Faculty Collaboration Database

Inhibition of the Ras/Raf/MEK/ERK and RET kinase pathways with the combination of the multikinase inhibitor sorafenib and the farnesyltransferase inhibitor tipifarnib in medullary and differentiated thyroid malignancies. J Clin Endocrinol Metab 2011 Apr;96(4):997-1005

Date

02/04/2011

Pubmed ID

21289252

Pubmed Central ID

PMC3070247

DOI

10.1210/jc.2010-1899

Scopus ID

2-s2.0-79953904634 (requires institutional sign-in at Scopus site)   91 Citations

Abstract

PURPOSE: Ras/Raf/MAPK kinase/ERK and rearranged in transformation (RET) kinase pathways are important in thyroid cancer. We tested sorafenib, a B-Raf, RET, and vascular endothelial growth factor receptor kinase inhibitor, combined with tipifarnib, a farnesyltransferase inhibitor that inactivates Ras and other farnesylated proteins.

PATIENTS AND METHODS: We treated 35 patients with differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in a phase I trial. Sorafenib and tipifarnib were given for 21 d with 7 d rest in each 28-d cycle.

RESULTS: We enrolled 22 patients with metastatic DTC (16 papillary, five follicular, and one poorly differentiated) and 13 patients with MTC, of whom 15 with DTC and 10 with MTC reached first restaging. When tissue was available, eight of 15 DTC patients (53%) had B-Raf mutations; eight of 13 MTC (61.5%) patients had RET mutations. MTC partial response rate was 38% (five of 13) (duration = 9+, 12, 13, 16+, and 34+ months), stable disease of at least 6 months was 31% (four of 13). The DTC partial response rate was 4.5% (one of 22), and stable disease of at least 6 months was 36% (eight of 22). Median progression-free survival for all 35 patients was 18 months (95% confidence interval, 14.6 to not reached months). Median overall survival has not been reached, with a median follow-up of 24 months with 80% overall survival. Grade 1-2 toxicities were mainly rash, fatigue, and diarrhea. The most common grade 3-4 toxicities were rash, rise in amylase/lipase, and fatigue.

CONCLUSIONS: Inhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.

Author List

Hong DS, Cabanillas ME, Wheler J, Naing A, Tsimberidou AM, Ye L, Busaidy NL, Waguespack SG, Hernandez M, El Naggar AK, Bidyasar S, Wright J, Sherman SI, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma, Follicular
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Benzenesulfonates
Carcinoma, Neuroendocrine
Cell Differentiation
Dose-Response Relationship, Drug
Extracellular Signal-Regulated MAP Kinases
Farnesyltranstransferase
Female
Humans
MAP Kinase Kinase Kinases
Male
Middle Aged
Niacinamide
Oncogene Protein p21(ras)
Phenylurea Compounds
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-ret
Pyridines
Quinolones
Signal Transduction
Thyroid Neoplasms
raf Kinases