Chemotherapy plus anti-PD-1 or anti-PD-L1 in advanced PD-L1–negative squamous cell lung carcinoma: A systematic review and meta-analysis.

Abstract

e20586 Background: Squamous cell lung carcinoma (sqNSCLC) accounts for 25-30% of all non-small cell lung cancer (NSCLC) cases and is associated with poor prognosis. Although the addition of anti-PD(L)1 immunotherapy to chemotherapy improves survival in all-comers with advanced sqNSCLC, the true benefit of chemotherapy plus anti-PD-(L)1 in patients with advanced PD-L1–negative sqNSCLC is unclear. Methods: We performed a systematic review and meta-analysis of phase 3 randomized clinical trials comparing chemotherapy plus anti-PD-(L)1 to chemotherapy with or without placebo in locally advanced (ineligible for concurrent chemoradiation or surgery) or metastatic PD-L1–negative sqNSCLC. Results: A total of 1,548 patients with advanced PD-L1–negative sqNSCLC from 11 studies were included: IMpower131, RATIONALE 307, ORIENT-12, CameL-Sq, GEMSTONE-302, CheckMate 227 Part 1, KEYNOTE-407, Empower-Lung 3, ASTRUM-004, AK105-302, and POSEIDON.Of these patient, 810 (52%) received chemotherapy plus anti-PD-(L)1 (intervention group), while 738 (48%) received chemotherapy with or without placebo (control group). All included studies used platinum-doublet chemotherapy regimens. Chemotherapy plus anti-PD-(L)1 was associated with an increased probability of overall response rate (risk ratio, 1.36; 95% CI, 1.16-1.60; P < 0.001; Cochran's Q test P-value = 0.25; I² = 24%), increased progression-free survival (PFS; HR, 0.58; 95% CI, 0.48-0.69; P < 0.001; Cochran's Q test P-value = 0.05; I² = 49%), and increased overall survival (HR, 0.81; 95% CI, 0.69-0.96; P = 0.02; Cochran's Q test P-value = 0.24; I² = 24%) compared to chemotherapy, with or without placebo. We observed high inter-study heterogeneity in the PFS meta-analysis, likely attributable to differences in the prevalence of liver metastases at baseline, which is a known poor prognostic factor in this patient population. However, when studies were stratified based on the prevalence of liver metastases at baseline ( < 15% vs. > 15% of patients), the heterogeneity was resolved in the PFS meta-analysis for both subgroups. Conclusions: Our findings support the use of combination anti-PD-(L)1 plus chemotherapy as first-line therapy for patients with advanced PD-L1–negative sqNSCLC. Prospective studies are warranted to determine whether dual checkpoint inhibition, with or without chemotherapy, is superior to anti-PD-(L)1 plus chemotherapy in this population.