Evaluation of gut leakage and bacterial translocation as efficacy biomarkers of immunotherapy in advanced non-small cell lung cancer (NSCLC).

BACKGROUND

Despite the therapeutic advancements achieved through immunotherapy [immune checkpoint inhibitors (ICIs)] in treating advanced non-small cell lung cancer (NSCLC), the majority of patients will experience tumor progression. There is an urgent need for new predictive biomarkers of ICI efficacy in this setting. Our study aims to demonstrate the role of gut leakage, evaluated by plasma citrulline, and bacterial translocation, through blood microbiome assessment, as predictive markers of response to ICIs in advanced NSCLC.

METHODS

We used two independent cohorts (n=89 and n=85) of patients treated with ICIs for advanced NSCLC, with prospective blood citrulline assays at baseline (T0), 1st follow-up (T1) and progression (T2), by ion exchange chromatography. Early use of antibiotics and other demographic data were also collected. Quantification of 16sRNA gene expression and qualitative analysis of the blood microbiome were also performed. We correlated these biomarkers with ICI efficacy.

RESULTS

In the first cohort, blood citrulline levels were available for 75 patients at baseline (T0), with 35 patients with low citrulline level (<28 µM) and 40 patients with high citrulline level (≥28 µM). High baseline citrulline level (T0) was linked to a reduced refractory rate (P=0.001), improved response rate (P=0.001), a higher clinical benefit rate (P=0.009), and better progression-free survival (PFS) and overall survival (OS). Median PFS was 27.8 months in patients with baseline high citrulline level, and 7.5 months in patients with low citrulline level (P=0.04); median OS was 55.9 and 24.17 months (P=0.008). Those results remained consistent in the validation cohort. Responder patients had also lower levels of bacterial 16sRNA in their blood at T0 (P=0.01).

CONCLUSIONS

Our study supports the potential utility of citrulline and quantification of 16sRNA in blood as predictive biomarkers for response to ICIs in treatment of NSCLC.