Progression-free survival and one-year milestone survival as surrogates for overall survival in previously treated advanced non-small cell lung cancer

The advent of immunotherapy leads to greater availability of effective subsequent treatments and extended survival in previously treated advanced non-small cell lung cancer (NSCLC), complicating the evaluation of overall survival (OS) in second-line NSCLC trials. Here, we aimed to assess the surrogacy of progression-free survival (PFS) and milestone survival for OS in second-line NSCLC trials investigating chemotherapy, targeted therapy and immunotherapy, respectively. We systemically searched for active-controlled, second-line NSCLC trials. The milestone time point was set at one-year based on pre-analysis. A two-stage meta-analytic validation model was adopted to assess associations between surrogate endpoint (SE) and OS and associations between treatment effects on SE and OS. Treatment effects on SE and OS were expressed as PFS hazard ratios (HRPFS), 1 yr-milestone ratio (Ratio(1y-SUR)) and HROS. Subgroup analyses stratified by treatment types and trial publication years evaluated the surrogacy in different clinical contexts. The study included 50 trials with 22,804 patients. One-year survival strongly correlated with OS (R-2[95% confidence interval]: one-year survival -median OS = 0.707 [0.704-0.708]; Ratio(1y-SUR)-HROS = 0.829 [0.828-0.831]). No correlation was established between PFS and OS (median PFS-median OS = 0.100 [0.098-0.101]; HRPFS-HROS = 0.064 [0.059-0.069]), except in immunotherapy subgroup (HRPFS-HROS = 0.835 [0.791-0.918]). In subgroup analyses, surrogacy of one-year survival persisted in different clinical contexts, and the disassociation between PFS and OS persisted in recent trials. One-year milestone survival showed strong surrogacy for OS in second-line NSCLC trials. Although no association was identified between PFS and OS, the strong HRPFS-HROS correlation in immunotherapy trials indicates the potential of PFS as a SE in NSCLC trials involving immunotherapies. What's new? The advent of immunotherapy has provided previously-treated advanced non-small cell lung cancer (NSCLC) patients with more subsequent treatment options. The evaluation of overall survival (OS) in second-line NSCLC trials has however become more complicated and time-consuming due to potential confounding effects, calling for the identification of surrogate endpoints. This literature-based study of 50 trials identified strong correlations between one-year survival and OS, supporting the use of milestone survival as a surrogate endpoint in future NSCLC trials. No correlation between progression-free survival (PFS) and OS was established. However, the strong HRPFS-HROS correlation in the immunotherapy subgroup suggested its potential utility in immunotherapy trials.