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: Twelve trials including 2,084 patients were analyzed. Chemotherapy plus anti–PD-(L)1 improved ORR (RR, 1.61; 95% CI, 1.26–2.05; p = 0.0001), PFS (HR, 0.68; 95% CI, 0.60–0.77; p < 0.00001), and OS (HR, 0.81; 95% CI, 0.70–0.94; p = 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.