Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials.
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Embargo End Date
ICR Authors
Authors
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
Roda, D
Rafii, S
Jimenez, B
Capelan, M
Rihawi, K
Montemurro, F
Yap, TA
Kaye, SB
De Bono, JS
Molife, LR
Banerji, U
Document Type
Journal Article
Date
2015-12-01
Date Accepted
2015-10-05
Abstract
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.
Citation
British journal of cancer, 2015, 113 (11), pp. 1541 - 1547
Source Title
Publisher
NATURE PUBLISHING GROUP
ISSN
0007-0920
eISSN
1532-1827
Research Team
Clinical Pharmacology – Adaptive Therapy
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)