title: Higher Risk of Infections with PI3K-AKT-mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials.
abstract: OBJECTIVE
  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.
  
  
  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) 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.
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Saeed
authors: S
authors: Rafii
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Desamparados
authors: D
authors: Roda
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Elena
authors: E
authors: Geuna
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Begona
authors: B
authors: Jimenez
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Karim
authors: K
authors: Rihawi
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Marta
authors: M
authors: Capelan
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Timothy A
authors: TA
authors: Yap
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: L Rhoda
authors: LR
authors: Molife
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Stanley B
authors: SB
authors: Kaye
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom.
authors: Johann S
authors: JS
authors: de Bono
authors: Drug Development Unit, Division of Cancer Therapeutics and Division of Clinical Studies, The Institute of Cancer Research and The Royal Marsden, London, United Kingdom. udai.banerji@icr.ac.uk.
authors: Udai
authors: U
authors: Banerji
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D015415:Biomarkers; D016022:Case-Control Studies; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D015994:Incidence; D007239:Infections / Q000453:epidemiology* / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D012306:Risk; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
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