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Prolonged Therapy with Imatinib Mesylate before Surgery for Advanced Gastrointestinal Stromal Tumor Results of a Phase II Trial.

ABSTRACT: Purpose. Proven efficacy of imatinib mesylate in gastrointestinal stromal tumour (GIST) has led to its use in advanced disease and, more recently, in adjuvant and neoadjuvant settings. The purpose of this study was to evaluate the optimal neoadjuvant imatinib duration to reduce the morbidity of surgery and increase the possibility of resection completeness in advanced tumours. Patients and Method. Patients with advanced GIST were enrolled into a registered open-label multicenter trial and received imatinib daily for a maximum of 12 months, followed by en bloc resection. Data were prospectively collected regarding tumour assessment, response rate, surgical characteristics, recurrence, and survival. Results. Fourteen patients with advanced GIST were enrolled. According to RECIST criteria, 6 patients had partial response and 8 had stable disease. The overall tumour size reduction was 25% (0-62.5%), and there was no tumour progression. Eleven patients underwent tumour resection, and all had R0 resection. After a median followup of 48 months, 4-year OS and DFS were 100% and 64%, respectively. Conclusion. This prospective trial showed that one year of neoadjuvant imatinib in advanced GIST is safe and associated with high rate of complete microscopic resection. It is not associated with increased resistance, progression, or complication rates.

SUBMITTER: Doyon C

PROVIDER: S-EPMC3534224 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Prolonged Therapy with Imatinib Mesylate before Surgery for Advanced Gastrointestinal Stromal Tumor Results of a Phase II Trial.

Doyon C C Sidéris L L Leblanc G G Leclerc Y E YE Boudreau D D Dubé P P

International journal of surgical oncology 20121217

Purpose. Proven efficacy of imatinib mesylate in gastrointestinal stromal tumour (GIST) has led to its use in advanced disease and, more recently, in adjuvant and neoadjuvant settings. The purpose of this study was to evaluate the optimal neoadjuvant imatinib duration to reduce the morbidity of surgery and increase the possibility of resection completeness in advanced tumours. Patients and Method. Patients with advanced GIST were enrolled into a registered open-label multicenter trial and receiv ...[more]

PMID: 23316352

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Project description:BackgroundGastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor alpha proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour.MethodsWe undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197.FindingsAll randomised patients were included in the analysis. At median follow-up of 19.7 months (minimum-maximum 0-56.4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96-100] vs 83% [78-88] at 1 year; hazard ratio [HR] 0.35 [0.22-0.53]; one-sided p<0.0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group.InterpretationAdjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour.FundingUS National Institutes of Health and Novartis Pharmaceuticals.

Project description:ImportanceAfter 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.ObectiveTo 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 participantsIn 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.InterventionsPatients 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 measuresThe 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.ResultsOf 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 relevanceA 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 registrationclinicaltrials.gov Identifier: NCT00009906.

Project description:PurposeDual targeting of the gastrointestinal stromal tumor (GIST) lineage-specific master regulators, ETV1 and KIT, by MEK and KIT inhibitors were synergistic preclinically and may enhance clinical efficacy. This trial was designed to test the efficacy and safety of imatinib plus binimetinib in first-line treatment of GIST.MethodsIn this trial (NCT01991379), treatment-naive adult patients with confirmed advanced GISTs received imatinib (400 mg once daily) plus binimetinib (30 mg twice daily), 28-day cycles. The primary end point was RECIST1.1 best objective response rate (ORR; complete response plus partial response [PR]). The study was designed to detect a 20% improvement in the ORR over imatinib alone (unacceptable rate of 45%; acceptable rate of 65%), using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1, and a planned sample size of 44 patients. Confirmed PR or complete response in > 24 patients are considered positive. Secondary end points included Choi and European Organisation for Research and Treatment of Cancer Response Rate, progression-free survival (PFS), overall survival (OS), pathologic responses, and toxicity.ResultsBetween September 15, 2014, and November 15, 2020, 29 of 42 evaluable patients with advanced GIST had confirmed RECIST1.1 PR. The best ORR was 69.0% (two-sided 95% CI, 52.9 to 82.4). Thirty-nine of 41 (95.1%) had Choi PR approximately 8 weeks. Median PFS was 29.9 months (95% CI, 24.2 to not estimable); median OS was not reached (95% CI, 50.4 to not estimable). Five of eight patients with locally advanced disease underwent surgery after treatment and achieved significant pathologic response (≥ 90% treatment effect). There were no unexpected toxicities. Grade 3 and 4 toxicity included asymptomatic creatinine phosphokinase elevation (79.1%), hypophosphatemia (14.0%), neutrophil decrease (9.3%), maculopapular rash (7.0%), and anemia (7.0%).ConclusionThe study met the primary end point. The combination of imatinib and binimetinib is effective with manageable toxicity and warrants further evaluation in direct comparison with imatinib in frontline treatment of GIST.

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Prolonged Therapy with Imatinib Mesylate before Surgery for Advanced Gastrointestinal Stromal Tumor Results of a Phase II Trial.

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Prolonged Therapy with Imatinib Mesylate before Surgery for Advanced Gastrointestinal Stromal Tumor Results of a Phase II Trial.

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