title: A phase 2 and biomarker study of cabozantinib in patients with advanced cholangiocarcinoma.
abstract: Advanced cholangiocarcinoma carries a poor prognosis, and no standard treatment exists beyond first-line gemcitabine/platinum-based chemotherapy. A single-arm, phase 2 and biomarker study of cabozantinib, a multikinase inhibitor with potent activity against vascular endothelial growth factor receptor 2 (VEGFR2) and MET, was performed for patients with advanced refractory cholangiocarcinoma.
  
  
  
  Previously treated patients with unresectable or metastatic cholangiocarcinoma received cabozantinib (60 mg orally and daily on a continuous schedule). The primary endpoint was progression-free survival (PFS). Tumor MET expression and plasma biomarkers were evaluated.
  
  
  
  The study enrolled 19 patients with cholangiocarcinoma (female, 68%; median age, 67 years; intrahepatic vs extrahepatic, 84% vs 16%). The median PFS was 1.8 months (95% confidence interval, 1.6-5.4 months), and the median overall survival (OS) was 5.2 months (95% confidence interval, 2.7-10.5 months). Grade 3/4 adverse events occurred in 89% of the patients and included neutropenia (5%), hyperbilirubinemia (5%), epistaxis (5%), bowel perforation (5%), enterocutaneous fistulas (5%), and hypertension (11%). One patient with 3 + MET expression in the tumor stayed on treatment for 278 days, but the MET expression did not correlate with the outcomes in the overall study population. Plasma vascular endothelial growth factor, placental growth factor, and stromal cell-derived factor 1α increased and soluble VEGFR2 and angiopoietin 2 decreased after treatment (all P values < .01). Plasma tissue inhibitor of matrix metalloproteinase 1 was inversely correlated with PFS, and soluble MET (sMET) and interleukin 6 were inversely correlated with OS.
  
  
  
  In unselected patients with cholangiocarcinoma, cabozantinib demonstrated limited activity and significant toxicity. In the first clinical trial to assess the role of MET inhibition in cholangiocarcinoma, 1 patient with a MET-high tumor had a prolonged benefit from treatment. Baseline plasma soluble MET was associated with OS. Any further development of this drug in cholangiocarcinoma should include a dose reduction and a biomarker-driven approach. Cancer 2017;123:1979-1988. © 2017 American Cancer Society.
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Lipika
authors.initials: L
authors.lastname: Goyal
authors.affiliation: Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Yurgelun
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Abrams
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Jill N
authors.initials: JN
authors.lastname: Allen
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: James M
authors.initials: JM
authors.lastname: Cleary
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Michelle
authors.initials: M
authors.lastname: Knowles
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Eileen
authors.initials: E
authors.lastname: Regan
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
authors.forename: Amanda
authors.initials: A
authors.lastname: Reardon
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Anna
authors.initials: A
authors.lastname: Khachatryan
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Valentina
authors.initials: V
authors.lastname: Nardi
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Borger
authors.affiliation: Harvard Medical School, Boston, Massachusetts.|Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dan G
authors.initials: DG
authors.lastname: Duda
authors.affiliation: Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.|Harvard Medical School, Boston, Massachusetts.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
mesh_terms: D000368:Aged; D042702:Angiopoietin-2 / Q000378:metabolism; D000813:Anilides / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D004844:Epistaxis / Q000139:chemically induced; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D006973:Hypertension / Q000139:chemically induced; D015850:Interleukin-6 / Q000378:metabolism; D007412:Intestinal Fistula / Q000139:chemically induced; D007416:Intestinal Perforation / Q000139:chemically induced; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D000072483:Placenta Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C586513:ANGPT2 protein, human; D042702:Angiopoietin-2; D000813:Anilides; D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C508600:IL6 protein, human; D015850:Interleukin-6; C000608036:PGF protein, human; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; C558660:cabozantinib; C000588866:KDR protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1
keywords: cabozantinib; cholangiocarcinoma; phase 2; soluble MET; vascular endothelial growth factor receptor 2 (VEGFR2)