Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis.

Bruno Vincenzi,Giuseppe Tonini,Giuseppe Badalamenti,Mariella Spalato Ceruso,Margherita Nannini,Daniele Santini,Delia De Lisi,Anna Maria Frezza,Antonio Russo,Angelo Paolo Dei Tos,Maria Abbondanza Pantaleo,Giuseppe Bronte,Paolo Casali,Elena Fumagalli

doi:10.18632/oncotarget.5136

Abstract

We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line.All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits.64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7–10.9) and 5 months (95% CI 3.6–6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370).A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line.

Highlights

GIST account for 0.1–3% of gastrointestinal (GI) malignant tumours and represent the most common mesenchymal tumour of the GI tract (80%)
GIST represents a paradigm for successful targeted treatment with tyrosine kinase inhibitors (TKIs) and imatinib is regarded as the 1st-line treatment of choice in the metastatic setting
It is widely demostrated that KIT and PDGFRA mutational status affect response to imatinib

Summary

Introduction

GIST account for 0.1–3% of gastrointestinal (GI) malignant tumours and represent the most common mesenchymal tumour of the GI tract (80%). About 85–95% of GIST harbour oncogenic mutations affecting KIT or PDGFRA, two highly homologues cell surface tyrosine kinase receptors for stem cells and platelet-derived growth factor. The introduction of imatinib mesylate (Glivec®), a small-molecule tyrosine kinase inhibitor active against BCR-ABL, KIT, and PDGFR, changed dramatically the prognosis of unresectable or metastatic/advanced GIST patients, achieving a disease response in more than 50% of treated cases and stabilisation in almost 30%. Sunitinib malate (Sutent®) is an oral multitargeted receptor tyrosine kinase inhibitor with selectivity for KIT and PDGFRA (and for PDGFRB, all three isoforms of vascular endothelial growth factor receptor, FMS-like tyrosine kinase 3, colony-stimulating factor 1 receptor and glial cell line-derived neurotrophic factor receptor) [6], whose administration is associated with a significant improvement in PFS (27.6 vs 6.4 weeks with placebo, P < 0.0001) for metastatic GIST patients progressing on imatinib. The continuous daily dosing of sunitinib at 37.5 daily is an active alternative dosing strategy with favourable safety [8]

Methods

Results

Conclusion