Efficacy and safety of first-line immune checkpoint inhibitors in patients with PD-L1 <1% metastatic non-small-cell lung cancer - implications for daily clinical practice.

[INTRODUCTION] Patients with advanced/metastatic non-small cell lung cancer (NSCLC) and programmed death ligand-1 (PD-L1) tumor cell expression <1% are difficult to treat, and an optimal treatment strategy for these patients is yet to be defined.

[AREAS COVERED] There have been significant advances in immunotherapy for NSCLC in the past decade. This article aims to answer the question of the optimal first-line treatment for patients with advanced/metastatic NSCLC and PD-L1 expression <1%, based on efficacy and safety data from phase 3 studies (published up to 31 December 2024).

[EXPERT OPINION] Current evidence from subgroup and exploratory analyses of phase 3 studies and indirect comparisons suggest that PD-1/PD-L1 inhibitors (with or without chemotherapy) combined with a cytotoxic T lymphocyte-associated protein-4 inhibitor or antiangiogenic therapy may provide the highest progression-free survival (PFS) and overall survival (OS) benefits in patients with newly diagnosed advanced/metastatic NSCLC and PD-L1 tumor cell expression <1%. Of these regimens, dual immunotherapy with nivolumab and ipilimumab combined with chemotherapy appeared to offer some advantages in terms of OS, PFS, objective response rates, and duration of response, relative to other treatment approaches. Well-designed, comparative studies are warranted to more definitively determine the best first-line treatment for these patients.