Exploration of modified progression-free survival as a novel surrogate endpoint for overall survival in immuno-oncology trials

Background Progression-free survival (PFS) exhibits suboptimal performance as the surrogate endpoint for overall survival (OS) in trials studying immune checkpoint inhibitors (ICIs). Here we propose a novel surrogate endpoint, modified PFS (mPFS), which omits the events of disease progression (but not deaths) within 3 months after randomization. Methods PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for randomized trials studying ICIs in advanced solid tumors with available PFS and OS data up to May 2020. Individual patient-level data (IPD) for PFS and OS were reconstructed for eligible trials. A simulation-based algorithm was used to match the reconstructed, disconnected PFS and OS IPD, and 1000 independent simulated datasets of matched PFS-OS IPD were generated for each trial. mPFS durations and statuses were then measured for each of the matched PFS-OS IPD. Trial-level correlation between Cox HRs for PFS or mPFS and HRs for OS was assessed using Pearson correlation coefficient (r(p)) weighted by trial size; patient-level correlation between PFS or mPFS and OS was assessed using Spearman's rank correlation coefficient (r(s)). Findings were further validated using the original IPD from two randomized ICI trials. Results Fifty-seven ICI trials totaling 29,429 participants were included. PFS HR showed moderate correlation with OS HR (r(p)=0.60), and PFS was moderately correlated with OS at the patient level (median r(s)=0.66; range, 0.65-0.68 among the 1000 simulations). In contrast, mPFS HR achieved stronger correlation with OS HR (median r(p)=0.81; range, 0.77-0.84), and mPFS was more strongly correlated with OS at the patient level (median r(s)=0.79; range, 0.78-0.80). The superiority of mPFS over PFS remained consistent in subgroup analyses by cancer type, therapeutic regimen, and treatment setting. In both trials with the original IPD where experimental treatment significantly improved OS, mPFS successfully captured such clinical benefits whereas PFS did not. Conclusions mPFS outperformed PFS as the surrogate endpoint for OS in ICI trials. mPFS is worthy of further investigation as a secondary endpoint in future ICI trials.