There are several considerations to take into account according to Dr. Schmidinger when deciding which combination therapy to use. First, the chance of complete remission. Patients treated with nivolumab plus ipilimumab over a median follow-up of 42 months had a complete response rate of 10%, compared to 8% for patients treated with pembrolizumab plus axitinib over a median follow-up of 30.6 months. Dr. Schmidinger notes that the complete response rate in CheckMate-214 is numerically the highest ever reported in mRCC, moreover, this included an 18.3% complete response rate in patients with sarcomatoid RCC. Furthermore, this high complete response rate is a result of the synergy seen with nivolumab plus ipilimumab: PD-1 inhibitor monotherapy has complete response rates of 0-5.7%.
Second, the importance of the durability of response. Patients treated with nivolumab plus ipilimumab have yet to reach a median duration of response, 88% had an ongoing complete response, and 68% had an ongoing objective response. Comparatively, patients treated with pembrolizumab plus axitinib had a median duration of response in the ITT population of 23.5 months and the ongoing objective response rate was 47% at 24 months (also in the ITT population).
Third, the important consideration of being able to go off treatment. Of note, Dr. Schmidinger notes that discontinuation in the absence of adverse events is currently not recommended. Currently, there is no data with this metric for patients receiving pembrolizumab plus axitinib. Among patients in CheckMate-214 receiving nivolumab plus ipilimumab, overall survival was not impacted in patients who discontinued treatment secondary to adverse events. 
The fourth consideration is the rapid reduction in tumor volume. Among patients receiving nivolumab plus ipilimumab, the median time to response was 2.8 months, whereas the median time to complete response was 5.8 months. Currently, these metrics for patients with intermediate-poor risk disease have not been evaluated for patients receiving pembrolizumab plus axitinib. Fifth, the risk of toxicity. Dr. Schmidinger notes that there is a perception that IO-IO therapy is more challenging to manage than IO-TKI therapy, but looking at the grade 3-4 adverse event rates suggest otherwise. Those receiving nivolumab plus ipilimumab had a rate of 47% compared to 65.9% for pembrolizumab plus axitinib. Both trials had one treatment-related death. The final consideration is the cost of treatment. Dr. Schmidinger notes that the one-year treatment cost of first-line therapy for mRCC is 178,755 euros for pembrolizumab plus axitinib, compared to 107,010 euros for patients treated with nivolumab plus ipilimumab.
Dr. Schmidinger concluded her presentation with the following take-home messages:
- Nivolumab plus ipilimumab provides unprecedented high complete response rates in intermediate-poor risk patients (10%)
- At a median follow-up of 42 months, the duration of response was not reached for nivolumab plus ipilimumab and complete responses were ongoing for 88% of patients. Comparatively, the median duration of response for pembrolizumab plus axitinib was 23.5 months
- Among patients stopping treatment for nivolumab plus ipilimumab, discontinuation did not impact overall survival
- Strategies studied in ongoing triplet trials (COSMIC trial: IO + IO + TKI) may lead to the best outcomes ever: the strength may lie in ipilimumab being part of the treatment regimen
Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the Virtual 2020 EAU Annual Meeting #EAU20, July 17-19, 2020.
References:
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.
- Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019;380(12):1116-1127.