title: Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing Results: Analysis of Phase 3 SWOG Intergroup Trial S0033.
abstract: OBJECTIVE
  After identification of activating mutations of the KIT gene in gastrointestinal stromal tumor (GIST)-the most common sarcomaof the gastrointestinal tract-a phase 2 study demonstrated efficacy of imatinib mesylate in patients with metastatic GIST harboring a KIT exon 11 mutation. Initial results of long-term follow-up have found a survival benefit in this subgroup of patients.
  
  
  OBJECTIVE
  To assess the long-term survival of patients with GIST who were treated in SWOG study S0033 and to present new molecular data regarding treatment outcomes.
  
  
  METHODS
  In this follow-up of randomized clinical trial participants (from December 15, 2000, to September 1, 2001), patients were required to have advanced GIST that was not surgically curable. Postprotocol data collection occurred from August 29, 2011, to July 15, 2015. Using modern sequencing technologies, 20 cases originally classified as having wild-type tumors underwent reanalysis. This intergroup study was coordinated by SWOG, a cooperative group member within the National Clinical Trials Network, with participation by member/affiliate institutions. This follow-up was not planned as part of the initial study.
  
  
  METHODS
  Patients were randomized to 1 of 2 dose levels of imatinib mesylate, including 400 mg once daily (400 mg/d) vs 400 mg twice daily (800 mg/d), and were treated until disease progression or unacceptable toxic effects of the drug occurred.
  
  
  METHODS
  The primary end point was overall survival. Updated survival data were correlated with clinical and molecular factors, and patterns of postprotocol therapies were enumerated and described in long-term survivors.
  
  
  RESULTS
  Of 695 eligible patients (376 men [54.1%]; 319 women [45.9%]; mean [SD] age, 60.1 [14.0] years), 189 survived 8 years or longer, including 95 in the 400-mg/d dose arm and 94 in the 800-mg/d arm. The 10-year estimate of overall survival was 23% (95% CI, 20%-26%). Among 142 long-term survivors, imatinib was the sole therapy administered in 69 (48.6%), with additional systemic agents administered to 54 patients (38.0%). Resequencing studies of 20 cases originally classified as KIT/PDGFRA wild-type GIST revealed that 17 (85.0%) harbored a pathogenic mutation, most commonly a mutation of a subunit of the succinate dehydrogenase complex.
  
  
  CONCLUSIONS
  A subset of patients with metastatic GIST experiences durable, long-term overall survival with imatinib treatment. Although this study provides guidance for management of GIST harboring the most common KIT and PDGFRA mutations, optimal management of other genotypic subtypes remains unclear.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00009906.
authors.affiliation: Division of Hematology and Medical Oncology, Portland Veterans Affairs Health Care System, Knight Cancer Institute, Oregon Health and Science University, Portland.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.affiliation: SWOG Statistical Center, Seattle, Washington.
authors.forename: Cathryn
authors.initials: C
authors.lastname: Rankin
authors.affiliation: Division of Hematology and Medical Oncology, SWOG Group Chair's Office, Knight Cancer Institute, Oregon Health and Science University, Portland.
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
authors.affiliation: Department of Medicine, Developmental Therapeutics and Gastrointestinal Malignancies Programs, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: Cancer Division, Departments of Solid Tumor Oncology and Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio.
authors.forename: Ernest C
authors.initials: EC
authors.lastname: Borden
authors.affiliation: Division of Hematology and Medical Oncology, Portland Veterans Affairs Health Care System, Knight Cancer Institute, Oregon Health and Science University, Portland.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ryan
authors.affiliation: Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.affiliation: Medical Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Blackstein
authors.affiliation: Medical Oncology, Washington Cancer Institute, Medstar Washington Hospital Center, Washington, DC.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Priebat
authors.affiliation: Medical Oncology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Medical Oncology, Monter Cancer Center, Northwell Health, Lake Success, New York11Medical Oncology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.affiliation: Division of Hematology and Medical Oncology, Portland Veterans Affairs Health Care System, Knight Cancer Institute, Oregon Health and Science University, Portland.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts13Department of Pediatrics, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina.
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.affiliation: SWOG Statistical Center, Seattle, Washington.
authors.forename: John J
authors.initials: JJ
authors.lastname: Crowley
authors.affiliation: Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor17Department of Pharmacology, University of Michigan, Ann Arbor.
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Baker
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D016016:Proportional Hazards Models; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D016032:Randomized Controlled Trials as Topic; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha