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Partitioned Overall Survival: Comprehensive Analysis of Survival States over 4 Years in CheckMate 9ER Comparing First-Line Nivolumab plus Cabozantinib versus Sunitinib in Advanced Renal Cell Carcinoma - Beyond the Abstract

Patients with advanced renal cell carcinoma can achieve prolonged survival after treatment with immunotherapy-based treatment regimens. There are currently four treatment regimens approved for first-line treatment of advanced renal cell carcinoma, which have been proven to prolong overall survival: immunotherapy combination ipilimumab/nivolumab and immunotherapy/VEGF TKI combinations nivolumab/cabozantinib, pembrolizumab/axitinib, and pembrolizumab/lenvatinib. With median overall survival of advanced disease approaching 4.5 years and multiple effective treatment regimens with varying side effect profiles, it is important to understand how patients are spending their survival time either on or off treatment and with or without treatment-related side effects.1 Treatment-free survival is a novel outcome measure, which characterizes the time that patients spend surviving off of anti-cancer therapy and is defined by the time between first-line systemic therapy discontinuation and the start of second-line therapy or death.2

We previously reported that 18% of patients with advanced renal cell carcinoma treated with ipilimumab/nivolumab and 5% of patients treated with sunitinib were alive and surviving treatment free 5 years after starting first-line therapy on the Checkmate 214 clinical trial.3 For favorable risk patients, the 60-month mean treatment-free survival was 14.4 months after treatment with ipilimumab/nivolumab vs 5.5 months after sunitinib. For intermediate/poor risk patients, the 60-month mean treatment-free survival was 10.1 months after ipilimumab/nivolumab vs 4.1 months after sunitinib.3 Out of the time spent surviving treatment-free, less than half was spent with ongoing grade 2+ adverse events (5.0 and 2.1 months for favorable risk and 4.0 and 2.0 for intermediate/poor risk patients treated with ipilimumab/nivolumab and sunitinib, respectively). Adverse events include stable endocrine toxicity such as hypothyroidism, hypophysitis, and adrenal insufficiency. There was less grade 3 toxicity during the 60-month follow up with an average of 0.5 months and 1.4 months spent with grade 3+ treatment-related side effects while on therapy with ipilimumab/nivolumab vs sunitinib, respectively, and 0.8 and 0.3 months with grade 3+ treatment-related side effects while off therapy after ipilimumab/nivolumab and sunitinib, respectively.3 Overall, both favorable and intermediate/poor risk patients who were treated with ipilimumab/nivolumab experienced a longer time surviving treatment-free without side effects compared to patients treated with sunitinib.

CheckMate 9ER is a phase III clinical trial of 651 patients with advanced renal cell carcinoma treated with first line nivolumab/cabozantinib vs sunitinib. With 55.6 month median (48-month minimum) follow up, overall survival was improved at 46.5 months with cabozantinib vs 36 months with sunitinib.4,5 At 4 years from initiation of first-line treatment, 17.6% and 4.7% of patients treated with nivolumab/cabozantinib and sunitinib were alive and treatment-free, respectively; while 15.8% and 8.2% of patients remained on first-line protocol therapy with nivolumab/cabozantinib and sunitinib, respectively.6 The 48-month mean treatment-free survival was 2.4 months (95% CI 0.8-3.9) longer for nivolumab/cabozantinib vs sunitinib at 7.0 and 4.6 months, respectively. Of the time that patients spent treatment-free, at least half was spent with grade 2+ treatment-related adverse events, with an average of 3.9 months with nivolumab/cabozantinib compared with 2.3 months with sunitinib. There were many fewer grade 3+ treatment-related adverse events during the 48-month follow up with an average of 1.3 months and 1.0 months while on therapy with nivolumab/cabozantinib and sunitinib, respectively; as well as 1.1 months and 0.4 months while off therapy after nivolumab/cabozantinib and sunitinib, respectively. The 48-month mean survival after second-line therapy was longer for sunitinib at 12.0 months compared with 5.5 months for nivolumab/cabozantinib. Patients treated with nivolumab/cabozantinib spent more time on protocol therapy (22.6 months) compared to patients treated with sunitinib (14.1 months).6

In addition to longer overall survival, patients treated with nivolumab/cabozantinib experienced 1.5 times longer mean treatment-free survival vs sunitinib (difference of 2.4 months, 95% CI 0.8 to 3.9). Partitioned overall survival analysis helps to characterize the way patients spend their survival time after starting systemic therapy to highlight how much time is spent on therapy with and without adverse events and off therapy with and without lingering adverse events. It remains important to continue monitoring patient status even after cessation of protocol therapy on clinical trials to understand patients’ survival experience.

Written by: Charlene Mantia, MD,1 Hollis Viray, MD,2 Michael Atkins, MD,3 David McDermott, MD,2 Meredith Regan, ScD1

  1. Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  2. Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
  3. Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA.

References:

  1. Tannir NM, Albigès L, McDermott DF et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Annals of Oncology, Volume 35, Issue 11, 1026-038.
  2. Regan MM, Werner L, Rao S, et al. Treatment- free survival: a novel outcome measure of the effects of immune checkpoint inhibition- a pooled analysis of patients with advanced melanoma. J Clin Oncol 2019;37:3350–8.
  3. Mantia CM, Jegede OA, Plimack ER, et al. Treatment- free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5- year update of CheckMate 214. Journal for ImmunoTherapy of Cancer 2024;12:e009495. doi:10.1136/jitc-2024-009495.
  4. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982.
  5. Bourlon MT, Escudier B, Burotto M et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Results from 55-month follow-up of the CheckMate 9ER trial. J Clin Oncol 42, 2024 (suppl 4; abstr 362).
  6. Viray H, Mantia CM, Jegede OA, et al. Partitioned overall survival: comprehensive analysis of survival states over 4 years in CheckMate 9ER comparing first-line nivolumab plus cabozantinib versus sunitinib in advanced renal cell carcinoma. J Immunother Cancer. 2026 Jan 30;14(1):e013546. doi: 10.1136/jitc-2025-013546. PMID: 41617395; PMCID: PMC12863367.
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