Long-term survivorship rates among patients with previously treated advanced renal cell carcinoma receiving nivolumab: Analyses based on ≥ 7 years of follow-up from CheckMate 025 trial.
Authors: George Saby , Larkin James , Chepynoga Kateryna , Sharpe Daniel , De Tuli , Dyer Matthew , Ejzykowicz Flavia , May Jessica , Kurt Murat 
Published: March 2023

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Background: The phase 3 CheckMate 025 study has shown sustainable and superior long-term survival outcomes for previously treated aRCC patients receiving NIVO over everolimus. This exploratory analysis investigated the survival heterogeneity within the NIVO arm of CheckMate 025 borne by the underlying fraction of potential long-term survivors (LTS). Methods: OS and PFS outcomes from the trial with minimum 7-years of follow-up were analyzed separately using mixture cure models (MCMs). In MCMs, patients were probabilistically classified in mutually exclusive subgroups as LTS or non-LTS, where LTS were assumed to be free of disease-related mortality risk. In the analysis of PFS outcomes, LTS were also assumed to be free of progression risk. In the MCMs, the survival trend for LTS was estimated using age- and sex-adjusted background mortality rates reported by the World Health Organization and patients’ enrolment distribution across the countries participating in the trial. Time-to-event outcomes for non-LTS were modelled using candidate parametric distributions, which were estimated simultaneously with the proportion of LTS by maximum likelihood methods. Model selection was based on statistical goodness-of-fit metrics, visual comparison to observed survival curves, and longer-term clinical plausibility. Effects of selected baseline covariates on the proportion of LTS were also analyzed using OS data. Results: The best-fitting models indicated that the proportion of LTS was 17.5% (95% confidence interval (CI): 13.0%-23.2%) from the OS data and 4.7% (95% CI: 2.5%-8.4%) from the PFS data. Across all clinically plausible candidate models, estimated proportion of LTS ranged between 15.2%-18.0% where the range of progression-free LTS was 2.6%-6.7%. Lifetime mean OS and PFS projected by the best-fitting MCMs over a 30-year time horizon was 64.6 (95% CI: 56.0-77.1) and 19.1 (95% CI: 15.0-25.3) months, respectively. Estimated 10- and 30-year OS rates from the best-fitting MCMs were 14.7% (95% CI: 11.9%-20.3%) and 4.6% (95% CI: 3.6%-6.4%), respectively. Corresponding 10- and 30-year PFS rates were 3.9% (95% CI: 2.0%-6.4%) and 1.2% (95% CI: 0.5%-2.0%), respectively. Odds ratios for likelihood of being LTS between subgroups classified by Memorial Sloan Kettering Cancer Center (MSKCC) Risk Criteria (intermediate/poor vs favourable) was 0.37 (95% CI: 0.28-0.48), by PD-L1 status (< 1% vs ≥ 1%) was 0.58 (95% CI: 0.45-0.75), and by number of sites with metastases (≥ 2 vs 1) was 0.25 (95% CI: 0.19-0.33). Conclusions: A moderate proportion of aRCC patients treated with NIVO in CheckMate 025 can be projected as LTS with a smaller fraction subject to no risk of progression. Having a favourable MSKCC risk score, positive PD-L1 status, or only one site of metastasis were associated with improved odds of long-term survivorship.