Early progression disadvantage of immunotherapy-only treatment versus chemotherapy in NSCLC: A meta-analysis of randomized controlled trials

Introduction : Immune checkpoint inhibitors (ICIs) have become a cornerstone in the treatment of advanced non-small cell lung cancer (NSCLC). However, across several randomized controlled trials (RCTs), immunotherapy-only arms have demonstrated an early disadvantage in progression-free survival (PFS) and overall survival when compared with chemotherapy or chemo-immunotherapy combinations. This early decline may reflect multiple factors, including lack of cytoreduction, delayed onset of immunotherapy efficacy relative to chemotherapy, or the phenomenon of hyperprogression. To better define this pattern, we conducted a meta-analysis of RCTs comparing immunotherapy-only regimens with chemotherapy in first-line NSCLC to determine whether this early disadvantage is consistent and generalizable. Methods: We systematically searched three databases (PubMed, Cochrane Library, and Embase) for phase II and III RCTs evaluating an immunotherapy-only regimen (Nivolumab plus Ipilimumab, Pembrolizumab, Atezolizumab, Avelumab, Nivolumab, Durvalumab, Durvalumab plus Tremelimumab, Cemiplimab) in the first-line treatment of advanced NSCLC. Trials limited to later-line therapy were excluded. Eligible studies required Kaplan-Meier curves for PFS. Twelve RCTs met inclusion criteria. Survival curves were digitized, and individual patient data were reconstructed using the Guyot algorithm. Combined Kaplan-Meier estimates were generated from pooled data, and hazard ratios (HRs) comparing immunotherapy-only vs platinum-based chemotherapy were obtained through two-stage meta-analysis with study-specific weights. Area under the curve (AUC) values were calculated to evaluate temporal changes in treatment effect. Results : Across 12 RCTs, immunotherapy-only regimens showed a clear early disadvantage in PFS. At three months, the hazard ratio for PFS was 2.03 (95% CI 1.77-2.32), indicating a significantly higher risk of progression in the immunotherapy arms. This persisted at six months (HR 1.36, 95% CI 1.18-1.57), but diminished by nine months (HR 1.13) and 12 months (HR 1.08). Over the full follow-up, immunotherapy ultimately outperformed chemotherapy (HR = 0.86, 95% CI 0.74-0.99, p = 0.048), showing a delayed benefit. AUC analysis confirmed an inferior cumulative PFS benefit during the first 6 months, followed by a gradual catch-up. Conclusion : First-line immunotherapy-only treatment in NSCLC shows an early PFS disadvantage relative to chemotherapy, followed by superior long-term outcomes. This pattern underscores the need for early monitoring and optimized combination strategies to prevent early progression while maintaining immunotherapy's durable benefits.