title: Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer.
abstract: BACKGROUND
  Cabozantinib significantly prolonged progression-free survival (PFS) versus a placebo in patients with progressive, metastatic medullary thyroid cancer (MTC; P < .001). An exploratory analysis of phase 3 trial data evaluated the influence of rearranged during transfection (RET) and RAS (HRAS, KRAS, and NRAS) mutations on cabozantinib clinical activity.
  
  
  METHODS
  Patients (n = 330) were randomized to cabozantinib (140 mg/day) or a placebo. The primary endpoint was PFS. Additional outcome measures included PFS, objective response rates (ORRs), and adverse events in RET and RAS mutation subgroups.
  
  
  RESULTS
  Among all study patients, 51.2% were RET mutation-positive (38.2% with RET M918T), 34.8% were RET mutation-unknown, and 13.9% were RET mutation-negative. Sixteen patients were RAS mutation-positive. Cabozantinib appeared to prolong PFS versus the placebo in the RET mutation-positive subgroup (hazard ratio [HR], 0.23; 95% confidence interval [CI], 0.14-0.38; P < .0001), the RET mutation-unknown subgroup (HR, 0.30; 95% CI, 0.16-0.57; P = .0001), and the RAS mutation-positive subgroup (HR, 0.15; 95% CI, 0.02-1.10; P = .0317). The RET M918T subgroup achieved the greatest observed PFS benefit from cabozantinib versus the placebo (HR, 0.15; 95% CI, 0.08-0.28; P < .0001). The ORRs for RET mutation-positive, RET mutation-negative, and RAS mutation-positive patients were 32%, 22%, and 31%, respectively. No PFS benefit was observed in patients lacking both RET and RAS mutations, although the ORR was 21%. The safety profile for all subgroups was similar to that for the overall cabozantinib arm.
  
  
  CONCLUSIONS
  These data suggest that cabozantinib provides the greatest clinical benefit to patients with MTC who have RET M918T or RAS mutations. However, a prospective trial is needed to confirm the relation between genetic variation and the response to cabozantinib. Cancer 2016;122:3856-3864. © 2016 American Cancer Society.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Steven I
authors.initials: SI
authors.lastname: Sherman
authors.affiliation: Exelixis, Inc, South San Francisco, California.
authors.forename: Douglas O
authors.initials: DO
authors.lastname: Clary
authors.affiliation: University of Pisa, Pisa, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Elisei
authors.affiliation: Institut Gustave Roussy, University Paris-Sud, Villejuif, France.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Schlumberger
authors.affiliation: Moores Cancer Center, University of San Diego, San Diego, California.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: University Hospitals Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.affiliation: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Wirth
authors.affiliation: Exelixis, Inc, South San Francisco, California.
authors.forename: Milan
authors.initials: M
authors.lastname: Mangeshkar
authors.affiliation: Exelixis, Inc, South San Francisco, California.
authors.forename: Dana T
authors.initials: DT
authors.lastname: Aftab
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Marcia S
authors.initials: MS
authors.lastname: Brose
mesh_terms: D000813:Anilides / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004311:Double-Blind Method; D006801:Humans; D009154:Mutation / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011725:Pyridines / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology*; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000813:Anilides; D011725:Pyridines; C558660:cabozantinib; D051096:Proto-Oncogene Proteins c-ret; D018631:ras Proteins
keywords: RAS; RET; cabozantinib; medullary thyroid cancer; tyrosine kinase inhibitor