• David S Hong, Maria E Cabanillas, Jennifer Wheler, Aung Naing, Apostolia M Tsimberidou, Lei Ye, Naifa L Busaidy, Steven G Waguespack, Mike Hernandez, Adel K El Naggar, Alder K El Naggar, Savita Bidyasar, John Wright, Steven I Sherman, and Razelle Kurzrock.
• Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. dshong@mdanderson.org
• J. Clin. Endocrinol. Metab. 2011 Apr 1; 96 (4): 997-1005.

PurposeRas/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 MethodsWe 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.ResultsWe 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.ConclusionsInhibiting the Ras/Raf/MAPK kinase/ERK and RET kinase pathways with sorafenib and tipifarnib is well tolerated and active against thyroid cancer.

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