Pazopanib: a new therapeutic option for advanced gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancy of the alimentary tract, with an annual incidence of 6,000 new cases in the United States (1). Surgery has been the mainstay of treatment for GIST, but a significant number of patients develop unresectable or metastatic disease. Since most GISTs are driven by constitutively active receptor tyrosine kinases (KIT in 85% and PDGFRA in 10%) (2,3), systemic therapy for advanced GIST consists primarily of tyrosine kinase inhibitors (TKIs). Imatinib, a multi-targeted TKI with activity against KIT and PDGFRA, was the first of these to show significant efficacy against unresectable or metastatic GIST, with a median progression-free survival (PFS) of 24 months (4). However, over 80% of patients eventually develop imatinib resistance. Sunitinib, another multi-targeted TKI, was shown to confer a median PFS of 24 weeks for imatinib-resistant/intolerant patients (5), and it has now become the second-line therapy for advanced GIST. Unfortunately, almost all of these patients also subsequently develop sunitinib resistance over time.