Phase II trial of sorafenib in patients with advanced thyroid cancer.

Abstract

5562 Background: Sorafenib is a multikinase inhibitor that targets VEGFR, PDGFR, and Raf. We report the results of UPCC 03305, our completed phase II trial of sorafenib for advanced thyroid carcinoma. Median progression-free and overall survival, response rates and genotyping data are included. Methods: 55 Patients with progressing advanced, iodine-refractory differentiated or poorly differentiated thyroid cancer (DTC/PD), and medullary and anaplastic thyroid carcinoma (MTC and ATC) were eligible. Patients were treated with sorafenib 400 mg BID and evaluated with imaging every two to three months per protocol. The primary outcome was progression-free survival (PFS) per RECIST. Secondary endpoints included overall survival (OS), response rate (RR), toxicity, and tumor cell genotype. Mutations in cancer cells were identified using a customized Sequenom panel containing 197 mutations known to occur in thyroid cancer including BRAF, RAS, MET, RET, and PIK3CA. Results: The study completed enrollment in 8/2009, and was closed in 2/2011. 47 (85%) patients had DTC/PD, 5 (9%) patients had ATC, and 3 (6%) patients had MTC. Overall median PFS was 93.6 wks (95% CI, 62.9-101.9), and median OS was 140.6 wks (95% CI, 79.3-204.7). For the 47 DTC/PD patients, PFS was 96 wks (95% CI, 75.1-135.4), and OS was 140.9 wks (95% CI, 93.9-). 18 (38%) DTC/PD patients achieved a partial response (PR), and 22 (47%) had stable disease (SD) for a clinical benefit rate (PR + SD) of 85%. Tissues from 31 (66%) DTC/PD patients were found to contain at least 1 mutation, including BRAF - 21 pts (45%), RAS - 9 (19%), RET - 5 (11%), and PIK3CA - 4 (9%). Tissue from 8 (17%) DTC/PD and 3 (60%) ATC patients harbored multiple mutations. Conclusions: Our data demonstrate that sorafenib has significant anti-tumor activity in patients with advanced differentiated thyroid cancer. DTC/PD patients treated with sorafenib experience a long progression-free survival, and overall survival compares favorably to historic controls. Mutations were common in thyroid tumor specimens. Our study is the first to report overall survival for patients treated with sorafenib and to fully document the results of a comprehensive mutational analysis of patients enrolled in a thyroid cancer clinical trial.