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

e20580 Background: Nonsquamous non-small cell lung cancer (nsqNSCLC) accounts for approximately 70–80% of all non-small cell lung cancer cases. Although immune checkpoint inhibitors improve outcomes in advanced nsqNSCLC, the true benefit of adding anti–PD-(L)1 to chemotherapy in patients with advanced PD-L1–negative nsqNSCLC remains unclear. Methods: We conducted a systematic review and meta-analysis of phase 3 randomized clinical trials comparing chemotherapy plus anti–PD-(L)1 versus chemotherapy with or without placebo in untreated, locally advanced (ineligible for concurrent chemoradiation or surgery) or metastatic PD-L1–negative nsqNSCLC. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were used as endpoints. Heterogeneity was assessed using the Cochran Q test (significant vs. nonsignificant) and the I² statistic (low, moderate, substantial, or considerable). Risk of bias was evaluated using RoB 2 and categorized as low, moderate, or high. Results: A total of 2,084 patients with advanced PD-L1–negative nsqNSCLC from 12 phase 3 randomized clinical trials were included: CameL, CheckMate 227 part 1, CheckMate 227 part 2, DOMAJOR, EMPOWER-Lung 3, GEMSTONE-302, IMpower130, IMpower132, KEYNOTE-189, ORIENT-11, POSEIDON, and RATIONALE-304. Of these, 1,196 (57%) received chemotherapy plus anti–PD-(L)1 (intervention arm), while 888 (43%) received chemotherapy with or without placebo (control arm). All included studies used platinum-doublet chemotherapy regimens. Chemotherapy plus anti–PD-(L)1 was associated with a higher probability of ORR (risk ratio, 1.61; 95% CI 1.26–2.05; P = 0.0001), improved PFS (HR 0.68, 95% CI 0.60–0.77; P < 0.00001), and improved OS (HR 0.81, 95% CI 0.70–0.94; P = 0.006) compared with chemotherapy with or without placebo. Moderate inter-study heterogeneity was observed in the OS meta-analysis, with a significant Cochran Q test. A post hoc sensitivity analysis of OS excluding RATIONALE-304, which included a disproportionately high number of never-smokers, demonstrated low and nonsignificant heterogeneity. Another post hoc sensitivity analysis excluding the two studies with a high overall risk of bias (IMpower130 and IMpower132) showed a statistically significant improvement in OS with chemotherapy plus anti–PD-(L)1 (HR 0.81, 95% CI 0.72–0.92; P = 0.001), further supporting the robustness of the survival benefit compared with chemotherapy with or without placebo. Conclusions: These findings support the use of anti–PD-(L)1 plus chemotherapy as first-line therapy for patients with advanced PD-L1–negative nsqNSCLC. Prospective investigation is warranted to determine whether dual checkpoint inhibition, with or without chemotherapy, is superior to anti–PD-(L)1 plus chemotherapy in this patient population.