Nivolumab/Ipilimumab Meets Primary OS End Point in Non–Clear Cell RCC

RCC | Image Credit: ©
Kellie Ehrmann/MJH Life Sciences using AI

Nivolumab (Opdivo) plus ipilimumab (Yervoy) demonstrated significantly longer 12-month overall survival (OS) with an acceptable safety profile for the treatment of patients with non–clear cell renal cell carcinoma (nccRCC) compared with standard of care (SOC), meeting the primary end point of OS, according to data from the phase 2 SUNNIFORECAST trial (NCT03075423).

The data, which were published in the Annals of Oncology, demonstrated that the 12-month OS rates were 78% (95% CI, 71%-84%) vs 68% (95% CI, 60%-75%) in the nivolumab/ipilimumab (n = 157) vs SOC (n = 152) arms, respectively (P = .026). The median OS also demonstrated favorability towards the combination at 33.2 months (95% CI, 23.4-40.8) in the combination arm compared with 25.2 months (95% CI, 18.8-33.0) in the SOC arm (HR, 0.81; 95% CI, 0.61-1.09; log-rank P = .163). Additionally, the 18-month OS rates were 67% (95% CI, 59%-73%) vs 60% (95% CI, 52%-68%) in the combination and control arms, respectively (P = .124).

“This prospective, randomized phase 2 trial in treatment-naïve patients with advanced or metastatic nccRCC was conducted to evaluate a possible benefit of the combination of ipilimumab plus nivolumab compared to SOC,” the study authors wrote. “To our knowledge, this is the largest randomized trial so far in nccRCC.”

SUNNIFORECAST Trial Design

The European, multicenter, open-label study evaluated the combination of nivolumab and ipilimumab followed by nivolumab monotherapy compared with investigator’s choice of SOC treatment in patients with nccRCC. Patients were required to be at least 18 years of age, have previously untreated advanced or metastatic histologically confirmed nccRCC with at least 50% non–clear cell disease according to WHO classification, measurable disease per RECIST 1.1 criteria, a Karnofsky performance status of at least 70%, and the ability to provide a recent or previous tumor tissue sample.

Patients were randomly assigned 1:1 to the combination or SOC arm and were stratified based on histology (papillary vs non-papillary nccRCC) and International Metastatic RCC Database Consortium (IMDC) prognostic score (0 vs 1-2 vs 3-6). In the combination arm, patients were treated with nivolumab at 3 mg/kg, then ipilimumab on the same day at 1 mg/kg intravenously every 3 weeks for an induction phase of 4 cycles. In the subsequent maintenance phase, patients received nivolumab at a fixed dose of 240 mg every 2 weeks or 480 mg every 4 weeks. Of note, isolated delays or discontinuations of only 1 of the 2-drug regimen were not permitted, and no dose reductions were allowed. Patients in the SOC arm were treated with investigator’s choice SOC treatment and any approved standard treatment for nccRCC was allowed.

The primary end point was 12-month OS rate; secondary end points included 6- and 18-month OS rates, progression-free survival (PFS), OS, and objective response rate (ORR). Additional secondary end points were tolerability, safety, and quality of life (QOL).

Baseline Patient Characteristics

In the combination and control arms, the median age was 61 years (range, 19-82) and 64 (range, 19-86), respectively, and the majority of patients were males (combination, 71%; control, 70%). The Karnofsky scores were 100 (51%; 54%), 90 (22%; 28%), 80 (17%; 16%), 70 (8%; 3%), 60 or less (1%; 0%), and missing (2%; 0%). Additionally, the IMDC prognostic risk scores were favorable (25%; 23%), intermediate (50%; 53%), and poor (25%; 24%). Prior therapies included any surgery (79%; 74%), total or partial tumor nephrectomy (59%; 51%), and any radiotherapy (9%; 10%). Notably, the most common sites of target lesions included lymph node (53%; 48%), lung (36%; 34%), kidney (33%; 34%), and liver (17%; 26%).

Furthermore, histological subtypes for stratification included papillary RCC (combination arm, 63%; control arm, 60%), non-papillary RCC (37%; 40%), and missing (0%; 1%). Histological subtypes according to extended reference pathology were papillary RCC (56% each), non-papillary (44% each), chromophobe renal cell carcinoma (17%; 21%), collecting duct carcinoma (4%; 3%), renal medullary carcinoma (1%; 3%), TFE3-rearranged and TFEB-altered RCC (7%; 3%), succinate dehydrogenase–deficient RCCs (1% each), mucinous tubular and spindle cell carcinoma (1%; 0%), tubulocystic RCC (1%; 0%), fumarate hydratase deficient (1%;2%), not otherwise specified (5%; 4%), sarcomatoid and/or rhabdoid (7%; 6%), SMARCA-4 deficient RCC (0%; 1%), and unclassifiable (0%; 1%). The PD-L1 combined positive scores (CPS) included a CPS of less than 1 (45%; 38%), 1 or greater (47%; 50%), less than 10 (68% each), 10 or greater (24%; 20%), and missing (8%; 12%). Time since initial diagnosis was a median of 34 months (range, 2-1417) and 25 months (range, 1-1098) in the respective arms.

Additional Efficacy and Safety Data

Between the nivolumab/ipilimumab and SOC arms, the PFS was comparable with a median PFS of 5.4 months (95% CI, 3.2-7.8) vs 5.7 months (95% CI, 5.4-8.3), respectively (HR, 0.99; 95% CI, 0.77-1.28). The ORR per RECIST 1.1 criteria was 33% among evaluable patients in the combination arm (n = 31/125), with 8% achieving a complete response (CR) and 25% of patients achieving a partial response (PR). The ORR in the combination arm was compared with 20% in the control arm (n = 16/77), of which 2% of patients had a CR and 18% had a PR. Notably, patients demonstrated similar responses by histology (papillary vs non-papillary RCC). In the papillary cohort, patients had a median OS of 28.4 months (95% CI, 18.4-40.9) vs 18.9 months (95% CI, 14.4-32.8) in the combination vs control arms, respectively (HR, 0.84; 95% CI, 0.59-1.21). The 12-month OS rates were 74.6% (95% CI, 64.7%-82.0%) vs 64.1% (95% CI, 5.3%-73.3%), respectively. The chromophobe RCC cohort demonstrated an ORR of 27% vs 10%, and the sarcomatoid/rhabdoid RCC cohort showed an ORR of 70% vs 25%, favoring the combination, respectively.

“Regarding the outcome in the different risk groups, there was a tendency towards a better OS outcome with ipilimumab/nivolumab in [patients with poor-risk compared with intermediate-risk [disease],” the study authors added. “Interestingly, patients without a tumor nephrectomy had a better OS than those with tumor resection in the ipilimumab/nivolumab arm.”

Any-grade adverse effects (AEs) occurred in 97% of patients in the combination arm and 99% of patients in the control arm. Any-grade treatment-related AEs (TRAEs) were reported in 87% vs 96% of patients from the combination and control arms, respectively, and serious AEs were observed in 48% vs 39% of patients, respectively. Of note, treatment discontinuations due to treatment toxicity occurred in 17% vs 9% of patients. AEs leading to death were reported in 8 patients total, with 5 from the combination arm and 3 from the control arm; none of these AEs were assessed as treatment-related deaths.

Reference

Bergmann L, Albiges L, Ahrens M, et al. Prospective randomised phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer - results of the SUNNIFORECAST trial. Ann Oncol. Published online April 1, 2025. doi:10.1016/j.annonc.2025.03.016