifan versus 17.6% for everolimus, and at 24 months, it was 17.5% versus 4.1%, favoring belzutifan. Median overall survival was 21.4 months with belzutifan versus 18.2 months with everolimus (HR 0.92; 95% CI 0.77–1.10; p = 0.18).
Objective response rate was 22.7% with belzutifan versus 3.5% with everolimus, and the median duration of response was 19.3 months versus 13.7 months, respectively.
One notable combination is belzutifan with cabozantinib, tested in the phase 2 LITESPARK-003 trial. Among 52 patients, 16 (30.8%, 95% CI 18.7-45.1) had a confirmed objective response. Belzutifan in combination with lenvatinib, assessed in the KEYMAKER-U038 trial (n = 30), showed an objective response rate of 50% (95% CI 29-71), but with a grade 3-4 adverse event incidence of 50%.
Developments in Urothelial Carcinoma
The treatment landscape for metastatic urothelial carcinoma has evolved significantly, especially in the first-line setting, with the introduction of CheckMate 901 and EV-302. Antibody-drug conjugates (ADCs) are also gaining prominence.
Disitamab vedotin, an ADC targeting HER-2, has shown a response rate of approximately 50% in previous phase 2 trials. Several ongoing trials are assessing this agent, including RC48G001 and SGNDV-001.
Trastuzumab deruxtecan, another HER-2 ADC, was evaluated in the pan-tumor DESTINY trial. In the bladder cancer cohort (n = 41), the objective response rate was 39.0%, with one patient achieving a complete response. Consequently, the FDA granted trastuzumab deruxtecan accelerated approval for unresectable or metastatic HER-2 positive solid tumors on April 5, 2024.
Sacituzumab govitecan, a Trop-2 ADC, is being assessed in the phase 3 TROPiCS-04 trial. However, a press release on May 30, 2024, stated that the trial did not meet its primary endpoint of overall survival. Datopotamab deruxtecan, another anti-Trop-2 ADC, showed an objective response rate of 19.2% in the pan-tumor TROPION trial (n = 32).
Considerations for Future Directions
Dr. Perez-Valderrama emphasized the need for caution in interpreting early trial results and highlighted several critical questions for the future, including the generalizability of clinical trial data to real-world patients, the importance of mature overall survival data, and the long-term toxicities of novel agents. She also stressed the need to incorporate local therapies in patients with complete and durable responses and address the challenges of early access to new alternatives in some countries.
