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Original Investigation
July 2017

Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing ResultsAnalysis of Phase 3 SWOG Intergroup Trial S0033

Author Affiliations
  • 1Division of Hematology and Medical Oncology, Portland Veterans Affairs Health Care System, Knight Cancer Institute, Oregon Health and Science University, Portland
  • 2SWOG Statistical Center, Seattle, Washington
  • 3Division of Hematology and Medical Oncology, SWOG Group Chair’s Office, Knight Cancer Institute, Oregon Health and Science University, Portland
  • 4Department of Medicine, Developmental Therapeutics and Gastrointestinal Malignancies Programs, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
  • 5Cancer Division, Departments of Solid Tumor Oncology and Cancer Biology, Cleveland Clinic Foundation, Cleveland, Ohio
  • 6Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
  • 7Medical Oncology, Mount Sinai Hospital, Toronto, Ontario, Canada
  • 8Medical Oncology, Washington Cancer Institute, Medstar Washington Hospital Center, Washington, DC
  • 9Medical Oncology, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York
  • 10Medical Oncology, Monter Cancer Center, Northwell Health, Lake Success, New York
  • 11Medical Oncology, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
  • 12Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 13Department of Pediatrics, Brigham and Women’s Hospital, Boston, Massachusetts
  • 14Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
  • 15Division of Cancer Medicine, University of Texas, MD Anderson Cancer Center, Houston
  • 16Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor
  • 17Department of Pharmacology, University of Michigan, Ann Arbor
JAMA Oncol. 2017;3(7):944-952. doi:10.1001/jamaoncol.2016.6728
Key Points

Question  What are the long-term clinical outcomes for patients with advanced gastrointestinal stromal tumors treated with front-line imatinib mesylate?

Findings  In this follow-up study of a randomized clinical trial of 695 adults treated with imatinib mesylate, the estimated 10-year progression-free and overall survival rates were approximately 7% and 23%, respectively. The highest 10-year progression-free and overall survival results were obtained for patients with KIT exon 11–mutant tumors or tumors lacking KIT/PDGFRA mutations (primarily succinate dehydrogenase–mutant tumors).

Meaning  Imatinib front-line treatment of advanced and/or metastatic gastrointestinal stromal tumors leads to long-term survival (≥10 years) in a substantial minority of treated patients, especially those with KIT exon 11–mutant gastrointestinal stromal tumors.


Importance  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.

Obective  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.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT00009906