The gut microbiome (GM) plays an important role in shaping systemic immune responses and influences immune checkpoint inhibitor (ICI) efficacy. Antibiotics worsen clinical outcomes in patients receiving ICI. However, whether GM profiling and baseline antibiotic can be a biomarker of ICI efficacy in advanced non–small cell lung cancer (NSCLC) remains unknown. We prospectively collected baseline (pre-ICI) fecal samples and clinical data of 70 Japanese patients suffering from advanced NSCLC and treated them with anti–PD-1/PD-L1 antibodies as a first-line or treatment-refractory therapy. We performed 16S rRNA V3–V4 sequencing of gene amplicons of fecal samples, and bacteria diversity and differential abundance analysis was performed. The clinical endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE). ORR was 34%, and median PFS and OS were 5.2 and 16.2 months, respectively. Patients who received pre-ICI antibiotic had lower alpha diversity at baseline and underrepresentation of Ruminococcaceae UCG 13 and Agathobacter. When analyzing antibiotic-free patients, alpha diversity correlated with OS. In addition, Ruminococcaceae UCG 13 and Agathobacter were enriched in patients with favorable ORR and PFS >6 months. Ruminococcaceae UCG 13 was enriched in patients with OS >12 months. GM differences were observed between patients who experienced low- versus high-grade irAE. We demonstrated the negative influence of antibiotic on the GM composition and identified the bacteria repertoire in patients experiencing favorable responses to ICI.

Gut microbiota serves an important role in shaping systemic immune responses. Antibiotics cause changes in the gut microbiota that may influence the efficacy of cancer immunotherapy. In the present study, a retrospective analysis of the data from 90 patients treated with nivolumab for non‑small cell lung cancer (NSCLC) was conducted. A total of 13 patients were treated with antibiotics prior to nivolumab therapy. The median progression‑free survival time in patients treated with antibiotics was 1.2 months [95% confidence interval (CI), 0.5‑5.8], while the time for patients who were not treated with antibiotics was 4.4 months (95% CI, 2.5‑7.4). The median overall survival time in patients treated with antibiotics was 8.8 months, while it was not reached in those not treated with antibiotics, respectively. The differences between the survival curves with regard to PFS and OS were statistically significant (P=0.04 and P=0.037, respectively). However, in multivariate analysis, no statistically significant association was indicated between survival and prior antibiotic use, although a certain trend concerning the negative influence of antibiotic use was conveyed.

Background: Based on several phase III studies, immune checkpoint inhibitors (ICIs) are essential and promising drugs for the treatment of non‐small cell lung cancer (NSCLC). However, in patients previously treated with ICI, the efficacy and safety of rechallenging the same or another type of ICI inhibitor remain unclear. Moreover, clinical data about the efficacy of switching the administration of anti‐programmed death‐1 (PD‐1) antibodies (e.g. nivolumab, pembrolizumab) and anti‐programmed death‐ligand 1 (PD‐L1) antibodies (e.g. atezolizumab) as ICI rechallenge are limited. Thus, the current study aimed to evaluate the efficacy and safety of such treatment strategy in NSCLC patients.Methods: We retrospectively reviewed the medical records of 17 patients with advanced or recurrent NSCLC who received both anti‐PD‐1 and anti‐PD‐L1 antibodies during their clinical courses.Results: Among the 17 patients, one (5.9%) and nine (52.9%) achieved partial response and stable disease, respectively, after ICI rechallenge. The median progression‐free survival of ICI rechallenge in these patients was 4.0 (range: 0.4–8.0) months, and the median overall survival from the start of the initial ICI was 31.0 (range: 7.6–46.8) months. Of the 10 patients who developed immune‐related adverse events (irAEs) during the first ICI treatment, five presented with these events after the readministration of ICI. Among them, four experienced relapsed irAEs and two patients had pneumonitis, which is a grade 3 or higher irAE. Almost all irAEs during the rechallenge treatment were manageable.Conclusions: Switching the administration of anti‐PD‐1 and anti‐PD‐L1 antibodies as ICI rechallenge could be a treatment option for some NSCLC patients.Key points: • Significant findings of the study: In this study, switching the administration of anti‐PD‐1 and anti‐PD‐L1 antibodies as ICI rechallenge could be an effective and safe treatment option for some patients with advanced or recurrent NSCLC.• What this study adds: Switching the administration of ICI may increase the efficacy of readministration. However, the mechanism is unknown. Thus, further accumulation of cases is required, and extensive investigations must be conducted to elucidate the mechanism and benefits of such treatment.

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.