A multicentre, European, prospective, randomised, open-label, investigator-initiated phase II SUNNIFORECAST study, conducted in treatment-naïve patients with advanced or metastatic non-clear cell renal cell cancer (RCC), evaluated a possible benefit of the combination of ipilimumab and nivolumab compared to standard-of-care (SoC). It is the largest randomised trial so far in non-clear cell RCC.
The results show a significant advantage in the overall survival (OS) rate at 12 months and a trend for prolongation of OS for the immune checkpoint inhibitor (ICI) combination. There were no major differences in terms of efficacy of the ICI combination compared to SoC between papillary and non-papillary RCC according to Prof. Lothar Bergmann of the Medical Clinic II, University Hospital in Frankfurt, Germany and colleagues, who published the findings on 1 April 2025 in the Annals of Oncology.
The authors wrote in the background that despite the transfer of improved systemic treatments for clear cell RCC to the non-clear cell RCC setting, patients with non-clear cell RCC have a poorer prognosis. Non-clear cell RCCs are a heterogeneous group of more than 20 different entities. Due to the heterogeneity and relative rarity of non-clear cell RCCs, these patients are included in large phase III RCC trials only as a small subgroup or even excluded.
None of the targeted agents available for clear cell RCC were able to demonstrate a significant improvement in OS when compared to each other in non-clear cell phase II studies, and immunotherapy combinations have mostly been tested in relatively small patient cohorts and single-arm settings.
As a result, European marketing authorisations for RCC are subtype-agnostic, equally applying to clear cell and non-clear cell histologies, despite the evidence bases for the two being fairly different. Tyrosine kinase inhibitors (TKIs) with or without ICI are considered as a SoC, but optimal treatment is not yet defined.
The CheckMate 920 single-arm multicohort phase IIIb/IV study assessed four cycles of treatment with a combination of ipilimumab and nivolumab followed by nivolumab monotherapy in 52 patients with non-clear cell RCC. The median OS was 21.2 months. The HCRN GU16260 study enrolled 35 patients with non-clear cell RCC for treatment with nivolumab followed by salvage ipilimumab/nivolumab. At median follow-up of 22.9 months, median OS had not been reached, but efficacy of the treatment approach was considered as limited. By comparison, sunitinib provided a median OS of 16.2 months in 33 patients with non-clear cell RCC in the ESPN study.
However, direct comparisons between immunotherapy strategies and targeted treatments in non-clear cell RCC are still missing. To close this gap, the investigators from the Interdisciplinary Renal Cell Carcinoma Working Group of the DKG (IAGN) conducted the SUNNIFORECAST, the first prospective randomised trial comparing the combination of ipilimumab and nivolumab strategy to physician’s choice SoC, which was dominated by TKI.
The study team randomised adult patients with previously untreated advanced or metastatic non-clear cell RCC 1:1 to nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by fixed dose nivolumab of 240 mg every 2 weeks or 480 mg every 4 weeks or to SoC. Patients were stratified by histology and by IMDC risk score. Central pathology review was mandatory. The primary endpoint was the OS rate at 12 months, secondary endpoints included median OS, response rate, progression-free survival (PFS), safety and quality-of-life.
In total, 157 patients were assigned to receive ipilimumab and nivolumab, and 152 to SoC. The 12-month survival rate was 78% with ipilimumab and nivolumab (95% confidence interval [CI] 71-84%) compared to 68% with SoC (95% CI 60-75%, p = 0.026). Median OS was 33.2 months versus 25.2 months (hazard ratio [HR] 0.81, 95% CI 0.61-1.099; p = 0.163). PFS was similar in both arms (HR 0.99, 95% CI 0.77-1.28). The ORR was 32.8% versus 19.3%.
About 62% of patients (56% according to central review) had papillary subtype, the most common entity in non-clear cell RCC. Within the non-papillary RCCs, chromophobe RCC was the largest entity, followed by 7% sarcomatoid or rhabdoid RCCs, 5% TFE3-rearranged and TFEB-altered RCC and more rare subtypes.
No major differences between papillary and non-papillary RCC subtypes were observed for any endpoint. Due to rather low numbers of rare non-papillary sub-entities, a possible superiority of ipilimumab and nivolumab versus SoC in OS rate or median OS could not be definitively elucidated, but responders could be observed in all of these entities.
In 90% of the specimens the combined positive score (CPS) could be determined. Exploratory analysis showed a significant OS advantage (HR 0.56, 95% CI 0.37-0.86) associated with a PD-L1 CPS score > 1.
Treatment discontinuation due to toxicity occurred in 27 patients (17%) with ipilimumab and nivolumab and in 13 patients (9%) with SoC.
The authors commented that some limitations may be the mixed therapies in the SoC arm, taking a landmark analysis as primary endpoint rather than logrank and some discrepancies between local and central pathological diagnosis. Whether a TKI/ICI combination has a similar efficacy has to be clarified by further randomised trials. Due to the rarity of different non-clear cell RCC entities, international cooperations will be essential.
This study was previously presented in part at the ESMO 2024 Congress (13-17 September 2024). The authors acknowledged the Bristol-Myers Squibb that made this investigator-initiated study possible through a grant to the Goethe University of Frankfurt, Germany.
Reference
Bergmann L, Albiges L, Ahrens M, et al. for the Interdisciplinary Renal Cell Carcinoma Working Group of the DKG (IAGN). Prospective Randomised Phase-II Trial of Ipilimumab/Nivolumab versus Standard of Care in non-clear cell Renal Cell Cancer - Results of the SUNNIFORECAST Trial. Annals of Oncology; Published online 1 April 2025. DOI: 10.1016/j.annonc.2025.03.016