Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

Abstract

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 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. Methods 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) vs 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 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 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. Conclusion 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.

Insulin and the phosphatidylinositol 3-kinase signaling pathway regulate Ribonuclease 7 expression in the human urinary tract

“…48, 49 Clinically, patients receiving treatment with PI3K/AKT/mTOR inhibitors have increased infection risk – with the urinary tract being the most likely site of infection. 54 These findings highlight the importance of understanding the role of PI3K/AKT signaling in host defense and evaluating specific PI3K/AKT targets for the development of clinical therapeutics. Ongoing studies in our laboratory are investigating how downstream PI3K/AKT effectors and transcription factors regulate the production of AMPs like RNase 7.…”

Hyperglycemia and Phosphatidylinositol 3-Kinase/Protein Kinase B/Mammalian Target of Rapamycin (PI3K/AKT/mTOR) Inhibitors in Phase I Trials: Incidence, Predictive Factors, and Management

“…Patients with grade 1 hyperglycemia were provided dietary advice; however, monitoring frequency again varied according to the trial protocols. Interestingly, we demonstrated in a separate series that agents targeting PI3K/AKT/mTOR pathway can be associated with higher risk for infections, which makes it all the more important to achieve good glycemic control to avoid such complications [17]. Diabetes mellitus can be associated with increased morbidity and mortality because of end-organ damage; certain cancers, such as breast and colorectal cancer, are also independently known to be associated with an increased risk for diabetes mellitus [18].…”

A First-in-Human Phase 1 Study of LY3023414, an Oral PI3K/mTOR Dual Inhibitor, in Patients with Advanced Cancer

“…Notably, no AEs indicative for mood alteration were reported for LY3023414 as reported for another pan-PI3K inhibitor (14). Rafii and colleagues (18) reported increased risk of bacterial infections in patients treated with inhibitors to components of the PI3K/mTOR pathway. While this risk might be of particular interest for PI3K/mTOR inhibitors coadministered with myelosuppressive agents, there was no increased rate of bacterial infections noted in the current monotherapy study.…”