Cancer Cachexia among Patients with Advanced Non-Small-Cell Lung Cancer on Immunotherapy: An Observational Study with Exploratory Gut Microbiota Analysis

SIMPLE SUMMARY: Immunotherapy has revolutionized the therapeutic options for patients living with non-small-cell lung cancer (NSCLC). Despite the unprecedented results achieved through immunotherapy, a low body mass index, which is referred to as cachexia, and the bacterial composition of the gut microbiota are known factors associated with resistance. In this paper, we enrolled 113 Japanese patients with NSCLC and demonstrated that cachexia was associated with poor outcomes. Moreover, microbiota sequencing revealed that patients without cachexia had abundant bacteria that correlated with a beneficial outcome. Altogether, our results demonstrated an association between the gut microbiota and cachexia. This study provides a rationale to launch clinical trials on the outcome of shifting the microbiota composition of patients with cachexia that are receiving immunotherapy. ABSTRACT: Cancer cachexia exerts a negative clinical influence on patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI). The prognostic impact of body weight change during ICI treatment remains unknown. The gut microbiota (GM) is a key contributor to the response to ICI therapy in cancer patients. However, the association between cancer cachexia and GM and their association with the response to ICIs remains unexplored. This study examined the association of cancer cachexia with GM composition and assessed the impact of GM on clinical outcomes in patients with NSCLC treated with ICIs. In this observational, prospective study, which included 113 Japanese patients with advanced NSCLC treated with ICIs, the prevalence of cachexia was 50.4% (57/113). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the cachexia group than in the non-cachexia group (4.3 vs. 11.6 months (p = 0.003) and 12.0 months vs. not reached (p = 0.02), respectively). A multivariable analysis revealed that baseline cachexia was independently associated with a shorter PFS. Moreover, a gain in body weight from the baseline (reversible cachexia) was associated with a significantly longer PFS and OS compared to irreversible cachexia. Microbiome profiling with 16S rRNA analysis revealed that the cachexia group presented an overrepresentation of the commensal bacteria, Escherichia-Shigella and Hungatella, while the non-cachexia group had a preponderance of Anaerostipes, Blautia, and Eubacterium ventriosum. Anaerostipes and E. ventriosum were associated with longer PFS and OS. Moreover, a cachexia status correlated with the systemic inflammatory marker-derived-neutrophil-to-lymphocytes ratio (dNLR) and Lung Immune Prognostic Index (LIPI) indexes. Our study demonstrates that cachexia and longitudinal bodyweight change have a prognostic impact on patients with advanced NSCLC treated with ICI therapy. Moreover, our study demonstrates that bacteria associated with ICI resistance are also linked to cachexia. Targeted microbiota interventions may represent a new type of treatment to overcome cachexia in patients with NSCLC.