title: Phase I study of neratinib in combination with temsirolimus in patients with human epidermal growth factor receptor 2-dependent and other solid tumors.
abstract: OBJECTIVE
  Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors.
  
  
  METHODS
  This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses.
  
  
  RESULTS
  Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway.
  
  
  CONCLUSIONS
  The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.
authors: Leena Gandhi, Sara M. Tolaney, James M. Cleary, and Geoffrey I. Shapiro, Dana-Farber Cancer Institute; Eunice L. Kwak, Massachusetts General Hospital; Shuchi S. Pandya, Beth Israel Deaconess Medical Center, Boston; Anna Berkenblit and Mizue Krygowski, Aveo Pharmaceuticals; Revathi Ananthakrishnan and Kathleen W. Turnbull, Inventiv Health, Cambridge, MA; Rastislav Bahleda, Antoine Hollebecque, and Jean-Charles Soria, Insitut Gussav Roussy, Villejuif, France; Richat Abbas and Yali Liang, Pfizer, Collegeville, PA.
authors: Leena
authors: L
authors: Gandhi
authors: Rastislav
authors: R
authors: Bahleda
authors: Sara M
authors: SM
authors: Tolaney
authors: Eunice L
authors: EL
authors: Kwak
authors: James M
authors: JM
authors: Cleary
authors: Shuchi S
authors: SS
authors: Pandya
authors: Antoine
authors: A
authors: Hollebecque
authors: Richat
authors: R
authors: Abbas
authors: Revathi
authors: R
authors: Ananthakrishnan
authors: Anna
authors: A
authors: Berkenblit
authors: Mizue
authors: M
authors: Krygowski
authors: Yali
authors: Y
authors: Liang
authors: Kathleen W
authors: KW
authors: Turnbull
authors: Geoffrey I
authors: GI
authors: Shapiro
authors: Jean-Charles
authors: JC
authors: Soria
mesh_terms: D000368:Aged; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013280:Stomatitis / Q000139:chemically induced; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C401859:temsirolimus; C508053:ERBB2 protein, human; C487932:neratinib