title: A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer.
abstract: OBJECTIVE
  Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.
  
  
  METHODS
  This was a phase Ib/II study (NCT00596648). The primary objectives of phase I were to assess the safety, pharmacokinetics, and pharmacodynamics and to determine maximum tolerated dose (MTD) of cabozantinib plus erlotinib in patients who failed prior erlotinib treatment. In phase II, patients with prior response or stable disease with erlotinib who progressed were randomized to single-agent cabozantinib 100 mg qd vs cabozantinib 100 mg qd and erlotinib 50 mg qd (phase I MTD), with a primary objective of estimating objective response rate (ORR).
  
  
  RESULTS
  Sixty-four patients were treated in phase I. Doses of 100 mg cabozantinib plus 50 mg erlotinib, or 40 mg cabozantinib plus 150 mg erlotinib were determined to be MTDs. Diarrhea was the most frequent dose-limiting toxicity and the most frequent AE (87.5% of patients). The ORR for phase I was 8.2% (90% CI 3.3-16.5). In phase II, one patient in the cabozantinib arm (N = 15) experienced a partial response, for an ORR of 6.7% (90% CI 0.3-27.9), with no responses for cabozantinib plus erlotinib (N = 13). There was no evidence that co-administration of cabozantinib markedly altered erlotinib pharmacokinetics or vice versa.
  
  
  CONCLUSIONS
  Despite responses with cabozantinib/erlotinib in phase I, there were no responses in the combination arm of phase II in patients with acquired resistance to erlotinib. Cabozantinib did not appear to re-sensitize these patients to erlotinib.
authors.affiliation: Stanford Cancer Institute, 875 Blake Wilbur Drive, Rm 2233, Stanford, CA, 94305-5826, USA. hwakelee@stanford.edu.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Wakelee
authors.affiliation: Yale University Cancer Center, New Haven, CT, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Gettinger
authors.affiliation: Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Engelman
authors.affiliation: Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Swedish Cancer Institute, Seattle, WA, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: West
authors.affiliation: Department of Hematology and Oncology, Georgetown University Hospital, Washington, DC, USA.
authors.forename: Deepa S
authors.initials: DS
authors.lastname: Subramaniam
authors.affiliation: Park Nicollet Cancer Center, Minneapolis, MN, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Leach
authors.affiliation: Summit Medical Group, Berkeley Heights, NJ, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wax
authors.affiliation: Exelixis, South San Francisco, CA, USA.
authors.forename: Yifah
authors.initials: Y
authors.lastname: Yaron
authors.affiliation: Exelixis, South San Francisco, CA, USA.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Miles
authors.affiliation: University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA.
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D011725:Pyridines; C558660:cabozantinib; D000069347:Erlotinib Hydrochloride
keywords: Cabozantinib; Combination therapy; Erlotinib; Non-small cell lung cancer; Phase Ib/II; Resistance