Gastrointestinal stromal tumors (GISTs) are the second most commonly found soft-tissue sarcoma, with an estimated 5,000 new cases diagnosed annually in the United States.1 They predominantly result from an activating mutation in KIT (CD-117), found in 95% of patients, that generally occurs in KIT exon 11 and less commonly in KIT exon 9 or elsewhere.1,2 Among GISTs with wild-type KIT, approximately 30% harbor a mutation in the gene encoding platelet-derived growth factor receptor A (PDGFRA); these tumors represent between 5% and 8% of all GISTs.2 The identification of an activating mutation associated with GIST led to the development of strategies to inhibit the KIT tyrosine kinase (TK), culminating in approval of imatinib in 2002. Today, imatinib is the standard of care for patients with GIST, and is used as neoadjuvant and adjuvant treatment for patients with resectable GIST and as primary therapy for patients with unresectable or metastatic disease.1,3

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Imatinib changed the outlook for patients with GIST—approximately 90% of patients with KIT exon 11 mutations and 50% of patients with KIT exon 9 mutations respond to imatinib, as do most patients with PDGFRA mutations (with the exception of those carrying the D842V variant). Imatinib response is much less predictable among patients wild-type KIT and PDGFRA, with rates ranging from 0% to 45%.1 Long-term follow-up confirms that imatinib delivers durable disease control in patients with advanced GIST, including a 9-year overall survival rate of 35%. Adjuvant imatinib improves overall survival (OS) in patients at high risk for recurrence following surgery.1,4 Imatinib response is limited by both primary resistance early in therapy and secondary resistance that develops over time.1

Sunitinib, a multi-targeted TK inhibitor (TKI), is currently indicated for second-line treatment of GIST following imatinib resistance or intolerance. Sunitinib inhibits KIT as well as PDGFRA, PDGFRB, and vascular endothelial growth factor (VEGF) receptors 1, 2, and 3.1,5 In longitudinal analysis of a phase 3 study, sunitinib produced objective responses and prolonged time to progression (TTP) compared with placebo in patients who were resistant to or intolerant of imatinib (Table 1). A higher percentage of patients had stable disease with sunitinib (53%) than with placebo (42%). The trial was unblinded when an interim analysis showed a longer TTP with sunitinib compared with placebo, and most patients who were assigned to placebo crossed over to open-label sunitinib. At a median 41.7 months of follow-up, the estimated OS in both groups was longer than 65 weeks.5

Table 1. Sunitinib for GIST Following Imatinib Resistance/Intolerance5

Sunitinib (n = 243) Placebo (n = 118)
Progression-free survival 22.9 weeks 6.0 weeks
P < 0.001
Time to progression 26.6 weeks 6.0 weeks
P < 0.001
Overall objective response rate 7% 0
P = 0.004
Overall survival 72.7 weeks 64.9 weeks

This article originally appeared on Cancer Therapy Advisor