What are the long-term clinical outcomes for patients with advanced gastrointestinal stromal tumors treated with front-line imatinib mesylate?
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).
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.
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.
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.
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.
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.
clinicaltrials.gov Identifier: NCT00009906
Heinrich MC, Rankin C, Blanke CD, et al. Correlation of Long-term Results of Imatinib in Advanced Gastrointestinal Stromal Tumors With Next-Generation Sequencing ResultsAnalysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncol. 2017;3(7):944–952. doi:10.1001/jamaoncol.2016.6728
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