title: Oral ridaforolimus plus trastuzumab for patients with HER2+ trastuzumab-refractory metastatic breast cancer.
abstract: BACKGROUND
  Although trastuzumab-containing therapies prolong survival in patients with metastatic breast cancer (MBC), most tumors develop trastuzumab resistance, potentially mediated by aberrant phosphatidylinositide 3-kinase (PI3K)/AKT signaling. Ridaforolimus (a mammalian target of rapamycin [mTOR] inhibitor) may overcome trastuzumab resistance by inhibiting PI3K signaling.
  
  
  METHODS
  A single-arm, phase IIb trial was conducted to evaluate the efficacy and safety of ridaforolimus-trastuzumab in human epidermal growth factor receptor 2-positive (HER2(+)) trastuzumab-refractory MBC (NCT00736970). Ridaforolimus was administered orally (40 mg daily) for 5 d/wk plus weekly trastuzumab. The primary end point was objective response (OR).
  
  
  RESULTS
  Thirty-four patients were enrolled (91% had received 1 or 2 previous trastuzumab-based therapies, whereas 9% had received 3 previous therapies). The most common reasons for discontinuation were disease progression (62%) and adverse events (AEs; 24%). Three patients died; 1 because of bowel perforation, which was possibly ridaforolimus related. Partial response was observed in 5 patients (15%). Median duration of response was 19.1 weeks (range, 15.9-80.1 weeks). Fourteen patients (41%) achieved stable disease (SD); 7 patients (21%) maintained SD for ≥ 24 weeks. The clinical benefit response (CBR) rate was 34.3%. Median progression-free survival (PFS) and overall survival (OS) were 5.4 months (range, 0-20.3 months; 95% confidence interval [CI], 2.0-7.4) and 17.7 months (range, 0-25.9 months; 95% CI, 8.8-20.8), respectively. PFS rate at 6 months was 37%. The most common treatment-related AEs were stomatitis (59%), diarrhea (27%), and rash (27%).
  
  
  CONCLUSIONS
  Ridaforolimus-trastuzumab was well tolerated and demonstrated antitumor activity in trastuzumab-resistant HER2(+) MBC.
authors.affiliation: Hematology and Oncology Specialists, LLC, New Orleans, LA. Electronic address: milton.seiler@touro.com.
authors.forename: Milton
authors.initials: M
authors.lastname: Seiler
authors.affiliation: Département d'oncologie médicale adulte, Lyon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.affiliation: Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic.
authors.forename: Bohuslav
authors.initials: B
authors.lastname: Melichar
authors.affiliation: Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.affiliation: Biostatistics and Research Decision Sciences, Asia Pacific MSD R&D (China) Co. Ltd., Beijing, China.
authors.forename: Rui X
authors.initials: RX
authors.lastname: Wang
authors.affiliation: ARIAD Pharmaceuticals, Inc., Cambridge, MA.
authors.forename: Pierre F
authors.initials: PF
authors.lastname: Dodion
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016019:Survival Analysis; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D020123:Sirolimus; D000068878:Trastuzumab; C515074:ridaforolimus; C508053:ERBB2 protein, human
keywords: Breast cancer; HER2; Ridaforolimus; Trastuzumab; mTOR inhibitor