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

Abstract

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 (Ratio1y‐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 (R2[95% confidence interval]: one‐year survival ‐median OS = 0.707 [0.704–0.708]; Ratio1y‐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.

Endpoint surrogacy in oncological randomized controlled trials with immunotherapies: a systematic review of trial-level and arm-level meta-analyses

“…Through article searching, we found 19 articles in PubMed and one eligible meta-analysis by hand searching; among those 20 articles, five were not meta-analyses that evaluated the association of OS and other endpoints, three were meta-analyses but without association results for immunotherapies, and one was a meta-analysis for immunotherapies but it was conducted based on individuallevel analysis. Therefore, a total of 11 studies were eligible according to our inclusion/exclusion criteria (Figure 1) (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). In these studies, surrogate endpoints included PFS (20,21,(23)(24)(25)(26)(27)(28)(29)(30), three-month PFS (29), 6-month PFS (20,23,29), ORR (20)(21)(22)(23)(24)(25)27,28), disease control rate (DCR) (23,24), 1-year survival (26,28,30) and 2-year survival (30).…”

“…• 5 were not a meta-analysis evaluating the association of OS and other endpoints • 3 were meta-analyses but without association results for immunotherapies • 1 was a meta-analysis for immunotherapies but was conducted by individual-level analysis 11 of eligible meta-analyses For statistical method, even though correlation analysis and/or linear regression were used, our included metaanalyses performed them not in an exactly same way: most meta-analyses (82%; 9/11) were weighted by sample size (20)(21)(22)(23)(24)(25)(26)(27)30); among them, four meta-analyses performed the statistics on a logarithmic scale (21,22,26,30), and two conducted adjustment in linear regression model (23,26). For association results, six meta-analyses had evaluation criteria for considering validated endpoint surrogacy for OS, including R 2 ≥0.80 (21), R 2 ≥0.75 (24), R 2 ≥0.72 (23), R 2 ≥0.64 (28,30), and R 2 ≥0.60 (26).…”

“…Among all 11 indications between median OS and the outcomes of traditional surrogate endpoints (median PFS and ORR), none of them met the lowest evaluation criteria (R 2 ≥0.60) for endpoint surrogacy in all included studies. The R 2 of median OS with median PFS, ORR, 1-year survival rate and 2-year survival rate ranged from <0.01 to 0.54 (24)(25)(26)(27)28,30), 0.01 to 0.29 (24,25,28), 0.65 to 0.97 (26,28,30), 0.62 to 0.66 (30), respectively.…”

“…The R 2 of OS HR and PFS HR ranged from 0.13 to 0.50 (20,21,23,24), and that of OS HR and ORR OR ranged from <0.01 to 0.52 (20,(21)(22)(23)(24), in meta-analyses based on multiple cancers. In meta-analyses for NSCLC, R 2 of OS HR and PFS HR ranged from 0.40 to 0.85 (20,26,27), and that of OS HR and ORR OR ranged from <0.01 to 0.57 (20,22,27). In a metaanalysis for advanced renal cell carcinoma, the R 2 of OS HR and PFS HR was 0.40 (29).…”

“…Three meta-analyses evaluated the surrogacy of survival rate for OS. Two were using the ratio of the 1-year survival rates between treatment arms, with the R 2 value of 0.78 and 0.64, respectively, between the ratio and the OS HR in trials with PD-1/PD-L1 inhibitor for advanced NSCLC and renal cell carcinoma (26,28). The other one was using the difference of the 1-year survival rates between treatment arms; the R 2 between the difference and the OS HR was 0.74 and 0.85, respectively, in trials with immune checkpoint inhibitors and ipilimumab only (CTLA4 inhibitor) for metastatic melanoma (30).…”