Efficacy of immune checkpoint inhibitors (ICIs) in PD-L1 negative Non-Small Cell Lung Cancer (NSCLC) – A meta-analysis based on reconstructed individual participant data

Background: despite advancements in NSCLC treatment, PD-L1 negative patients remain a therapeutic challenge. This meta-analysis evaluates the efficacy of immune checkpoint inhibitors (ICIs) and their combinations in PD-L1 negative NSCLC. Materials and Methods: Major databases (PubMed, Embase, Cochrane Library) were searched using terms such as "PD-L1 negative," "NSCLC," "chemotherapy," and "immunotherapy." Phase I-III clinical trials comparing ICIsbased treatments in PD-L1 negative NSCLC were included, excluding non-peer-reviewed studies. Data extraction followed PRISMA guidelines, with independent review by two researchers. Random-effects models were used to pool data, assessing overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: This analysis included 43 trials with 7039 patients. Immunotherapy alone yielded an ORR of 11 %, while immunotherapy combined with chemotherapy achieved the highest ORR (48 %). Combination immunotherapy alone and chemotherapy alone showed comparable ORRs (23 % vs. 22 %). Median PFS was 2.3 months for immunotherapy alone, 6.8 months for immunotherapy plus chemotherapy, and 5.7 months for combo immunotherapy. OS was 10.1 months for immunotherapy alone, 15.6 months for immunotherapy plus chemotherapy, and 17.6 months for combo immunotherapy. Network meta-analysis highlighted pembrolizumab with platinumbased chemotherapy as the most effective, achieving the highest ORR and a 45 % PFS improvement compared to chemotherapy alone. Conclusions: Combination therapies, particularly ICIs with chemotherapy, significantly improve ORR, PFS, and OS in PD-L1 negative NSCLC, underscoring their potential as optimal strategies for this population.