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PURPOSE: Recent evidence has shown that higher tumor mutational burden strongly correlates with an increased risk of immune-related adverse events (irAEs). By using an integrated multiomics approach, we further studied the association between relevant tumor immune microenvironment (TIME) features and irAEs. METHODS: Leveraging the US Food and Drug Administration Adverse Event Reporting System, we extracted cases of suspected irAEs to calculate the reporting odds ratios (RORs) of irAEs for cancers treated with immune checkpoint inhibitors (ICIs). TIME features for 32 cancer types were calculated on the basis of the cancer genomic atlas cohorts and indirectly correlated with each cancer's ROR for irAEs. A separate ICI-treated cohort of non–small-cell lung cancer (NSCLC) was used to evaluate the correlation between tissue-based immune markers (CD8+, PD-1/L1+, FOXP3+, tumor-infiltrating lymphocytes [TILs]) and irAE occurrence. RESULTS: The analysis of 32 cancers and 33 TIME features demonstrated a significant association between irAE RORs and the median number of base insertions and deletions (INDEL), neoantigens (r = 0.72), single-nucleotide variant neoantigens (r = 0.67), and CD8+ T-cell fraction (r = 0.51). A bivariate model using the median number of INDEL neoantigens and CD8 T-cell fraction had the highest accuracy in predicting RORs (adjusted r2 = 0.52, P =.002). Immunoprofile assessment of 156 patients with NSCLC revealed a strong trend for higher baseline median CD8+ T cells within patients' tumors who experienced any grade irAEs. Using machine learning, an expanded ICI-treated NSCLC cohort (n = 378) further showed a treatment duration–independent association of an increased proportion of high TIL (>median) in patients with irAEs (59.7% v 44%, P =.005). This was confirmed by using the Fine-Gray competing risk approach, demonstrating higher baseline TIL density (>median) associated with a higher cumulative incidence of irAEs (P =.028). CONCLUSION: Our findings highlight a potential role for TIME features, specifically INDEL neoantigens and baseline-immune infiltration, in enabling optimal irAE risk stratification of patients. [ABSTRACT FROM AUTHOR]

Introduction: Immune checkpoint inhibitors (ICIs) became the standard of care for several solid tumors. A limited fraction of patients (pts) achieves a long-term benefit. Plasmatic and intracellular cholesterol levels have emerged as promising biomarkers. The aim of the present study was to determine whether cholesterol efflux capacity (CEC), mediated by serum transporters (ABCA1 and ABCG1) and passive diffusion (PD), impacts on clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs. Material and methods: We retrospectively enrolled advanced NSCLC and mRCC pts consecutively treated with ICIs between October 2013 and October 2018. CEC and cholesterol loading capacity (CLC) were assessed by well-established specific cell models. As primary endpoint, CEC, PD and CLC were correlated with overall survival (OS) while the effects of these parameters on progression-free survival (PFS) and clinical benefit (CB), defined as complete/partial response or stable disease, represented secondary endpoints. Results: NSCLC accounted for 94.2% of 70 enrolled cases, and serum sample suitable for CEC and PD determination was available in 68. Blood cholesterol and serum ABCA1, ABCG1, PD and CLC were associated with outcomes (OS, PFS and CB) at univariate analysis. At the multivariate analysis, only PD confirmed its positive prognostic value in terms of OS, PFS and CB. Conclusion: The favorable impact of cholesterol PD on clinical outcome might reflect its main conformation in mature HDL particles which potentially shape an inflamed context, ultimately promoting ICI efficacy. Further prospective studies are needed to support our findings and uncover targetable pathways. [ABSTRACT FROM AUTHOR]

Background Real-life spectrum and survival implications of immune-related adverse events (irAEs) in patients treated with extended interval dosing (ED) immune checkpoint inhibitors (ICIs) are unknown. Methods Characteristics of 812 consecutive solid cancer patients who received at least 1 cycle of ED monotherapy (pembrolizumab 400 mg Q6W or nivolumab 480 mg Q4W) after switching from canonical interval dosing (CD; pembrolizumab 200 mg Q3W or nivolumab 240 mg Q2W) or treated upfront with ED were retrieved. The primary objective was to compare irAEs patterns within the same population (before and after switch to ED). irAEs spectrum in patients treated upfront with ED and association between irAEs and overall survival were also described. Results A total of 550 (68%) patients started ICIs with CD and switched to ED. During CD, 225 (41%) patients developed any grade and 17 (3%) G3 or G4 irAEs; after switching to ED, any grade and G3 or G4 irAEs were experienced by 155 (36%) and 20 (5%) patients. Switching to ED was associated with a lower probability of any grade irAEs (adjusted odds ratio [aOR] = 0.83, 95% confidence interval [CI] = 0.64 to 0.99; P  = .047), whereas no difference for G3 or G4 events was noted (aOR = 1.55, 95% CI = 0.81 to 2.94; P  = .18). Among patients who started upfront with ED (n = 232, 32%), 107 (41%) developed any grade and 14 (5%) G3 or G4 irAEs during ED. Patients with irAEs during ED had improved overall survival (adjusted hazard ratio [aHR] = 0.53, 95% CI = 0.34 to 0.82; P  = .004 after switching; aHR = 0.57, 95% CI = 0.35 to 0.93; P  = .025 upfront). Conclusions Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials. [ABSTRACT FROM AUTHOR]