Nilotinib vs Best Supportive Care With or Without a TKI in GIST
Nilotinib vs Best Supportive Care With or Without a TKI in GIST
Background 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 and methods 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.
Results 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.
Conclusion 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.
Historically, the prognosis for patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) has been poor The introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec®/Glivec®, Novartis Pharma AG, Basel, Switzerland) revolutionized the management of GIST, providing a median overall survival (OS) of 57 months versus the 19 expected in the preimatinib era.
Despite these improvements, most patients eventually progress on imatinib, and a small percentage of patients are intolerant of the drug. Sunitinib malate (Sutent®, Pfizer Pharmaceuticals, New York), a multiple receptor TKI, is the only approved second-line treatment option for GIST patients intolerant of or progressing on imatinib.
To date, there are no approved therapies available for patients with GIST following failure of both imatinib and sunitinib. Nilotinib (Tasigna®, AMN107; Novartis Pharma AG), a phenylaminopyrimidine, is a selective TKI that may address this important unmet medical need. Like imatinib, nilotinib potently inhibits receptor tyrosine kinases KIT and PDGFR as well as BCR-ABL. Nilotinib has greater in vitro potency against BCR-ABL than imatinib but exhibits similar inhibitory activity against KIT and PDGFR kinases. In cell lines expressing mutant KIT, nilotinib reduces cell viability to an extent similar to imatinib; it also has potent antiproliferative activity against imatinib-sensitive forms of KIT and some activity against certain imatinib-resistant forms of KIT. Whereas imatinib requires an active transport mechanism via organic cation transporter-1 for cell entry, nilotinib transport is mostly passive, which has been shown to result in a 7- to 10-fold higher intracellular concentration in imatinib-sensitive and -resistant cell lines, with comparable inhibitory activity to imatinib. This differential cellular uptake is thought to make nilotinib less susceptible to cellular transport-driven imatinib resistance. In fact, experimental evidence indicates that P-glycoprotein, associated with multidrug resistance, functions to reduce intracellular concentrations of imatinib in transformed cell lines, conferring drug resistance.
Results from clinical studies have shown that nilotinib has some demonstrable activity in patients with advanced GIST who are intolerant or resistant to approved TKIs. In a phase I study of imatinib-resistant/intolerant GIST patients, nilotinib (400 mg b.i.d.) was well tolerated and demonstrated clinical activity. Furthermore, retrospective analysis of data from patients in a compassionate use program with unresectable or metastatic GIST following failure of all other treatment options reported that nilotinib treatment resulted in clinical responses and stable disease (SD) in 10% and 37% of assessable patients, respectively.
The Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST) g3 study was conducted to assess the potential clinical benefit of nilotinib in heavily pretreated patients with advanced GIST and evaluated efficacy and safety of nilotinib versus best supportive care (BSC) with investigator choice to include imatinib or sunitinib as part of the BSC regimen in patients with advanced GIST following failure of both approved TKIs.
Abstract and Introduction
Abstract
Background 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 and methods 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.
Results 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.
Conclusion 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.
Introduction
Historically, the prognosis for patients with unresectable or metastatic gastrointestinal stromal tumors (GIST) has been poor The introduction of the tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec®/Glivec®, Novartis Pharma AG, Basel, Switzerland) revolutionized the management of GIST, providing a median overall survival (OS) of 57 months versus the 19 expected in the preimatinib era.
Despite these improvements, most patients eventually progress on imatinib, and a small percentage of patients are intolerant of the drug. Sunitinib malate (Sutent®, Pfizer Pharmaceuticals, New York), a multiple receptor TKI, is the only approved second-line treatment option for GIST patients intolerant of or progressing on imatinib.
To date, there are no approved therapies available for patients with GIST following failure of both imatinib and sunitinib. Nilotinib (Tasigna®, AMN107; Novartis Pharma AG), a phenylaminopyrimidine, is a selective TKI that may address this important unmet medical need. Like imatinib, nilotinib potently inhibits receptor tyrosine kinases KIT and PDGFR as well as BCR-ABL. Nilotinib has greater in vitro potency against BCR-ABL than imatinib but exhibits similar inhibitory activity against KIT and PDGFR kinases. In cell lines expressing mutant KIT, nilotinib reduces cell viability to an extent similar to imatinib; it also has potent antiproliferative activity against imatinib-sensitive forms of KIT and some activity against certain imatinib-resistant forms of KIT. Whereas imatinib requires an active transport mechanism via organic cation transporter-1 for cell entry, nilotinib transport is mostly passive, which has been shown to result in a 7- to 10-fold higher intracellular concentration in imatinib-sensitive and -resistant cell lines, with comparable inhibitory activity to imatinib. This differential cellular uptake is thought to make nilotinib less susceptible to cellular transport-driven imatinib resistance. In fact, experimental evidence indicates that P-glycoprotein, associated with multidrug resistance, functions to reduce intracellular concentrations of imatinib in transformed cell lines, conferring drug resistance.
Results from clinical studies have shown that nilotinib has some demonstrable activity in patients with advanced GIST who are intolerant or resistant to approved TKIs. In a phase I study of imatinib-resistant/intolerant GIST patients, nilotinib (400 mg b.i.d.) was well tolerated and demonstrated clinical activity. Furthermore, retrospective analysis of data from patients in a compassionate use program with unresectable or metastatic GIST following failure of all other treatment options reported that nilotinib treatment resulted in clinical responses and stable disease (SD) in 10% and 37% of assessable patients, respectively.
The Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST) g3 study was conducted to assess the potential clinical benefit of nilotinib in heavily pretreated patients with advanced GIST and evaluated efficacy and safety of nilotinib versus best supportive care (BSC) with investigator choice to include imatinib or sunitinib as part of the BSC regimen in patients with advanced GIST following failure of both approved TKIs.
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