Higher risk of infections with PI3K-AKT-mTOR pathway inhibitors in patients with advanced solid tumors on Phase I clinical Trials
A partir de données portant sur 598 patients atteints d'une tumeur solide de stade avancé et inclus dans des essais cliniques de phase I, cette étude rétrospective évalue l'incidence des infections associées à un traitement par un inhibiteur de la signalisation PI3K-AKT-mTOR en combinaison avec une chimiothérapie
Purpose: Antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer. Although not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogs. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2 or multi-kinase inhibitors is unknown. Experimental Design: In this retrospective case-control study, we determined the incidence of infection in 432 patients treated on 15 phase I clinical trials involving PI3K-AKT-mTOR inhibitors vs 100 patients on 10 phase I clinical trials of non-cytotoxic single agent non-PI3K-AKT-mTOR inhibitors. We also collected data from 42 patients treated with phase I trials of PI3K-AKT-mTOR and MEK inhibitors combinations and 24 patients with PI3K-AKT-mTOR inhibitors and chemotherapy combinations. Results: The incidence of all grade infection was significantly higher with all single agent PI3K-AKT-mTOR inhibitors compared to the control group (27% vs 8% respectively, OR: 4.26, 95% 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 to the control group (10.3% vs 3%, OR: 3.74, 95% CI: 1.1- 12.4, p=0.02). Also PI3K-AKT-mTOR inhibitors and chemotherapy combination was associated with 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: The increased risk of infection with PI3K-AKT-mTOR inhibitors should be taken into consideration during the design and conduct of trials particularly when these agents are combined with chemotherapy or myelosuppressive agents.