Metabolic tumor burden assessed by [18F] FDG - PET CT scan as a predictive biomarker for immune checkpoint blockers in advanced NSCLC and its biological correlates: a multicentric study.

Introduction: Only a proportion of patients with advanced non-small cell lung cancer (NSCLC) benefit from immune checkpoint blockers (ICBs). Biomarkers other than PD-L1 expression biomarkers are required to guide treatment strategy with ICB as monotherapy or in combination, especially in high PDL1 NSCLC. This study aimed to explore metabolic tumor volume MTV as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F FDG-PET-CT), and understand its biological meaning in patients with NSCLC exposed to chemotherapy and or ICBs.Materials and methods: In this multicentric retrospective cohort study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment with ICBs, chemotherapy plus ICBs or chemotherapy alone were enrolled in 12 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42 percent SUVmax threshold. Survival was analyzed according to high tMTV (greater than or equal to median). Cytokines, T cell senescence, RNA sequencing and gut microbiota analyses were performed in three independent monocentric cohorts.Results: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. No correlation was found between PD-L1 expression and tMTV. Median overall survival OS for patients with high tMTV treated with ICBs was 11.4 months 95 percent CI 8.4 - 19.1) vs 33.1 months (95 percent CI 22.6 - NR, P = lower than 0.0001) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P = 0.099). In patients with PD-L1 greater than or equal to 1 percent NSCLC and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months, p = 0.026), while no survival differences observed in low tMTV group. High tMTV correlated with a specific inflammatory signals (elevated serum neutrophils, CRP, CCL23, LIF and TGF-alpha), while no correlation was found with gene alterations or TMB, with T cell senescence and with intestinal microbiota. At the lesion level, high MTV correlated with suppressed expression of immune response related pathways and reduced immune infiltrate.Conclusion: Our analysis indicates high tTMV is linked to a negative immune environment. tTMV is therefore an independent biomarker to predict ICBs monotherapy benefit, and may serve to select the best upfront strategy in patients with PD-L1 high advanced NSCLC.