Second-event endpoints (EFS2, PRFS2 and PFS2) after anti-PD-(L)1-based RCTs : a systematic review and meta-analysis

Immune checkpoint inhibitors (ICIs), particularly anti-PD-(L)1s, have transformed cancer care by their extended efficacy, even receiving next-line. Event-free survival 2 (EFS2), progression/recurrence-free survival 2 (PRFS2) and progression-free survival 2 (PFS2) capture the time from randomization to objective recurrence/progression or death on the first subsequent therapy, potentially offering a more accurate measure of durable benefit than first-event endpoints. Our aim is to review the magnitude of this benefit and evaluate long-term endpoints as surrogates for overall survival (OS) in immunotherapy for solid malignancies. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review and meta-analysis searched Web of Science, National Institutes of Health Clinical Trials Registry, American Society of Clinical Oncology and European Society of Medical Oncology conference databases from inception until June 12, 2025, for anti-PD-(L)1-based randomized controlled phase II/III clinical trials (RCTs) in patients with solid malignancies that reported EFS2, PRFS2 or PFS2. HRs comparing ICI and non-ICI arms were pooled using a random-effects meta-analytic approach. Sensitivity analyses and meta-regressions assessed effect modifiers. A linear regression compared EFS2/PRFS2/PFS2 and EFS/disease-free survival (DFS)/PFS versus OS HRs. 47 RCTs met inclusion criteria from 2,078 citations, comprising 58 intervention comparisons (ICs) and 34,973 patients. Non-small cell lung cancer (NSCLC) was the most investigated tumor (17 RCTs). Anti-PD-(L)1s performed generally worse when administered as a subsequent therapy in non-ICI-experienced patients (p.