Impact of patient ethnicity on the metabolic and immunologic effects of PI3K–mTOR pathway inhibition in patients with solid tumor malignancies

PURPOSE: Inhibition of the phosphatidylinositol 3-kinase (PI3K)/mammalian target of Rapamycin (mTOR) pathway is associated with metabolic and immunologic perturbations that impact drug tolerability. Here, we studied whether PI3 kinase/mTOR pathway inhibitors are associated with greater metabolic impact and decreased tolerability in Asian patients. METHODS: A retrospective analysis was conducted of consecutive patients with advanced malignancies treated on Phase 1 trials of PI3K/mTOR inhibitors. Adverse events related to PI3K/mTOR inhibition, fasting plasma glucose (FPG), insulin, and cpeptide levels, hemoglobin A1c (HgbA1c), and T-cell subsets, were prospectively collected. Mann-Whitney and chi-squared tests were used to compare continuous and categorical variables, respectively, between Asian and Caucasian patients. RESULTS: A total of 103 patients (31 Asian; 72 Caucasian) were treated consecutively across five clinical trials. Baseline age, gender distribution, and metabolic parameters were comparable with the exception of lower median body mass index (BMI) in Asian patients (23.0 vs. 24.8 kg/m(2), p=0.024). There were no differences in drug tolerability, adherence or duration of therapy. Asian patients experienced a higher incidence of grade ≥ 2 hyperglycemia (40.4% vs. 18%, p = 0.03), and greater increases in FPG, HgbA1c, and insulin resistance. No differences in incidence or severity of mucositis, rash, or pneumonitis were observed. Drug effects on neutrophils, lymphocytes and T-cell subsets were similar. CONCLUSIONS: PI3K/mTOR inhibitors have greater glycemic impact in Asian patients, despite similar baseline metabolic parameters, comparable dose intensity, and a lower median BMI. Further studies are warranted to explore the mechanisms underlying these differences and optimize dosing in Asian patients

Complications of hyperglycaemia with PI3K–AKT–mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials

Background: PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. Methods: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. Results: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P = 0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P = 0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. Conclusions: PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers