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

Abstract

Immune checkpoint inhibitor; Immunotherapy; Solid tumor

Inhibidor de puntos de control inmunitario; Inmunoterapia; Tumor sólido

Inhibidor de punts de control immunitari; Immunoteràpia; Tumor sòlid

Background 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. Methods 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. Results 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<0.05). Early anti-PD-(L)1 use was associated with significantly improved EFS2/PRFS2/PFS2 (HR 0.72; 95% CI 0.68 to 0.76), with consistent findings across curative and recurrent/metastatic settings, and particularly strong effects in RCTs involving patients with deficient mismatch repair or high microsatellite instability tumors and those with more radiological responses. In 54 ICs reporting both OS and EFS2/PRFS2/PFS2 HRs, a strong correlation (R²=0.74) was observed across all RCTs, and an even stronger 0.86 specifically among patients with NSCLC (22 ICs). Conversely, EFS/DFS/PFS presented R² 0.39 across all RCTs (51 ICs), and 0.65 in NSCLC (21 ICs; p<0.01). Conclusions Early use of anti-PD-(L)1 therapy is associated with prolonged disease control and may be linked to enhanced responsiveness to subsequent therapies, mostly based on NSCLC data. Additionally, EFS2/PRFS2/PFS2 are solid candidate surrogates for OS and could be considered for routine inclusion and prespecified into immunotherapy RCTs to better capture long-term benefit and inform regulatory, clinical, and reimbursement decision-making. PROSPERO registration number CRD42024585378.