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

Abstract

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.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1. CONSORT diagram

A randomised, open label, multi-centre phase III study to evaluate the efficacy and safety of nilotinib vs imatinib in adult patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1)—ClinicalTrials.gov identifier: NCT00785785. Note: 11 patients were assigned to imatinib therapy (as forced randomization) because they signed an informed consent form prior to termination of patient accrual on April 8, 2011. *Dose: nilotinib 400 mg twice daily; imatinib 400 mg once daily. Patients whose tumour has confirmed KIT exon 9 mutation before the study entry could start imatinib at 400 mg twice daily.

Figure 2. PFS

PFS by adjudicated central review in the full-analysis set (A) and in the subsets of patients with KIT exon 9 mutations (B) or KIT exon 11 mutations (C). Following the interim analysis and decision to stop recruitment for futility, no subsequent formal inferences could be made; therefore, P values are not presented. *All exon 9 mutants on nilotinib had a PFS event or censoring within 6 months. HR=hazard ratio. PFS=progression-free survival. NE=not estimable.

Figure 2. PFS

PFS by adjudicated central review in the full-analysis set (A) and in the subsets of patients with KIT exon 9 mutations (B) or KIT exon 11 mutations (C). Following the interim analysis and decision to stop recruitment for futility, no subsequent formal inferences could be made; therefore, P values are not presented. *All exon 9 mutants on nilotinib had a PFS event or censoring within 6 months. HR=hazard ratio. PFS=progression-free survival. NE=not estimable.

Figure 2. PFS

PFS by adjudicated central review in the full-analysis set (A) and in the subsets of patients with KIT exon 9 mutations (B) or KIT exon 11 mutations (C). Following the interim analysis and decision to stop recruitment for futility, no subsequent formal inferences could be made; therefore, P values are not presented. *All exon 9 mutants on nilotinib had a PFS event or censoring within 6 months. HR=hazard ratio. PFS=progression-free survival. NE=not estimable.

Figure 3. OS

OS in the full-analysis set (A) and in the subsets of patients with KIT exon 9 mutations (B) or KIT exon 11 mutations (C). HR=hazard ratio. OS=overall survival. Median OS was not reached in either arm in the overall population or in the mutation subgroups.

Figure 3. OS

OS in the full-analysis set (A) and in the subsets of patients with KIT exon 9 mutations (B) or KIT exon 11 mutations (C). HR=hazard ratio. OS=overall survival. Median OS was not reached in either arm in the overall population or in the mutation subgroups.

Figure 3. OS

OS in the full-analysis set (A) and in the subsets of patients with KIT exon 9 mutations (B) or KIT exon 11 mutations (C). HR=hazard ratio. OS=overall survival. Median OS was not reached in either arm in the overall population or in the mutation subgroups.

Figure 4. Progression-free survival of the full-analysis set by local and central review