Yiqi Jiedu granules plus first-line anti-PD-1 immunotherapy prolongs overall survival in PD-L1-high advanced non-small cell lung cancer: a randomized, double-blind, placebo-controlled trial

Anti-PD-1 immunotherapy is a standard initial treatment for advanced non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression, yet its long-term benefit remains limited. Prior studies suggest that Yiqi Jiedu granules (YJG) provide clinical benefits in NSCLC. The study aimed to assess the long-term efficacy and safety of YJG in combination with first-line anti-PD-1 immunotherapy for advanced NSCLC and to explore potential associations. This randomized, double-blind, placebo-controlled trial enrolled 190 patients with PD-L1-high advanced NSCLC at Longhua Hospital from April 2021 to December 2023. Patients were randomized to receive anti-PD-1 therapy plus either YJG or placebo granules for a maximum of 35 cycles or until disease progression or intolerable toxicity. The primary endpoint was overall survival (OS). After a median follow-up of 25.7 months, YJG plus anti-PD-1 significantly prolonged OS compared to placebo plus anti-PD-1. The 2-year survival rates were 67.0% and 41.1%, respectively. Median progression-free survival (PFS) was longer in the YJG plus anti-PD-1 group than in the placebo group, although the difference was not statistically significant. Adverse events were comparable, and no grade 4–5 events occurred. Exploratory analyses showed that YJG plus anti-PD-1 was associated with lower IL-6 levels, higher peripheral CD8 + T-cell counts, and better quality of life at week 48. Metabolomic profiling further suggested nominally lower serum asparagine levels and potential alterations in tricarboxylic acid cycle-related metabolism. Adding YJG to first-line anti-PD-1 immunotherapy improved OS with favorable safety in PD-L1-high advanced NSCLC, supporting this combination as a promising adjunctive treatment. Registered on January 10, 2021 (registration number: ChiCTR2100041920).