Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis.

AIMS: The risk and incidence of cardiovascular (CV) immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) in cancer patients remain unknown. METHODS AND RESULTS: We systematically reviewed all randomized clinical trials (RCTs) including at least one ICI-containing arm and available CV adverse event (CVAE) data in cancer patients in the ClinicalTrials.gov registry, Medline, and the Cochrane CENTRAL Register of Controlled Trials, up to 31 August 2020 (CRD42020165672). The primary outcome was the summary risk of 16 different CVAEs associated with ICI exposure vs. controls (placebo and non-placebo) in RCTs. CVAEs with an increased risk associated with ICI exposure were considered as CV irAEs. Summary incidences of CV irAEs identified in our primary outcome analyses were computed using all RCTs including at least one ICI-containing arm. We used a random-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% confidence intervals (CIs) and logit transformation and inverse variance weighting to compute summary incidences. Sixty-three unique RCTs with at least one ICI-containing arm (32 518 patients) were retrieved, among which 48 (29 592 patients) had a control arm. Among the 16 CVAEs studied, ICI use was associated with an increased risk of 6 CV irAEs including myocarditis, pericardial diseases, heart failure, dyslipidemia, myocardial infarction, and cerebral arterial ischaemia with higher risks for myocarditis (Peto OR: 4.42, 95% CI: 1.56-12.50, P < 0.01; I2 = 0%, P = 0.93) and dyslipidemia (Peto OR: 3.68, 95% CI: 1.89-7.19, P < 0.01; I2 = 0%, P = 0.66). The incidence of these CVAEs ranged from 3.2 (95% CI 2.0-5.1) to 19.3 (6.7-54.1) per 1000 patients, in studies with a median follow-up ranging from 3.2 to 32.8 months. CONCLUSION: In RCTs, ICI use was associated with six CV irAEs, not confined to myocarditis and pericarditis.

Assessing immune organs on 18F-FDG PET/CT imaging for therapy monitoring of immune checkpoint inhibitors: inter-observer variability, prognostic value and evolution during the treatment course of melanoma patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved survival in advanced melanoma. There is a need for robust biomarkers to identify patients who do not respond. We analysed 14 baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) metrics and their evolution to assess their correlation with patient outcome, compared with 7 established biological markers and 7 clinical variables. METHODS: We conducted a retrospective monocentric observational study of 29 patients with advanced melanoma who underwent baseline 18F-FDG PET/CT, followed by an early monitoring PET/CT (iPET) scan after 1 month of treatment and follow-up studies at 3rd (M3PET) and 6th month (M6PET). 18F-FDG uptake in immune organs (spleen, bone marrow, ileocecal valve) and derived spleen-to-liver (SLR) and bone-to-liver (BLR) ratios were reviewed by two PET readers for reproducibility analysis purposes including 14 PET variables. The most reproducible indexes were used for evaluation as predictors of overall survival (OS) in comparison with PET response using imPERCIST5, whole-body metabolic active tumour volume (WB-MATV) and biological parameters (lactate dehydrogenases (LDH), reactive protein c (CRP), white blood count (WBC), absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio (NLR) and derived neutrophils to lymphocyte ratio). RESULTS: Strong reproducibility's (intraclass coefficients of correlation (ICC) > 0.90) were observed for spleen anterior SUVpeak, spleen MV, spleen TLG, spleen length and BLRmean. ICC for SLRmean and ileocecal SUVmean were 0.86 and 0.65, respectively. In the 1-year OS 1 group, SLRmean tended to increase at each time point to reach a significant difference at M6-PET (p = 0.019). The same trends were observed with spleen SUVpeak anterior and spleen length. In the 1-year OS 0 group, a significative increase of spleen length was found at iPET, as compared with baseline PET (p = 0.014) and M3-PET (p = 0.0239). Univariable Kaplan-Meier survival analysis found that i%var spleen length, M3%var SLRmean, baseline LDH, i%var NLR and response at M6PET were all predictors of 1-year OS. CONCLUSIONS: SLRmean is recommended as a prognosticator in melanoma patients under immunotherapy: its increase greater than 25% at 3 months, compared with baseline, was associated with poor outcome after ICIs.

Chimeric antigen receptor T-cells safety: A pharmacovigilance and meta-analysis study.

