Impact of adding immune checkpoint inhibitors to standard therapies in non-small cell lung cancer: A systematic review of efficacy outcomes

Abstract

Introduction

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 85 % of all cases. Although immune checkpoint inhibitors (ICIs) have revolutionized NSCLC treatment, the extent to which they improve survival when combined with standard therapies, rather than used alone, remains unclear. Here, we systematically review published clinical trials evaluating ICIs combined with other standard systemic therapies versus each strategy alone. Methods: A systematic review was conducted using MEDLINE (via PubMed) and EMBASE, following PRISMA guidelines. Randomized controlled trials published until December 2024 that studied the efficacy of immunotherapy regimens combining approved ICIs and other systemic therapies in NSCLC were included. Results We included 36 RCTs with a combined 24,495 participants. Most were open-label (n = 21, 58.3 %), while the remaining studies were double-blinded (n = 15, 41.7 %). Most studies were phase 3 trials (n = 33, 91.7 %) and only three trials were phase 2 (8.3 %). Included trials utilized platinum-doublet chemotherapy as the backbone, with some also incorporating bevacizumab and/or additional immunotherapy. In the included studies, combining immunotherapy with other standard therapies significantly improved survival outcomes compared to either strategy alone. These benefits were consistent across histological subtypes, PD-L1 expression levels, and disease stage. However, the efficacy of this combined approach was limited in EGFR-mutated NSCLC after progression on tyrosine kinase inhibitors. Conclusions: By synthesizing existing evidence from RCTs, this systematic review demonstrates the benefits and limitations of combining immune checkpoint inhibitors with other systemic treatments, clarifying which clinical situations may benefit the most from a combined approach.