Higher Risk of Infections with PI3K-AKT-mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials.
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Date
2015-04-15Author
Rafii, S
Roda, D
Geuna, E
Jimenez, B
Rihawi, K
Capelan, M
Yap, TA
Molife, LR
Kaye, SB
de Bono, JS
Banerji, U
Type
Journal Article
Metadata
Show full item recordAbstract
PURPOSE: Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogues. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2, or multikinase inhibitors is unknown. EXPERIMENTAL DESIGN: In this retrospective case-control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K-AKT-mTOR pathway inhibitors (cases) versus a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K-AKT-mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K-AKT-mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapies. RESULTS: The incidence of all grade infection was significantly higher with all single-agent PI3K-AKT-mTOR inhibitors compared with the control group [27% vs. 8%, respectively, OR, 4.26; 95% confidence intervals (CI), 1.9-9.1, P = 0.0001]. The incidence of grade 3 and 4 infection was also significantly higher with PI3K-AKT-mTOR inhibitors compared with the control group (10.3% vs. 3%, OR, 3.74; 95% CI, 1.1-12.4; P = 0.02). Also, the combination of PI3K-AKT-mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR, 4.79; 95% CI, 2.0-11.2; P = 0.0001) and high-grade (OR, 2.87; 95% CI, 1.0-7.6; P = 0.03) infection when compared with single-agent PI3K-AKT-mTOR inhibitors. CONCLUSIONS: Inhibitors of the PI3K-AKT-mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K-AKT-mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents.
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Subject
Humans
Neoplasms
Neoplasm Metastasis
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Protein Kinase Inhibitors
Neoplasm Staging
Incidence
Risk
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
Biomarkers
Phosphoinositide-3 Kinase Inhibitors
Infections
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
2015-01-28
License start date
2015-04
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2015, 21 (8), pp. 1869 - 1876
Publisher
AMER ASSOC CANCER RESEARCH