TY - JOUR
T1 - Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1)
T2 - A randomised phase 3 trial
AU - Blay, Jean Yves
AU - Shen, Lin
AU - Kang, Yoon Koo
AU - Rutkowski, Piotr
AU - Qin, Shukui
AU - Nosov, Dmitry
AU - Wan, Desen
AU - Trent, Jonathan
AU - Srimuninnimit, Vichien
AU - Pápai, Zsuzsanna
AU - Le Cesne, Axel
AU - Novick, Steven
AU - Taningco, Lilia
AU - Mo, Shuyuan
AU - Green, Steven
AU - Reichardt, Peter
AU - Demetri, George D.
N1 - Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: Novartis Pharmaceuticals.
AB - Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: Novartis Pharmaceuticals.
UR - http://www.scopus.com/inward/record.url?scp=84933676269&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(15)70105-1
DO - 10.1016/S1470-2045(15)70105-1
M3 - Article
C2 - 25882987
AN - SCOPUS:84933676269
SN - 1470-2045
VL - 16
SP - 550
EP - 560
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 5
ER -