Abstract
Objectives: Sorafenib is a multi-kinase inhibitor affecting RAF kinase, VEGFR, PDGFR and RET. We are conducting a phase II study of sorafenib in patients with advanced thyroid carcinoma to determine the efficacy and to characterize the biologic basis of responses.
Methods: Patients with progressive, metastatic, iodine-refractory, unresectable or locally-advanced thyroid cancer receive sorafenib 400 mg orally BID. Responses are monitored by PET and CT. Primary endpoints are response rate (RR) and progression free survival (PFS) by RECIST criteria. Pre-treatment and on-treatment tissue is analyzed for BRAF mutation status and immunohistochemistry for markers of early biologic activity is performed.
Results: Currently 45 patients are enrolled. We completed a planned interim analysis of 30 patients. Patient ages ranged from 31 to 89, and 15 pts (50%) were male. Histological subtypes included papillary: 28 patients (60%); follicular/Hurthle cell: 9 patients (30%); medullary: 1 patientt (3%), and poorly differentiated/anaplastic: 2 patients (7%). PR was achieved in 7 (23%) patients with a duration of response of 23.7+ to 82+ weeks. 16 (54%) had stable disease with a duration of response of 13.9+ to 87.9+ weeks. Overall median PFS was 79 weeks. For patients with differentiated thyroid cancer the median PFS was 84 weeks. Sorafenib was well-tolerated; treatment-related adverse events included fatigue, rash, diarrhea, palmer-plantar erythema (PPE), musculoskeletal pain, and weight loss. Grade 3 events included HTN and PPE and one patient died due to liver failure. 95% of patients experienced decreased thyroglobulin levels (mean -70%). Correlative tissue studies, analysis of PET scans, BRAF mutation status with an updated analysis including RR and PFS of the current 45 patients will be presented.
Conclusions: Sorafenib has anti-tumor activity in patients with advanced thyroid cancer and, with an overall clinical benefit rate (PR + SD) of 77%, marks a significant advance in the treatment of these patients.