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.

[BACKGROUND] Immune checkpoint inhibitor (ICI)-based regimens can be associated with prolonged survival and disease control after treatment discontinuation without further anticancer therapy. An integrated, comprehensive partitioned survival analysis describes how patients spend overall survival (OS) time both on/off treatment and with/without toxicity. Previous analysis of first-line (1L) nivolumab+ipilimumab for advanced renal cell carcinoma (aRCC) in CheckMate 214 showed treatment-free survival (TFS; time between 1L and second-line (2L) therapies) was twice as long versus sunitinib. TFS and survival states for ICI plus vascular endothelial growth factor receptor-tyrosine kinase inhibitor are of interest.

[METHODS] In CheckMate 9ER, 651 randomized patients with aRCC received 1L nivolumab+cabozantinib or sunitinib. Minimum follow-up was 4 years. We partitioned area under the Kaplan-Meier OS curve into three survival states defined from randomization: time on 1L protocol therapy, TFS, and survival after 2L subsequent systemic therapy initiation. TFS and protocol therapy were subdivided into mean times with/without grade 2+ treatment-related adverse events. Areas under and between Kaplan-Meier curves were estimated by 48-month restricted mean times to event. Bootstrapped 95% CIs for between-group differences are reported.

[RESULTS] At 4 years post-randomization, Kaplan-Meier OS estimates were 49.2% versus 40.2% with nivolumab+cabozantinib and sunitinib, respectively; 17.6% versus 4.7% of patients were in TFS; 15.8% versus 8.2% remained on 1L protocol therapy. The 48-month mean time on protocol therapy for nivolumab+cabozantinib versus sunitinib was 22.6 and 14.1 months; 48-month mean TFS was 7.0 and 4.6 months (difference, 2.4 (95% CI 0.8 to 3.9)); 48-month mean survival after 2L therapy initiation was 5.5 and 12.0 months, respectively. The nivolumab+cabozantinib group spent 8.5 (95% CI 6.2 to 10.8) months more mean survival time on 1L protocol therapy, whereas the sunitinib group had 6.5 (95% CI 4.4 to 8.6) months more mean survival time after 2L therapy initiation. Both treatment groups spent at least half of TFS with grade 2+toxicity, resulting in a difference in mean TFS without toxicity of 0.7 (95% CI -0.4 to 1.8) months.

[CONCLUSIONS] Partitioned survival analysis over 4 years after initiation of 1L therapy for aRCC indicated that longer OS with nivolumab+cabozantinib versus sunitinib involved more time on 1L therapy and in TFS, and less survival time after 2L therapy initiation.

[TRIAL REGISTRATION NUMBER] NCT03141177.