Abstract
IMPORTANCE: Progression-free survival (PFS) rate at 6 months has been proposed as a potential surrogate for overall survival (OS) rate at 12 months for immune checkpoint inhibitor (ICI) trials but requires further assessment for validation. OBJECTIVE: To validate 6-month PFS and objective response rate (ORR) as estimators of 12-month OS in the ICI arms of randomized clinical trials (RCTs). DATA SOURCES: Electronic databases (Medline, EMBASE, and the Cochrane Central Register of Controlled Trials) were searched for ICI RCTs published between January 2000 and June 2019. STUDY SELECTION: Eligible studies were phase 2 and phase 3 ICI RCTs in advanced solid cancers that reported ORR, PFS, and OS. A total of 99 articles (from 60 studies) of 2502 articles were selected by consensus. DATA EXTRACTION AND SYNTHESIS: Data were screened and extracted independently. Estimation models for 12-month OS and to assess correlation coefficient between end points were developed using linear regression. Data were extracted in July 2019, and analyses were conducted in September 2019. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. MAIN OUTCOMES AND MEASURES: Validation of previously reported 6-month PFS and ORR estimation models for 12-month OS using contemporary RCTs. Calibration of 6-month PFS and ORR model-estimated vs observed 12-month OS in ICI arms were assessed by correlation coefficient (r) and weighted Brier scores. Secondary analyses were performed for subgroups (ie, ICI-only, ICI-combination, line of therapy, programmed cell death 1 ligand 1 selected, and unselected). RESULTS: Data from 60 RCTs with 74 experimental ICI arms were used. The development data set included 25 arms from studies published January 2000 to January 2017. The estimation model for 12-month OS using 6-month PFS was: (1.06 × PFS6) + 0.16 + (0.04 × melanoma) - (0.03 × NSCLC) + (0 × other tumors), in which PFS6 indicates 6-month PFS and NSCLC indicates non-small cell lung cancer. The estimation model for 12-month OS using ORR was (0.15 × ORR) + 0.52 + (0 × melanoma) - (0.02 × NSCLC) - (0.01 × other tumors). A total of 49 arms from studies published after January 2017 to June 2019 formed the validation data set. When the models were applied on the validation data set, calibration between the 6-month PFS model estimated vs observed 12-month OS was good (r = 0.89; Brier score, 0.008), but poor for the ORR model (r = 0.47; Brier score, 0.03). Findings were similar across all subgroups. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that the estimation model using 6-month PFS could reliably estimate 12-month OS in ICI trials. This study could assist in better selection and prioritization of ICI agents for testing in RCTs based on phase 2 single-arm RCT results.