Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials.
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Date
2015-12-01Author
Geuna, E
Roda, D
Rafii, S
Jimenez, B
Capelan, M
Rihawi, K
Montemurro, F
Yap, TA
Kaye, SB
De Bono, JS
Molife, LR
Banerji, U
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Neoplasms
Hyperglycemia
Blood Glucose
Antineoplastic Agents
Protein Kinase Inhibitors
Hypoglycemic Agents
Severity of Illness Index
Risk Factors
Case-Control Studies
Retrospective Studies
Signal Transduction
Adolescent
Adult
Aged
Aged, 80 and over
Middle Aged
Female
Male
Proto-Oncogene Proteins c-akt
Clinical Trials, Phase I as Topic
Young Adult
TOR Serine-Threonine Kinases
Phosphoinositide-3 Kinase Inhibitors
Research team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)
Language
eng
Date accepted
2015-10-05
License start date
2015-12
Citation
British journal of cancer, 2015, 113 (11), pp. 1541 - 1547
Publisher
NATURE PUBLISHING GROUP