Chemotherapy Plus Anti-PD-1 or Anti-PD-L1 in Advanced PD-L1-Negative Squamous Cell Lung Carcinoma: A Systematic Review and Meta-Analysis

Nicolas Peruzzo; Gabriel Lenz; Ted Akhiwu; Mariah Bilalaga; Greeshma Nihitha Gaddipati; Nathalia Luisy Farias Müller; Loren Zarpellon; Fernando Venero; Marcelo Corassa; Andrés F Cardona; Joshua E Reuss; Bruna Pellini

doi:10.1016/j.cllc.2025.04.006

Chemotherapy Plus Anti-PD-1 or Anti-PD-L1 in Advanced PD-L1-Negative Squamous Cell Lung Carcinoma: A Systematic Review and Meta-Analysis

Clin Lung Cancer. 2025 May 22:S1525-7304(25)00076-2. doi: 10.1016/j.cllc.2025.04.006. Online ahead of print.

Affiliations

¹ Department of Medicine, MedStar Union Memorial Hospital, Baltimore, MD; Georgetown University, Washington, DC. Electronic address: Nicolas.DaCostaPeruzzo@gunet.georgetown.edu.
² Department of Medicine, Hospital Regional Terezinha Gaio Basso, São Miguel Do Oeste, SC, Brazil.
³ Department of Medicine, MedStar Union Memorial Hospital, Baltimore, MD; Georgetown University, Washington, DC.
⁴ School of Medicine, Universidade do Sul de Santa Catarina (Unisul), Palhoça, SC, Brazil.
⁵ Complexo Hospitalar de Niterói, Niterói, RJ, Brazil.
⁶ Department of Oncology, Hospital Moinhos de Vento, Porto Alegre, RS, Brazil.
⁷ Thoracic Oncology Unit, Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil.
⁸ Thoracic Oncology Unit and Institute of Research and Education, Luis Carlos Sarmiento Angulo Cancer Treatment and Research Center (CTIC), Bogota, Colombia.
⁹ Georgetown University, Washington, DC.
¹⁰ Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL; Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL.

PMID: 40494752
DOI: 10.1016/j.cllc.2025.04.006

Abstract

Introduction: Squamous cell lung carcinoma (sqNSCLC) accounts for 25% to 30% of all non-small cell lung cancer (NSCLC) cases and is associated with a worse prognosis. Although immune checkpoint inhibitors improve outcomes in advanced sqNSCLC, the true benefit of chemotherapy plus anti-PD-(L)1 in patients with advanced PD-L1-negative sqNSCLC is unclear.

Material and methods: We performed a systematic review and meta-analysis of 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 1548 patients with advanced PD-L1-negative sqNSCLC from 11 studies were included. Of these, 810 patients (52%) received chemotherapy plus anti-PD-(L)1 (intervention group), while 738 patients (48%) received chemotherapy with or without placebo (control group). All included studies were phase 3 trials and used platinum-doublet chemotherapy regimens. Chemotherapy plus anti-PD-(L)1 was associated with increased probability of overall response rate (risk ratio, 1.36; 95% CI, 1.16-1.60; P = .0001), increased progression-free survival (HR = 0.58; 95% CI, 0.48-0.69; P < .00001), and increased overall survival (HR = 0.81; 95% CI, 0.69-0.96; P = .02) compared to chemotherapy, with or without placebo.

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 patient population.

Keywords: Chemotherapy; Immune checkpoint inhibitor; Immunotherapy; Lung cancer; Non-small cell lung cancer; PD-1 inhibitor; PD-L1 inhibitor; Squamous cell lung carcinoma.