This phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure.
Patients were randomized 2:1 to nilotinib 400 mg b.i.d. or best supportive care (BSC; BSC without tyrosine kinase inhibitor, BSC+imatinib, or BSC+sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib.
Two hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days; P=0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days; P=0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days; P=0.29). Post hoc subset analyses in patients with progression and only one prior regimen each of imatinib and sunitinib revealed a significant difference in median OS of >4 months in favor of nilotinib (405 versus 280 days; P=0.02). Nilotinib was well tolerated.
In the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS.
"Other identified mechanisms of acquired resistance have included amplification of KIT and pharmacokinetic resistance that may involve altered activity of drug transporters, induction of the cytochrome P450 (CYP)3A4 isoenzyme, and poor patient compliance [40, 41]. Dose-escalation of Imatinib or second-generation tyrosine kinase inhibitors (TKIs) may be considered in these settings [42–44]. "
[Show abstract][Hide abstract] ABSTRACT: Deregulated protein tyrosine kinase activity is central to the pathogenesis of human cancers. Targeted therapy in the form of selective tyrosine kinase inhibitors (TKIs) has transformed the approach to management of various cancers and represents a therapeutic breakthrough. Imatinib was one of the first cancer therapies to show the potential for such targeted action. Imatinib, an oral targeted therapy, inhibits tyrosine kinases specifically BCR-ABL, c-KIT, and PDGFRA. Apart from its remarkable success in CML and GIST, Imatinib benefits various other tumors caused by Imatinib-specific abnormalities of PDGFR and c-KIT. Imatinib has also been proven to be effective in steroid-refractory chronic graft-versus-host disease because of its anti-PDGFR action. This paper is a comprehensive review of the role of Imatinib in oncology.
05/2014; 2014(2):357027. DOI:10.1155/2014/357027
"Nilotinib, a second generation tyrosine kinase inhibitor, prevents autophosphorylation of c-KIT and platelet GFR. In a phase III, open label trial, nilotinib was studied in advanced GIST resistant to imatinib and sunitinib. Patients (n = 248) were randomized to nilotinib or best supportive care with imatinib/sunitinib/placbo. Median PFS was similar in both arms (nilotinib 109 days vs. best supportive care 111 days; P = 0.56) based on central radiology review. "
[Show abstract][Hide abstract] ABSTRACT: Increased understanding of cancer pathogenesis has identified several pathways that serve as potential targets for novel targeted agents in development. The selection of targeted cancer therapy based on biomarkers has instigated a new era of personalized medicine and changed the way we practice oncology. Many targeted agents are approved for treatment of gastrointestinal malignancies most targeting tumor angiogenesis, and many more are in different phases of development. Here we briefly summarize nine different targeted agents that are approved currently in the U.S. and several other agents currently being studied in various gastrointestinal cancers.
Journal of Carcinogenesis 02/2014; 13(1):4. DOI:10.4103/1477-3163.127639
"Nilotinib was studied in a randomized phase 3 clinical trial (ENEST g3) . In this trial nilotinib was compared to a heterogeneous control arm in patients advanced/metastatic GIST who had failed imatinib and sunitinib. "
[Show abstract][Hide abstract] ABSTRACT: The discovery of CD117 mutation in almost all gastrointestinal stromal tumors (GISTs) marked a milestone. Other spindle cell neoplasms arising from the GI tract including lipoma, schwannoma, hemangioma, leiomyoma, and leiomyosarcoma are typically CD117-negative. GIST research and clinical care now represent a paradigm of translating discoveries in the molecular pathogenesis of cancer into highly effective targeted therapies that selectively inhibit etiologic "driver" pathways, leading to dramatically improved clinical outcomes. A series of investigations and trials are underway to develop novel and effective ways to treat patients with GIST. In this review, we discuss the highlights of recent advances and novel agents for GIST therapy.
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