Anti–PD-(L)1 plus chemotherapy in advanced PD-L1–negative nonsquamous non-small cell lung cancer: a systematic review and meta-analysis

INTRODUCTION: The benefit of adding anti-PD-(L)1 to chemotherapy in untreated advanced PD-L1-negative nonsquamous non-small cell lung cancer (nsqNSCLC) remains unclear. We conducted a systematic review and meta-analysis to determine whether adding anti-PD-(L)1 therapy to chemotherapy improves outcomes in this population. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched in September 2025. Eligible studies were phase III randomized clinical trials comparing frontline chemotherapy plus anti-PD-1 or anti-PD-L1 therapy versus chemotherapy with or without placebo in advanced PD-L1-negative nsqNSCLC. Risk of bias was assessed using the Risk of Bias 2 tool. Random-effects models were used to pool hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) and risk ratios (RRs) for overall response rate (ORR). RESULTS: = 0.006). CONCLUSIONS: Chemotherapy plus anti-PD-(L)1 therapy may be an effective first-line option for advanced PD-L1-negative nsqNSCLC, although the evidence is limited by subgroup-level data and between-study heterogeneity. Protocol registration: PROSPERO, www.crd.york.ac.uk/prospero, identifier 1371679.