Background: Non-small cell lung cancer (NSCLC) exhibits low survival rates. Although immune checkpoint inhibitors (ICIs) have become first-line treatment for NSCLC, their limited response to ICI monotherapy has led to exploration of combination treatments. However, the high incidence of treatment-related adverse events associated with conventional drug combinations has highlighted the need for alternative herbal therapy. Bojungikki-tang (BJIKT), a traditional herbal medicine, has been used to treat gastrointestinal disorders and enhance immune function. Our preclinical studies have demonstrated that BJIKT combined with anti-PD-1 or anti-PD-L1 antibodies exhibits significant efficacy in suppressing tumor growth by modulating the immunosuppressive tumor microenvironment. Building on these preclinical findings, this study aims to evaluate the efficacy and safety of BJIKT with pembrolizumab combination therapy compared to pembrolizumab monotherapy in advanced NSCLC patients. Methods: 70 individuals with stage IV NSCLC scheduled for first-line pembrolizumab monotherapy will be randomly assigned to intervention or control groups. The primary outcome will be progression-free survival, with secondary outcomes including disease control rate, overall survival, and quality of life assessment. Adverse events will be monitored for safety. This study will explore the synergistic mechanism of combinatorial therapy using immune profiling and multi-omics analysis, and the possibility for personalized integrative therapy based on cold-heat syndrome differentiation (SD) types in East Asian medicine. Discussion: This study will provide novel evidence regarding survival outcomes, quality of life, and safety profiles of combined ICI and BJIKT therapy for advanced NSCLC. The exploratory data will contribute to tailoring treatments to immune-based SD types in NSCLC patients.

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) is a major treatment option for several types of cancer, including non-small cell lung cancer (NSCLC). The proposed study aims to investigate the safety and efficacy of Bojungikki-tang (BJIKT) therapy (an herbal medicine) in patients with advanced NSCLC treated with ICIs. This multicenter, randomized, placebo-controlled pilot study will be performed at three academic hospitals. Thirty patients with advanced NSCLC, undergoing atezolizumab monotherapy as second- and subsequent-line treatment, will be recruited and randomly assigned to either BJIKT treatment (atezolizumab + BJIKT) or placebo (atezolizumab + placebo). The primary and secondary outcomes are the incidence of adverse events (AEs), including immune- related AEs (irAEs) and non-immune-related AEs (non-irAEs); and early termination rate, withdrawal period, symptom improvement of fatigue, and skeletal muscle loss, respectively. The exploratory outcomes are patient objective response rate and immune profile. This is an ongoing trial. Recruitment started on 25 March 2022 and is expected to be completed by 30 June 2023. This study will provide basic evidence for the safety profiles, including irAEs, of herbal medicine in patients with advanced NSCLC treated with ICIs.

Circulating cell-free DNA (cfDNA) sequencing offers a minimally invasive approach for profiling tumor genomes, but detecting copy number alterations (CNAs) from cfDNA whole-exome sequencing (WES) remains technically challenging due to noise and guanine–cytosine (GC)-related bias. Building upon our previous study that characterized read count patterns in cfDNA WES data, we developed and evaluated an advanced pipeline for robust CNA detection in patients with advanced non-small cell lung cancer (NSCLC). Read count signals showed strong correlation with GC content, and applying locally estimated scatterplot smoothing (LOESS)-based GC bias correction effectively reduced false positives and improved CNA detection. The resulting cfDNA CNA profiles were reproducible within patients and showed strong concordance with The Cancer Genome Atlas (TCGA) tissue-level patterns for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These findings demonstrate that cfDNA WES, when combined with appropriate bias correction, can serve as a practical and minimally invasive alternative for genomic characterization of NSCLC.