Transient sunitinib resistance in gastrointestinal stromal tumors.

Sunitinib — an oral tyrosine kinase inhibitor targeting KIT, platelet-derived growth factor receptors α and β, vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3, and other receptors — is an effective second-line therapy for metastatic gastrointestinal stromal-cell tumors after the use of first-line imatinib.1,2 If disease progresses during treatment with sunitinib, current therapeutic options are limited. We describe two patients who were successfully rechallenged with sunitinib after disease progression and had an objective response and a persistent clinical benefit. Both patients, a 62-year-old man and a 58-year-old woman, underwent a gastric resection for a high-risk gastrointestinal stromal-cell tumor harboring KIT exon 11 mutations. When progression occurred to the peritoneum and liver, each patient began to receive imatinib at a dose of 400 mg per day and continued treatment for almost 3 years, with a prolonged partial response. When disease progression was detected on computed tomography (CT), the dose of imatinib was increased to 800 mg per day. A few months later, for progressing disease, both patients began to receive sunitinib at a dose of 37.5 mg per day. They had a partial response that lasted more than 2 years. After further disease progression, both patients received nilotinib without a response and reexposure to imatinib without any benefit. Each patient had a rapid decline in performance status, and sunitinib treatment was tried again. Within a few days, both patients' symptoms started to improve. CT scans showed a partial response. The male patient had stable disease after 12 months of retreatment with sunitinib, whereas the female patient had progression after 9 months and began to receive regorafenib. Mechanisms of resistance to sunitinib and other tyrosine kinase inhibitors that target VEGFRs are largely unknown, but studies involving patients with renal-cell carcinoma suggest that resistance may be transient.3 The clinical histories of these two patients have similar features: the gastrointestinal site of the tumor, a prolonged response to imatinib and sunitinib, and a months-long interval before reexposure. In contrast to imatinib, in which secondary resistance is mostly due to emergence of new KIT mutations, mechanisms of sunitinib resistance are unclear.4 Is resistance routinely reversible after a sunitinib-free interval, similar to the responses to platinum-based chemotherapy in patients with ovarian cancer after a platinum-free interval? The positive trial with regorafenib as third-line therapy versus supportive care is encouraging, but given that regorafenib also targets angiogenesis, could it be just reexposure to an antiangiogenic drug that is effective?5