Effects of Bojungikki-Tang on immune response and clinical outcomes in NSCLC patients receiving immune checkpoint inhibitors: a randomized pilot study

Background: Cancer immunotherapy with immune checkpoint inhibitors (ICIs) is a pivotal treatment for cancers, including non-small cell lung cancer (NSCLC). ICIs are often associated with adverse events (AEs), including immune-related AEs (irAEs). Bojungikki-tang (BJIKT), a traditional herbal medicine, has immunomodulatory properties and may alleviate fatigue and inflammation in patients with advanced cancer.In this multicenter, randomized, placebo-controlled pilot trial, we evaluated the safety and potential effects of BJIKT on fatigue, muscle loss, and immune response in patients with advanced NSCLC undergoing atezolizumab monotherapy. Methods: Twenty-eight patients were randomized to either the BJIKT (n = 14) or placebo (n = 14) groups. Primary outcomes included AEs and irAEs, while secondary outcomes assessed fatigue and muscle loss. Exploratory immune profiling was performed on peripheral blood mononuclear cells and plasma samples from a subset of patients (BJIKT n = 12, placebo n = 7). Results: AEs occurred in 53.57% of participants, with 64.29% in the BJIKT group (23 events, including one severe irAE) and 42.86% in the placebo group (12 events). Most AEs were mild or moderate and resolved by the study’s completion. The objective response rate was 16.67% in the BJIKT group and 8.33% in the placebo group, while the disease control rate was 41.67% and 25.0%, respectively; however, these differences were not statistically significant. BJIKT showed non-significant trends toward reducing fatigue and mitigating muscle-related symptoms. Immune profiling suggested that BJIKT may activated CD4 + T cells, increased the proportion of CD3 + CD4 + cells, and enhanced T cell function while reducing immune exhaustion. Notably, a statistically significant decrease in PD-1 + CD8 + T cells was observed, while the reduction in PD-1 + CD4 + T cells did not reach significance. Additionally, a significant increase in natural killer cell counts was observed in the BJIKT group, suggesting a possible improvement in innate immune surveillance. These exploratory immune trends, although largely not statistically significant, may point to potential synergy with ICIs in enhancing anti-tumor immunity in advanced NSCLC. Conclusions: BJIKT may enhance immune response and potentially improve clinical outcomes in patients with NSCLC receiving immune checkpoint inhibitor therapy; however, these exploratory and mostly non-significant findings warrant cautious interpretation and further validation in larger trials. Trial registrations: The trial was registered with the Clinical Research Information Service (https://cris.nih.go.kr/cris; identifier number: KCT0006689) in October 2021.