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Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.

ABSTRACT: Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1 and KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFR? are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib versus imatinib as first-line therapy for patients with advanced GISTs.In this randomised, open-label, multicentre, phase 3 trial (ENESTg1), participants from academic centres were aged 18 years or older and had previously untreated, histologically confirmed, metastatic or unresectable GISTs. Patients were stratified by previous adjuvant therapy and randomly assigned (1:1) via a randomisation list to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. The primary endpoint was centrally reviewed progression-free survival. Efficacy endpoints were assessed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00785785.Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April, 2011. Between March 16, 2009, and April 21, 2011, 647 patients were enrolled; of whom 324 were allocated nilotinib and 320 were allocated imatinib. At final analysis of the core study (data cutoff, October, 2012), 2-year progression-free survival was higher in the imatinib group (59·2% [95% CI 50·9-66·5]) than in the nilotinib group (51·6% [43·0-59·5]; hazard ratio 1·47 [95% CI 1·10-1·95]). In the imatinib group, the most common grade 3-4 adverse events were hypophosphataemia (19 [6%]), anaemia (17 [5%]), abdominal pain (13; 4%), and elevated lipase level (15; 5%), and in the nilotinib group were anaemia (18; 6%), elevated lipase level (15; 5%), elevated alanine aminotransferase concentration (12; 4%), and abdominal pain (11; 3%). The most common serious adverse event in both groups was abdominal pain (11 [4%] in the imatinib group, 14 [4%] in the nilotinib group).Nilotinib cannot be recommended for broad use to treat first-line GIST. However, future studies might identify patient subsets for whom first-line nilotinib could be of clinical benefit.Novartis Pharmaceuticals.

SUBMITTER: Blay JY

PROVIDER: S-EPMC4521211 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.

Blay Jean-Yves JY Shen Lin L Kang Yoon-Koo YK Rutkowski Piotr P Qin Shukui S Nosov Dmitry D Wan Desen D Trent Jonathan J Srimuninnimit Vichien V Pápai Zsuzsanna Z Le Cesne Axel A Novick Steven S Taningco Lilia L Mo Shuyuan S Green Steven S Reichardt Peter P Demetri George D GD

The Lancet. Oncology 20150414 5

<h4>Background</h4>Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1 and KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFRα are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib versus imatinib as first-line therapy for patients with advanced GISTs.<h4>Methods</h4>In this randomised, open-label, multicentre, phase 3 tr ...[more]

PMID: 25882987

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Project description:Few treatment options remain for patients with metastatic or unresectable gastrointestinal stromal tumours (GIST) after objective progression on approved tyrosine-kinase inhibitors. We aimed to assess efficacy of imatinib rechallenge in these patients.In our prospective, randomised, double-blind trial, we enrolled adults (?18 years) who had previously benefited from first-line imatinib (initial response or stable disease for ?6 months) but whose metastatic or unresectable GIST had progressed on at least imatinib and sunitinib. We randomly allocated participants in a 1:1 ratio, with a centralised computer-generated allocation procedure (random permuted blocks of two, four, and six) and stratified by previous treatment and Eastern Cooperative Oncology Group performance status, to receive best supportive care with imatinib 400 mg per day or matched placebo. Crossover to open-label imatinib was allowed after investigator-adjudicated disease progression. The primary endpoint was progression-free survival (PFS), as determined by a masked external radiological review. All analyses were done for all patients who received at least one dose of study drug.Between July 20, 2010, and Jan 17, 2013, we randomly allocated 41 patients to the imatinib group and 40 patients to the placebo group. After a median follow-up of 5·2 months (IQR 3·4-9·4), median PFS was 1·8 months (95% CI 1·7-3·6) with imatinib compared with 0·9 months (0·9-1·7) with placebo (hazard ratio for progression or death 0·46, 95% CI 0·27-0·78; p=0·005). 37 (93%) patients in the placebo group crossed over to open-label imatinib after progression. The most common grade 3 or worse adverse events were anaemia (12 [29%] of 41 patients in the imatinib group vs three [8%] of 40 in the placebo group), fatigue (four [10%] vs none), and hyperbilirubinaemia (three [7%] vs one [3%]).In patients with GIST that is refractory to treatment with all standard tyrosine-kinase inhibitors, the disease continues to harbour many clones that are sensitive to kinase inhibitors. Continued kinase suppression might slow, although not halt, disease progression.

Project description:BackgroundImatinib is the standard first-line treatment for advanced gastrointestinal stromal tumors (GISTs); however, most patients eventually develop imatinib resistance, leading to considerable clinical challenges. Few direct comparisons have been made between different post-first-line therapies on clinical efficacy in advanced GIST following imatinib failure.MethodsDatabases including PubMed, Embase, Scopus, Google Scholars, and Cochrane Library from inception to February 2023 were retrieved for randomized controlled trials evaluating the clinical efficacy of different post-first-line agents for advanced GIST following imatinib failure. Network and conventional meta-analysis were carried out using Stata/MP 16.0.ResultsRipretinib showed significant improvement in progression-free survival (PFS) rates from the 2nd to the 12th month compared to placebo, while there was virtually no evidence that the rest active agents had a significant benefit at the 12th month. Masitinib, ripretinib, sunitinib, regorafenib, and pimitespib exhibited significantly longer median PFS than placebo, and pairwise comparisons indicated there were no significant differences among masitinib, ripretinib, and sunitinib. These post-first-line agents decreased the risk of disease progression or death by 65% (HR = 0.35, 95% CI: 0.26-0.47) compared to placebo. Ripretinib and sunitinib came into effect earlier and exhibited more consistent overall survival (OS) rate improvements than masitinib and pimitespib, while pairwise comparisons revealed no significant differences in these four active agents concerning the improvement in OS rate. These post-first-line agents decreased the risk of death by 39% (HR = 0.61, 95% CI: 0.44-0.83) over placebo for advanced GIST following imatinib failure.ConclusionThe active agents in our analysis as post-first-line therapies are able to provide superior clinical efficacy, with improved PFS rate and OS rate at certain time points, as well as absolute values of PFS and OS for advanced GIST. Ripretinib might be the optimal recommendation as a post-first-line treatment for advanced GIST following imatinib failure.

Dataset Information

Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.

Publications

Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial.

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