Abstract
Advanced non-small cell lung cancer (NSCLC) presents significant therapeutic challenges, with limited long-term survival using conventional chemotherapy. This review aims to evaluate the efficacy and pulmonary safety of dual immunotherapy (nivolumab, ipilimumab, tremelimumab, and durvalumab) plus chemotherapy compared with standard chemotherapy in advanced NSCLC. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-based systematic review searched PubMed, Cochrane Library, and ScienceDirect (from inception till June 2025) using MeSH/free-text terms for "NSCLC," "dual immunotherapy," "checkpoint inhibitor," "chemotherapy," and "pulmonary outcomes." Two reviewers screened studies, extracted data, and assessed risk of bias with Cochrane RoB 2.0. Phase II/III randomized controlled trials (RCTs) comparing dual immunotherapy plus chemotherapy versus chemotherapy were narratively synthesized for survival and lung-related outcomes due to endpoint heterogeneity. Nine studies, including 7,271 participants with advanced or metastatic NSCLC, were analyzed. Dual immunotherapy plus chemotherapy consistently improved outcomes compared with chemotherapy alone. Median overall survival (OS) increased to approximately 15.8 months versus 11.0 months, with hazard ratios (HRs) ranging from 0.66 to 0.77. Progression-free survival (PFS) and response rates (HRs) were also higher, with pooled PFS HRs of 0.67-0.72 and longer duration of response. Pulmonary safety was acceptable, with immune-related pneumonitis reported in 2%-5% of patients, mostly low-grade and responsive to corticosteroids. Infection rates were comparable between groups, primarily involving mild respiratory infections typical of chemotherapy exposure. Survival benefits were observed across PD-L1 strata, tumor histologies, and high-risk molecular subgroups such as KRAS, STK11, and KEAP1, and in patients with brain metastases. Dual immunotherapy plus chemotherapy provides sustained survival benefit with manageable toxicity. Dual immunotherapy plus chemotherapy significantly improves survival and response in advanced NSCLC with acceptable pulmonary safety, supporting its adoption as a first-line standard of care.