Updated guidelines suggest using a VEGFR systemic therapy after IO therapy failure, with cabozantinib as a preferred agent based on CONTACT-03 data. However, the aspiration for durable responses achievable with IO-based therapies remains. Manuela Schmidinger, MD, discussed key abstracts at ESMO 2024, including the TiNivo-2, LITESPARK-005, and SUNNIFORECAST trials, highlighting the evolving treatment landscape for renal cell carcinoma (RCC).
TiNivo-2: Tivozanib and Nivolumab Combination
The TiNivo-2 phase III trial evaluated tivozanib plus nivolumab versus tivozanib monotherapy in RCC patients after prior IO therapy. The results indicated that the combination was not superior in terms of progression-free survival, objective response rate, complete response rate, or overall survival. Notably, the dose of tivozanib was reduced by 50% in the combination arm due to potential hypertension risks, a decision Dr. Schmidinger questioned, suggesting it may have hindered the combination's efficacy.
Dr. Schmidinger raised critical questions about the trial design's validity in assessing IO after IO, the potential abandonment of IO after IO, and whether tivozanib is a new standard of care after IO failure. She noted that while single-agent, full-dose tivozanib is efficacious post-IO, its efficacy appears inferior to cabozantinib or lenvatinib plus pembrolizumab. Cabozantinib, a broader TKI (VEGF-MET-AXL) and more potent VEGFR-2 inhibitor, shows higher objective response rates and longer progression-free survival.
LITESPARK-005: Belzutifan Efficacy
The final analysis of the LITESPARK-005 study explored belzutifan versus everolimus in previously treated advanced clear cell RCC. The trial demonstrated a maintained progression-free survival benefit with belzutifan (median 5.6 months versus 5.6 months; HR 0.75; 95% CI 0.63–0.88), with improved survival rates at 12 and 24 months. The 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).
While belzutifan shows solid efficacy in the post-IO space, it is not considered a new benchmark. Dr. Schmidinger highlighted that nearly half (45.2%) of the patients in LITESPARK-005 were in a fourth-line setting, suggesting that earlier use in the disease course may be more beneficial. She also noted that belzutifan is the only targeted agent that can be combined at a full dose with a TKI, potentially driving future RCC breakthroughs.
SUNNIFORECAST: Ipilimumab and Nivolumab in Non-Clear Cell RCC
The SUNNIFORECAST trial investigated nivolumab plus ipilimumab versus standard of care in non-clear cell RCC. Key findings over a median follow-up of 24.3 months included a 12-month overall survival rate of 86.92% versus 76.79% (p = 0.0141) and an objective response rate of 32.8% versus 19.8% (p = 0.001). However, the improved overall survival rate was not maintained with longer follow-up, unlike observations in clear cell RCC.
Dr. Schmidinger emphasized that the standard of care arm may have underperformed due to trial heterogeneity and imbalances in PD-L1 expression. Notably, cabozantinib was not the standard of care in at least 40% of patients, despite most having papillary RCC. She concluded that while the data are encouraging, the role of CTLA-4 inhibition in non-clear cell RCC beyond sarcomatoid remains vague, with IO plus TKI combinations appearing more promising.
