Dataset Information

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: 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.

SUBMITTER: Heinrich MC

PROVIDER: S-EPMC5727908 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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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.

Heinrich Michael C MC Rankin Cathryn C Blanke Charles D CD Demetri George D GD Borden Ernest C EC Ryan Christopher W CW von Mehren Margaret M Blackstein Martin E ME Priebat Dennis A DA Tap William D WD Maki Robert G RG Corless Christopher L CL Fletcher Jonathan A JA Owzar Kouros K Crowley John J JJ Benjamin Robert S RS Baker Laurence H LH

JAMA oncology 20170701 7

<h4>Importance</h4>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.<h4>Obective</h4>To assess the long-term survival of patients with GIST who were treated in SWOG study ...[more]

PMID: 28196207

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Project description:ImportanceThe association between quality of surgery and overall survival in patients affected by localized gastrointestinal stromal tumors (GIST) is not completely understood.ObjectiveTo assess the risk of death with and without imatinib according to microscopic margins status (R0/R1) using data from a randomized study on adjuvant imatinib.Design, setting, and participantsThis is a post hoc observational study on patients included in the randomized, open-label, phase III trial, performed between December 2004 and October 2008. Median follow-up was 9.1 years (IQR, 8-10 years). The study was performed at 112 hospitals in 12 countries. Inclusion criteria were diagnosis of primary GIST, with intermediate or high risk of relapse; no evidence of residual disease after surgery; older than 18 years; and no prior malignancies or concurrent severe/uncontrolled medical conditions. Data were analyzed between July 17, 2017, and March 1, 2020.InterventionsPatients were randomized after surgery to either receive imatinib (400 mg/d) for 2 years or no adjuvant treatment. Randomization was stratified by center, risk category (high vs intermediate), tumor site (gastric vs other), and quality of surgery (R0 vs R1). Tumor rupture was included in the R1 category but also analyzed separately.Main outcomes and measuresPrimary end point of this substudy was overall survival (OS), estimated using Kaplan-Meier method and compared between R0/R1 using Cox models adjusted for treatment and stratification factors.ResultsA total of 908 patients were included; 51.4% were men (465) and 48.6% were women (440), and the median age was 59 years (range, 18-89 years). One hundred sixty-two (17.8%) had an R1 resection, and 97 of 162 (59.9%) had tumor rupture. There was a significant difference in OS for patients undergoing an R1 vs R0 resection, overall (hazard ratio [HR], 2.05; 95% CI, 1.45-2.89) and by treatment arm (HR, 2.65; 95% CI, 1.37-3.75 with adjuvant imatinib and HR, 1.86; 95% CI, 1.16-2.99 without adjuvant imatinib). When tumor rupture was excluded, this difference in OS between R1 and R0 resections disappeared (HR, 1.05; 95% CI, 0.54-2.01).Conclusions and relevanceThe difference in OS by quality of surgery with or without imatinib was associated with the presence of tumor rupture. When the latter was excluded, the presence of R1 margins was not associated with worse OS.Trial registrationClinicalTrials.gov Identifier: NCT00103168.

Project description:Despite having significant rationale, S0502 failed to accrue for a number of reasons.Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy.In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study.Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19-23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis.Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST.S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia.No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use.

Dataset Information

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.

Publications

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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