Chimeric-antigen-receptor T cells directed against CD19 (CAR-T) are emerging hematological therapeutics with scarce data on its overall safety profile spectrum. To determine the clinical features and incidence of adverse-drug reactions (ADR) associated with CAR-T. This observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase and meta-analysis of data from CAR-T trials and cohorts in the literature was also performed through March, 2020. The primary objective was to identify ADR associated with approved CAR-T (axicabtagene-ciloleucel; tisagenlecleucel). We conducted a Bayesian disproportionate analysis with the 95% lower credibility-interval of information component (IC025 , significance > 0). We also performed a systematic-review and meta-analysis of CAR-T trials and cohorts in the literature to evaluate ADR incidence. Nine ADR classes were associated with CAR-T: Cytokine release syndrome (CRS, n = 1378, IC025  = 4.24), neurological disorders (n = 963, IC025  = 2.42), hematological disorders (n = 532, IC025  = 3.32), infections (n = 287, IC025  = 2.38), cardiovascular disorders (n = 256, IC025  = 2.81), pulmonary disorders (n = 186, IC025  = 3.80), reno-metabolic disorders (n = 123, IC025  = 1.89), hemophagocytic-lymphohistiocytosis (n = 36, IC025  = 5.01) and hepatic disorders (n = 32, IC025  = 2.49). ADR-related fatalities accounted for 99/1783 (5.5%) of the reports and 262/1783 (14.7%) for all-cause mortality. These ADR-related fatalities were associated with hemophagocytic-lymphohistiocytosis, cerebral vascular disorder, infections, and respiratory failure. In meta-analyses, the most frequent any-grade ADRs were CRS, hematological disorders, and neurological disorders. Fatal ADR were most found with neurological disorders, CRS, and infections. Note, CAR-T infusion may be associated with severe ADR mainly following the week of administration, though rarely fatal. Infections, hemophagocytic-lymphohistiocytosis and end organ failures including neurological or lung involvements require scrutiny.

Unmasking the tumourigenic role of SIN1/MAPKAP1 in the mTOR complex 2.

BACKGROUND: Although the PI3K/AKT/mTOR pathway is one of the most altered pathways in human tumours, therapies targeting this pathway have shown numerous adverse effects due to positive feedback paradoxically activating upstream signaling nodes. The somewhat limited clinical efficacy of these inhibitors calls for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer. MAIN BODY: Recent studies have shown the central role of mTOR complex 2 (mTORC2) as a pro-tumourigenic factor of the PI3K/AKT/mTOR pathway in a number of cancers. SIN1/MAPKAP1 is a major partner of mTORC2, acting as a scaffold and responsible for the substrate specificity of the mTOR catalytic subunit. Its overexpression promotes the proliferation, invasion and metastasis of certain cancers whereas its inhibition decreases tumour growth in vitro and in vivo. It is also involved in epithelial-mesenchymal transition, stress response and lipogenesis. Moreover, the numerous interactions of SIN1 inside or outside mTORC2 connect it with other signaling pathways, which are often disrupted in human tumours such as Hippo, WNT, Notch and MAPK. CONCLUSION: Therefore, SIN1's fundamental characteristics and numerous connexions with oncogenic pathways make it a particularly interesting therapeutic target. This review is an opportunity to highlight the tumourigenic role of SIN1 across many solid cancers and demonstrates the importance of targeting SIN1 with a specific therapy.

Cardiovascular safety of rapidly accelerated fibrosarcoma B-type and/or mitogen-activated extracellular signal-regulated kinase inhibitors: A mixed approach combining a meta-analysis and a pharmacovigilance disproportionality analysis.

BACKGROUND: The risk of cardiovascular adverse events from rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is not fully characterized. AIM: To evaluate the cardiovascular adverse events risks related to BRAF and/or MEK inhibitors in randomized placebo-controlled clinical trials and in the real-life setting. METHODS: We used two approaches. First, we conducted a systematic review and meta-analysis of randomized placebo-controlled clinical trials reporting the incidence of cardiovascular adverse events for BRAF and/or MEK inhibitors in cancer patients. Second, we performed a disproportionality analysis, using age- and sex-adjusted reporting odds ratios (arORs) and their 95% confidence intervals (CIs) from the World Health Organization's pharmacovigilance database (VigiBase®) of anticancer drug-associated reports, to investigate real-life data. RESULTS: MEK inhibitors increased the risk of ejection fraction decrease (odds ratio [OR] 3.35, 95% CI 1.58-7.07), peripheral oedema (OR 2.87 95% CI 1.93-4.27) and syncope (OR 6.71, 95% CI 3.00-14.99) compared with placebo in randomized placebo-controlled clinical trials. BRAF and MEK inhibitor combination therapy further increased the risk of ejection fraction decrease. In the disproportionality analysis, we found over-reporting of ejection fraction decrease (arOR 8.42, 95% CI 7.03-10.09), peripheral oedema (arOR 1.39, 95% CI 1.17-1.66), syncope (arOR 1.56, 95% CI 1.22-1.99), torsade de pointes/QT prolongation (arOR 6.13, 95% CI 5.04-7.47) and supraventricular arrhythmias (arOR 1.50, 95% CI 1.21-1.85) for BRAF and MEK inhibitors. BRAF and MEK inhibitors were not associated with hypertension in either approach. CONCLUSIONS: In conclusion, MEK inhibitors increase the risk of ejection fraction decrease, peripheral oedema and syncope in randomized placebo-controlled clinical trials. Real-life data confirm these findings, and suggested additional risks of torsade de pointes/QT prolongation and supraventricular arrhythmias with BRAF/MEK inhibitors.