Phase II trial of sorafenib in metastatic thyroid cancer.
OBJECTIVE
Based on the pivotal role of Ras-Raf-MAP-ERK signaling and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC), we conducted a phase II clinical trial of sorafenib targeting RAF and VEGF receptor kinases in PTC.


METHODS
The primary end point was the objective response rate. Secondary end points included response correlation with serum thyroglobulin (Tg); functional imaging; tumor genotype; and signaling inhibition in tumor biopsies. Using a Simon minimax two-stage design, 16 or 25 chemotherapy-naïve metastatic PTC patients were to be enrolled in arm A (accessible tumor for biopsy). Arm B patients had other subtypes of thyroid carcinoma or prior chemotherapy, and did not require tumor biopsies. Patients received 400 mg orally twice per day of sorafenib. Response was assessed every 2 months using RECIST (Response Evaluation Criteria in Solid Tumors).


RESULTS
Of 41 PTC patients, six patients had a partial response (PR; 15%; 95% CI, 6 to 29) and 23 patients (56%; 95% CI, 40 to 72) had stable disease longer than 6 months. Median duration of PR was 7.5 months (range, 6 to 14). Median progression-free survival was 15 months (95% CI, 10 to 27.5). In 14 (78%) of 18 Tg-assessable PTC patients, Tg declined more than 25%. Common grade 3 adverse events included hand-foot skin reaction, musculoskeletal pain, and fatigue. BRAF mutation was detected in 17 (77%) of 22 PTCs analyzed. Four of 10 paired tumor biopsies from PTC patients showed a reduction in levels of vascular endothelial growth factor receptor phosphorylation, ERK phosphorylation, and in VEGF expression during sorafenib therapy. No PRs were noted among non-PTC patients.


CONCLUSIONS
Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.
Kloos
Richard T
RT
Ohio State University, Department of Internal Medicine, Molecular Virology, Immunology, and Genetics, Pathology, Radiology, Center for Biostatistics, Ohio State University, Columbus, OH 43210, USA.
Ringel
Matthew D
MD
Knopp
Michael V
MV
Hall
Nathan C
NC
King
Mark
M
Stevens
Robert
R
Liang
Jiachao
J
Wakely
Paul E
PE
Vasko
Vasyl V
VV
Saji
Motoyasu
M
Rittenberry
Jennifer
J
Wei
Lai
L
Arbogast
Daria
D
Collamore
Minden
M
Wright
John J
JJ
Grever
Michael
M
Shah
Manisha H
MH
D000231:Adenocarcinoma, Papillary / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D013954:Thyroglobulin / Q000097:blood / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D013954:Thyroglobulin; D000077157:Sorafenib