Ipilimumab/nivolumab versus standard of care in non-clear cell renal cancer: Results of the SUNNIFORECAST trial and potential role of the CPS score and tumor nephrectomy.

4522 Background: Non-clear cell renal cancers (nccRCC) are a rare and heterogeneous group of >20 histological and molecular defined entities. Due to the rarity of these entities, the clinical data are limited and large randomized trials are missing resulting in uncertainties for optimal treatment recommendations. So far, TKI therapy with or without immune checkpoint inhibitors (ICI) are considered standard of care (SOC) options in these diseases. Here we report the results of the academic prospective randomised European trial in therapy-naïve patients with advanced nccRCC entities, which compared ipilimumab/nivolumab (Ipi/Nivo) vs SOC. Methods: We randomly assigned patients (pts) with nccRCC in a 1:1 ratio to receive either nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV every 3 weeks for 4 doses followed by a flat dose of 240 mg IV every 2 weeks or 480 mg every 4 weeks versus SOC by investigators choice until disease progression or intolerance occurred. Pts were stratified in papillary vs. non-papillary nccRCC and according to IMDC risk score. Central pathology was mandatory to confirm the correct diagnosis of the nccRCC subtype according to the WHO classification 2022.The primary endpoint was the overall survival (OS) rate at 12 months (mos), secondary endpoints were the OS rate at 6 mos and 18 mos, OS, progression-free survival (PFS) and response rate (RR). Results: 309 pts ( 70.9% male, 29.1% female) out of 316 pts were randomized to receive either Ipi/Nivo or SOC. 173 (56.0%) pts were of papillary subtype (pRCC) and 143 (44.0%) pts of non-papillary subtypes, whereas 59 pts had chromophobe (ccRCC), 20 sarcomatoid/rhabdoid, 10 collecting duct, 11 TFE3-rearranged or TFEB-altered RCC and 37 other histological features. According to the IMDC score, 23.9% were of favorable, 51.8% of intermediate and 24.3% of poor risk. The 12 mos OS rate for Ipi/Nivo of 78.3% (95%-CI 70.9%-83.9%) vs 68.3% (95%-CI 60.0%-75.3%) in the SOC arm was statistically significant (p=0.026). Median OS was 33.2 mos for the Ipi/Nivo arm and 25.2 mos for the SOC arm. The ORR of 32.8% vs. 19.4% and the median PFS of 5.4 mos vs 5.7 mos was not statistically significant different between both arms. The explorative endpoint CPS score differed between the various subentities and was associated with an advantage in OS. Pts with a CPS≥1 had an OS-rate at 12 months of 79.3% in the Ipi/Nivo arm vs. 58.3% and a median OS of 38.6 mos vs. 18.8 mos (p=0.007). Furthermore, pts who did not underwent a tumor nephrectomy (possibly due to high risk) had a survival benefit with 26.3 mos in the Ipi/Nivo arm vs 16.5 mos in the SOC arm (p=0.065) in contrast to nephrectomized pts with 38.9 mos vs 34.0 mos. Conclusions: The OS-Rate at 12 mos was significantly superior for Ipi/Nivo in comparison to SOC and the primary endpoint was met. Additionally, pts in the Ipi/Nivo arm had a longer median OS, especially those with a CPS≥1. Clinical trial information: NCT03075423 .