SUNNIFORECAST Trial Review

A recent European phase 3 randomized clinical trial provided new insight into first-line treatment for patients with non–clear cell renal cell carcinoma (RCC). This was the largest prospective study conducted in this population, comparing a combination of CTLA-4 and PD-1 inhibitors (ipilimumab and nivolumab) to various investigator-chosen standard-of-care therapies. The majority of patients in the control arm received sunitinib, while fewer received cabozantinib or IO-TKI combinations, which are more commonly used today. The trial enrolled over 300 patients, with central pathology review ensuring accurate classification of non-clear cell subtypes such as papillary, chromophobe, and others.

The study met its primary end point, showing a significantly higher 12-month overall survival rate with the immunotherapy combination (78%) compared to standard-of-care treatments (68%). Secondary outcomes also favored the combination arm, including a median overall survival of 33 months vs 25.2 months, and an objective response rate of nearly 33% vs 19%. However, progression-free survival was similar between both groups. The complete response rate in the immunotherapy arm was modest, at about 8%, and toxicity leading to treatment discontinuation occurred more frequently in the combination arm (17% vs 9%).

Importantly, subgroup analyses suggested that the benefit of immunotherapy was consistent across different histologic subtypes, including papillary and, to a lesser extent, chromophobe RCC. Chromophobe tumors have historically been considered resistant to immune checkpoint inhibitors, but this study observed some responses in that group, which is being further explored in upcoming data presentations. While the results are not as robust as those seen in clear cell RCC, this trial supports the use of immune-based combinations in non–clear cell RCC and highlights the need for histology- and biology-specific studies to guide treatment decisions in these diverse patient populations.