Selecting optimal immunotherapy based on inflammation in stage IV PD-L1 ≥50% gene mutation-negative non-small cell lung cancer: pembrolizumab monotherapy versus combination chemoimmunotherapy

Background: Systemic inflammation may reduce the efficacy of immunotherapy. For advanced non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) expression ≥50% and without driver gene mutations, both immunotherapy monotherapy and combination chemoimmunotherapy are considered standard treatment options; however, it remains unclear which treatment is more appropriate depending on the degree of inflammation. This study investigated the impact of inflammation on the effectiveness of pembrolizumab monotherapy versus combination chemoimmunotherapy. Methods: In this retrospective multicenter cohort study, we included patients with advanced NSCLC from 13 Japanese institutions who received pembrolizumab monotherapy or combination chemoimmunotherapy as first-line treatment between March 2017 and October 2021. The systemic immune-inflammation index (SII) was used as an inflammation marker, with a cutoff value of 1,444 based on previous data. Patients were classified into high (SII ≥1,444) and low (SII <1,444) inflammation groups. Results: This study included 347 patients with advanced NSCLC: 212 (61.1%) in the pembrolizumab group and 135 (38.9%) in the combination chemoimmunotherapy group. In the high inflammation population, there were no significant differences in progression-free survival (PFS) and overall survival (OS) between the pembrolizumab and combination chemoimmunotherapy groups. In the low inflammation population, PFS and OS were significantly improved in the combination chemoimmunotherapy group compared to the pembrolizumab group [median PFS: 8.8 vs. 16.0 months, hazard ratio (HR) =0.69, P=0.04; median OS: 29.4 vs. not reached (NR), HR =0.55, P=0.007]. Conclusions: In patients with advanced, driver gene mutation-negative NSCLC, high PD-L1 expression (≥50%), and low systemic inflammation, combination chemoimmunotherapy significantly improved PFS and OS compared to pembrolizumab monotherapy.