Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer

Abstract

Purpose: Mutations in the RET proto-oncogene and vascular endothelial growth factor receptor (VEGFR) activity are critical in the pathogenesis of medullary thyroid cancer (MTC). Sorafenib, a multikinase inhibitor targeting Ret and VEGFR, showed antitumor activity in preclinical studies of MTC.

Patients and methods: In this phase II trial of sorafenib in patients with advanced MTC, the primary end point was objective response. Secondary end points included toxicity assessment and response correlation with tumor markers, functional imaging, and RET mutations. Using a two-stage design, 16 or 25 patients were to be enrolled onto arms A (hereditary) and B (sporadic). Patients received sorafenib 400 mg orally twice daily.

Results: Of 16 patients treated in arm B, one achieved partial response (PR; 6.3%; 95% CI, 0.2% to 30.2%), 14 had stable disease (SD; 87.5%; 95% CI, 61.7% to 99.5%), and one was nonevaluable. In a post hoc analysis of 10 arm B patients with progressive disease (PD) before study, one patient had PR of 21+ months, four patients had SD >or= 15 months, four patients had SD <or= 6 months, and one patient had clinical PD. Median progression-free survival was 17.9 months. Arm A was prematurely terminated because of slow accrual. Common adverse events (AEs) included diarrhea, hand-foot-skin reaction, rash, and hypertension. Although serious AEs were rare, one death was seen. Tumor markers decreased in the majority of patients, and RET mutations were detected in 10 of 12 sporadic MTCs analyzed.

Conclusion: Sorafenib is reasonably well tolerated, with suggestion of clinical benefit for patients with sporadic MTC. Caution should be taken because of the rare but fatal toxicity potentially associated with sorafenib.

Fig 1.

CONSORT diagram. MTC, medullary thyroid carcinoma; MEN-2A, multiple endocrine neoplasia type 2A; MEN-2B, multiple endocrine neoplasia type 2B; FMTC, familial medullary thyroid carcinoma; PO, oral; BID, twice a day.

Fig 2.

(A) Waterfall plot of Response Evaluation Criteria in Solid Tumors (RECIST) responses for arm B patients (maximum percentage of tumor reduction for target lesions by RECIST). Each bar represents an individual patient evaluable for RECIST response on arm B (n = 15). (*) Patients with RET M918T mutation. SD, stable disease; PR, partial response. (B) Progression-free survival for arm B patients. The median progression-free survival time is 17.9 months (95% CI, 8.0 months to not available). (C) Overall survival for arm B patients. The median overall survival was not estimable at the data analysis cutoff point.

Fig 3.

Comparison of the best Response Evaluation Criteria in Solid Tumors (RECIST) and serum (A) calcitonin and (B) carcinoembryonic antigen (CEA) changes from baseline for arm B patients. RECIST response refers to the change from baseline in the sum of the diameter of all indexed lesions.