title: Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy.
abstract: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST.
  
  
  
  The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg once daily, days 1-21 of a 28-day cycle. Clinical benefit rate (CBR), defined as complete or partial response (PR), or stable disease lasting ≥16 weeks per RECIST 1.1, progression-free survival (PFS), overall survival (OS), long-term safety data, and metabolic response by functional imaging were assessed.
  
  
  
  Thirty-three patients received at least one dose of regorafenib. The median follow-up was 41 months. CBR was documented in 25 of 33 patients [76%; 95% confidence interval (CI) 58% to 89%], including six PRs. The median PFS was 13.2 months (95% CI 9.2-18.3 months) including four patients who remained progression-free at study closure, each achieving clinical benefit for more than 3 years (range 36.8-43.5 months). The median OS was 25 months (95% CI 13.2-39.1 months). Patients whose tumors harbored a KIT exon 11 mutation demonstrated the longest median PFS (13.4 months), whereas patients with KIT/PDGFRA wild-type, non-SDH-deficient tumors experienced a median 1.6 months PFS (P < 0.0001). Long-term safety profile is consistent with previous reports; hand-foot skin reaction and hypertension were the most common reasons for dose reduction. Notably, regorafenib induced objective responses and durable benefit in SDH-deficient GIST.
  
  
  
  Long-term follow-up of patients with metastatic GIST treated with regorafenib suggests particular benefit among patients with primary KIT exon 11 mutations and those with SDH-deficient GIST. Dose modifications are frequently required to manage treatment-related toxicities.
  
  
  
  NCT01068769.
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, Boston.
authors.forename: E
authors.initials: E
authors.lastname: Ben-Ami
authors.affiliation: Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston.
authors.forename: C M
authors.initials: CM
authors.lastname: Barysauskas
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia.
authors.forename: M
authors.initials: M
authors.lastname: von Mehren
authors.affiliation: VA Portland Health Care System and Oregon Health and Science University, Portland.
authors.forename: M C
authors.initials: MC
authors.lastname: Heinrich
authors.affiliation: Oregon Health and Science University, Portland.
authors.forename: C L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, Boston.
authors.forename: J E
authors.initials: JE
authors.lastname: Butrynski
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, Boston.
authors.forename: J A
authors.initials: JA
authors.lastname: Morgan
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, Boston.
authors.forename: A J
authors.initials: AJ
authors.lastname: Wagner
authors.affiliation: Division of Hematology Oncology, Massachusetts General Hospital, Boston.
authors.forename: E
authors.initials: E
authors.lastname: Choy
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City Department of Radiology, University of Utah, Salt Lake City.
authors.forename: J T
authors.initials: JT
authors.lastname: Yap
authors.affiliation: Department of Imaging, Dana Farber Cancer Institute, Boston Department of Radiology.
authors.forename: A D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, Boston.
authors.forename: S M
authors.initials: SM
authors.lastname: Solomon
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston.
authors.forename: J A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, Boston Department of Ludwig Center at Dana Farber/Harvard Cancer Center and Harvard Medical School, Boston, USA.
authors.forename: G D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana Farber Cancer Institute, Boston suzanne_george@dfci.harvard.edu.
authors.forename: S
authors.initials: S
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000009:adverse effects; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects; D000077210:Sunitinib
chemical_list: D007211:Indoles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011758:Pyrroles; C559147:regorafenib; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib
keywords: GIST; KIT mutation; SDH-deficient GIST; regorafenib