Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Lam
Elaine T
ET
Departments of Internal Medicine, Center for Biostatistics, The Ohio State University, Columbus, OH, USA. manisha.shah@osumc.edu
Ringel
Matthew D
MD
Kloos
Richard T
RT
Prior
Thomas W
TW
Knopp
Michael V
MV
Liang
Jiachao
J
Sammet
Steffen
S
Hall
Nathan C
NC
Wakely
Paul E
PE
Vasko
Vasyl V
VV
Saji
Motoyasu
M
Snyder
Pamela J
PJ
Wei
Lai
L
Arbogast
Daria
D
Collamore
Minden
M
Wright
John J
JJ
Moley
Jeffrey F
JF
Villalona-Calero
Miguel A
MA
Shah
Manisha H
MH
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018276:Carcinoma, Medullary / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D000077157:Sorafenib; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
D001557:Benzenesulfonates; D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D040262:Receptors, Vascular Endothelial Growth Factor