(UroToday.com) The 2024 ESMO annual meeting included a session on kidney cancer, featuring a presentation by Dr. Lothar Bergmann discussing results of the phase II SUNNIFORECAST trial assessing ipilimumab + nivolumab versus standard of care in non-clear RCC. Non-clear cell RCC is a rare and heterogeneous group of more than 20 histological and molecular-defined entities.
The rarity of these entities has contributed to the dearth of large randomized trials and uncertainties for optimal treatment recommendations. At ESMO 2024, Dr. Bergmann and colleagues reported the final results of the prospective randomized European trial SUNNIFORECAST in therapy-naïve patients with advanced non-clear cell RCC.
This trial randomly assigned patients with non-clear cell RCC 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 standard of care by investigators choice until disease progression or intolerance occurred. Patients were stratified in papillary versus non-papillary non-clear cell RCC and according to the IMDC risk score. The trial design for SUNNIFORECAST is as follows:
Central pathology was mandatory to confirm the diagnosis and non-clear cell RCC subtype according to the WHO classification 2022. As far as the statistical plan, there are only limited survival data available for metastatic nonclear cell RCC treated with standard of care. Taking the limited source data and the data available from the randomized US trial with everolimus versus sunitinib,1 which were in favor of sunitinib, a 12-month survival rate of 65% was assumed. An increase in overall survival was considered as clinically relevant to be obtained by ipilimumab + nivolumab. Thus, the 12-month overall survival rate for ipilimumab + nivolumab was chosen as the primary endpoint and assumed to be 80%. A sample size of 244 patients (122 patients per arm) was calculated based on a one-sided Fisher’s exact test for comparison of two independent proportions based on the assumptions enumerated above and applying a 1:1 randomization. Accounting for dropout and a censoring of 20%, a total of 306 patients (153 patients per arm) was calculated.
A total of 316 patients were screened in 7 European countries and 31 centers. The randomized population of 309 patients (70.9% male, 29.1% female) were randomized to receive either nivolumab plus ipilimumab (157 patients) or standard of care (152 patients: 124 TKI, 17 TKI/IO, 2 other treatment regimens, 9 patients did not receive any treatment):
There were 178 patients (57.6%) with papillary, 60 patients (19.4%) with chromophobe, 12 patients (3.9%) with MIT, 9 patients (2.9%) with collecting duct carcinoma, and 50 patients with other subtypes. According to the IMDC score, 23.9% were of low, 51.8% of intermediate, and 24.3% of high risk. The 12-month overall survival rate for the entire population was 82.5%. The 12-month overall survival rate for Ipilimumab + Nivolumab 86.9% (95%-CI 80.2%-91.5%) was statistically significantly superior to the standard of care 76.8% (95%-CI 68.6%-83.1%) (p = 0.014). Median overall survival was 42.4 months for the Ipilimumab + Nivolumab arm and 33.9 months for the standard-of-care arm:
Patients that were PDL1 positive (>= 1%) derived a benefit from ipilimumab + nivolumab (HR 0.56, 95% 0.33-0.95), as did patients with lymph node metastasis (HR 0.62, 95% CI 0.39-0.98):
Overall survival in papillary and nonpapillary RCC according to IMDC risk score are as follows:
The median progression-free survival of 5.52 (95% CI 4.30–8.23) months versus 5.65 (95% CI 5.49–8.46) months was not statistically significant different between ipilimumab + nivolumab and standard of care:
The objective response rate for all nonclear cell RCC patients was 32.8% for ipilimumab + nivolumab, compared to 19.6% for standard of care. Additionally, overall response by histology is listed below:
Dr. Bergmann also highlighted subsequent therapies based on 2nd, 3rd, and 4th lines of therapy:
Dr. Bergmann concluded his presentation discussing results of the phase II SUNNIFORECAST trial with the following take-home points:
- This is the first prospective randomized trial that compared dual checkpoint inhibitor therapy with an actual standard of care in nonclear cell RCC
- The overall survival rate at 12 months was significantly superior for ipilimumab + nivolumab versus standard of care (predominantly TKI monotherapy), thus the primary endpoint was met.
- The overall survival and objective response rate suggest a benefit for the ipilimumab + nivolumab.
- Progression-free survival was not statistically different between both arms.
- Papillary and non-papillary RCC showed a similar benefit in overall survival rate for ipilimumab + nivolumab.
- The randomized SUNNIFORECAST trial underlines a relevant clinical benefit of ipilimumab + nivolumab in nonclear cell RCC and may be a new standard in these entities.
- Further data and translational research are needed in these very rare entities and international cooperation is essential in order to obtain sufficient patient numbers.
Presented by: Lothar Bergmann, MD, Professor, Academic Researcher, J.W. Goethe University, Frankfurt, Germany
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Meeting, Barcelona, Spain, Fri, Sept 13 – Tues, Sept 17, 2024.
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