title: Randomized phase Ib/II trial of rilotumumab or ganitumab with panitumumab versus panitumumab alone in patients with wild-type KRAS metastatic colorectal cancer.
abstract: OBJECTIVE
  Panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody (mAb), has demonstrated efficacy in patients with wild-type KRAS metastatic colorectal cancer (mCRC). Rilotumumab and ganitumab are investigational, fully human mAbs against hepatocyte growth factor (HGF)/scatter factor and IGF1R, respectively. Here we evaluate combining rilotumumab or ganitumab with panitumumab in previously treated patients with wild-type KRAS mCRC.
  
  
  METHODS
  Part 1 was a phase Ib dose-finding study of panitumumab plus rilotumumab. The primary endpoint was the incidence of dose-limiting toxicities (DLT). Part 2 was a randomized phase II trial of panitumumab in combination with rilotumumab, ganitumab, or placebo. The primary endpoint was objective response rate (ORR); safety, progression-free survival (PFS), and overall survival (OS) were secondary endpoints. Archival tissue specimens were collected for exploratory correlative work.
  
  
  RESULTS
  In part 1, no DLTs were reported. A recommended phase II dose of 10 mg/kg rilotumumab was selected. In part 2, for the panitumumab plus rilotumumab (n = 48), panitumumab plus ganitumab (n = 46), and panitumumab plus placebo arms (n = 48), the ORRs were 31%, 22%, and 21%, respectively. The median PFS was 5.2, 5.3, and 3.7 months and median OS 13.8, 10.6, and 11.6 months, respectively. Adverse events were tolerable. Exploratory biomarker analyses, including MET and IGF-related protein expression, failed to indicate conclusive predictive evidence on efficacy endpoints.
  
  
  CONCLUSIONS
  Panitumumab plus rilotumumab met the prespecified criterion for improvement in ORR whereas ganitumab did not. This is the first study to suggest a benefit for combining an HGF inhibitor (rilotumumab) with panitumumab in previously treated patients with wild-type KRAS mCRC.
authors.affiliation: University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium; eric.vancutsem@uzleuven.be.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.affiliation: University of Texas M.D. Anderson Cancer Center, Houston, Texas;
authors.forename: Cathy
authors.initials: C
authors.lastname: Eng
authors.affiliation: Instytut im. M. Sklodowskiej-Curie, Gliwice;
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Nowara
authors.affiliation: Warszawski Uniwersytet Medyczny, Warszawa, Poland;
authors.forename: Anna
authors.initials: A
authors.lastname: Swieboda-Sadlej
authors.affiliation: Austin Health, Heidelberg, VIC, Australia;
authors.forename: Niall C
authors.initials: NC
authors.lastname: Tebbutt
authors.affiliation: Thomas Jefferson University, Philadelphia, Pennsylvania;
authors.forename: Edith
authors.initials: E
authors.lastname: Mitchell
authors.affiliation: Krasnodar City Oncology Center, Krasnodar, Russia;
authors.forename: Irina
authors.initials: I
authors.lastname: Davidenko
authors.affiliation: Cancer Centers of the Carolinas, Greenville, South Carolina;
authors.forename: Joe
authors.initials: J
authors.lastname: Stephenson
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain; and.
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.affiliation: University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium;
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.affiliation: Amgen Inc., Thousand Oaks;
authors.forename: Hongjie
authors.initials: H
authors.lastname: Deng
authors.affiliation: Amgen Inc., Thousand Oaks;
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.affiliation: Amgen Inc., Thousand Oaks;
authors.forename: Ian
authors.initials: I
authors.lastname: McCaffery
authors.affiliation: Amgen Inc., Thousand Oaks;
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Oliner
authors.affiliation: Amgen Inc., Thousand Oaks;
authors.forename: Lisa
authors.initials: L
authors.lastname: Chen
authors.affiliation: Amgen Inc., Thousand Oaks;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gansert
authors.affiliation: Amgen Inc., South San Francisco, California;
authors.forename: Elwyn
authors.initials: E
authors.lastname: Loh
authors.affiliation: Amgen Ltd., London, United Kingdom.
authors.forename: Dominic
authors.initials: D
authors.lastname: Smethurst
authors.affiliation: Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain; and.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D000077544:Panitumumab; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D015996:Survival Rate; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C524459:rilotumumab; D000077544:Panitumumab; C545764:ganitumab; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins