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, as well as 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 vs imatinib as first-line therapy for patients with advanced GISTs. Methods This randomised, open-label, multicentre phase 3 trial included 647 adult patients with previously untreated, histologically confirmed, metastatic and/or unresectable GISTs. Patients were stratified by prior adjuvant therapy and randomised in a 1:1 ratio to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. Centrally reviewed progression-free survival (PFS) was the primary endpoint. Response rates, toxicity, and overall survival were also analysed for the overall population and for mutation-defined subsets. Efficacy endpoints used the intention to treat principle. Here, the final results are reported. 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. At final analysis of the core study (data cutoff, October 2012), PFS was higher with imatinib overall (hazard ratio [HR] 1.47) and in the KIT exon 9 subgroup (HR 32.46) but roughly similar between arms in the KIT exon 11 subgroup (HR 1.12). Sensitivity analyses suggested that informative censoring may have contributed, because of the high proportion of premature nilotinib progressions declared by local investigators and the design changes implemented following the interim analysis, potentially biasing PFS data in favour of the nilotinib arm. The most common adverse events were nausea, diarrhoea, and peripheral oedema in the imatinib arm and rash, nausea, and abdominal pain in the nilotinib arm. The most common serious adverse event in both arms was abdominal pain (imatinib, n=11 [3.5%]); nilotinib, n= 14 [4.4%]). Interpretation Our results suggest that nilotinib is not an optimal treatment approach for first-line GIST; however, future studies may identify patient subsets form whom first-line nilotinib could be of clinical benefit. Funding Novartis Pharmaceuticals.

Neoadjuvant Therapy to Downstage the Extent of Resection of Gastrointestinal Stromal Tumors

“…The oncological efficacy of nilotinib as a first-line treatment has been compared to that of imatinib in a randomized phase III trial [47]. The primary endpoint of the trial was PFS.…”

Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years

“…Based on article identification and selection, we totally included 28 trials from 35 articles (9-30), involving 17,466 randomly assigned patients ( Figure 1) (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

CD117/c-kit in Cancer Stem Cell-Mediated Progression and Therapeutic Resistance

“…Phase 3 randomized trials found that nilotinib was unsuccessful as either first-line therapy for GIST or as second-line therapy for imatinib-resistant GIST, relegating its use mainly to CML [139], [140]. In clinical trials of patients with AIDS-associated Karposi's sarcoma, imatinib has demonstrated clinical benefit through its inhibition of both CD117 and platelet-derived growth factor (PDGF) [141]- [143].…”