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

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.

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).

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).

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.