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.

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Citation: JAMA Oncology. , 2017 Feb 09JAMA Oncology. 3(7):944-952, 2017 Jul 01PMID: 28196207Institution: Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Journal ArticleSubject headings: *Antineoplastic Agents/tu [Therapeutic Use] | *Gastrointestinal Neoplasms/dt [Drug Therapy] | *Gastrointestinal Stromal Tumors/dt [Drug Therapy] | *Imatinib Mesylate/tu [Therapeutic Use] | *Proto-Oncogene Proteins c-kit/ge [Genetics] | Aged | Clinical Trials, Phase III as Topic | Disease-Free Survival | Female | Follow-Up Studies | Gastrointestinal Neoplasms/ge [Genetics] | Gastrointestinal Stromal Tumors/ge [Genetics] | High-Throughput Nucleotide Sequencing | Humans | Male | Middle Aged | Mutation | Prognosis | Proportional Hazards Models | Randomized Controlled Trials as Topic | Receptor, Platelet-Derived Growth Factor alpha/ge [Genetics] | Succinate Dehydrogenase/ge [Genetics] | Survival Rate | Treatment OutcomeYear: 2017ISSN:
  • 2374-2437
Name of journal: JAMA oncologyAbstract: 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.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.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.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.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.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.Trial Registration: clinicaltrials.gov Identifier: NCT00009906.All authors: Baker LH, Benjamin RS, Blackstein ME, Blanke CD, Borden EC, Corless CL, Crowley JJ, Demetri GD, Fletcher JA, Heinrich M, Maki RG, Owzar K, Priebat DA, Rankin C, Ryan CW, Tap WD, von Mehren MFiscal year: FY2017Digital Object Identifier: Date added to catalog: 2017-05-06
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Journal Article MedStar Authors Catalog Article 28196207 Available 28196207

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.

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.

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.

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.

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.

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.

Trial Registration: clinicaltrials.gov Identifier: NCT00009906.

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