Phase-2 study of imatinib in metastasized medullary thyroid carcinoma

Abstract

15500 Background: Medullary thyroid carcinoma (MTC) is a relatively rare tumor that metastasizes to regional lymph nodes, lung, liver and bone. When surgery is no longer a curative treatment option, no effective systemic therapy is currently available. In most cases a (somatic or germline) mutation in the RET (REarranged during Transfection) gene is considered to be an essential step in the pathogenesis of MTC. Imatinib is an oral inhibitor of several protein-tyrosine kinases including RET kinase. It has shown to be an effective drug in chronic myeloid leukemia and gastrointestinal stromal tumors. Methods: A two-step open label phase-2 study was initiated using 600 mg imatinib daily with a scheduled dose increase to 800 mg in case of minimal toxicity. Standard RECIST criteria were used for response evaluation using CT/MRI scans every 2 months. The two-step design allowed no further inclusion in the absence of objective responses in 15 patients. Results: 15 patients with metastasized MTC were included. No objective responses were observed but long term stable disease over 18 months was noted in 4 patients. However, toxicity was considerable. Emergency tracheotomy had to be performed in 2 cases due to mucosal swelling in patients with laryngeal nerve palsy and a narrow vocal cleft. In 3 cases the dose of Imatinib had to be decreased because of unacceptable toxicity (malaise, mucosal swelling (2) and fatigue). In 7 patients with a history of a thyreoidectomy, the dose of thyroxine had to be increased considerably to avoid serious hypothyroidism due to an incompletely understood interaction. Conclusion: Treatment with Imatinib yielded no objective responses and considerable toxicity in patients with MTC. Long-term stabilization of the disease was observed in only a minority of the patients. Patients with hypothyroidism and with laryngeal nerve palsy are at risk for serious adverse events and need special attention when treated with Imatinib. No significant financial relationships to disclose.