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.

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.

• Authors: 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, Razelle Kurzrock
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 96 Issue 4 Pg. 997-1005 (Apr 2011) ISSN: 1945-7197 [Electronic] United States
• PMID: 21289252 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzenesulfonates
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyridines
• Quinolones
• Niacinamide
• Sorafenib
• Farnesyltranstransferase
• Proto-Oncogene Proteins c-ret
• RET protein, human
• raf Kinases
• Extracellular Signal-Regulated MAP Kinases
• MAP Kinase Kinase Kinases
• Oncogene Protein p21(ras)
• tipifarnib

Topics

• Adenocarcinoma, Follicular
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Benzenesulfonates (administration & dosage, adverse effects, pharmacology)
• Carcinoma, Neuroendocrine
• Cell Differentiation (drug effects)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors)
• Farnesyltranstransferase (antagonists & inhibitors)
• Female
• Humans
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• Male
• Middle Aged
• Niacinamide (analogs & derivatives)
• Oncogene Protein p21(ras) (antagonists & inhibitors)
• Phenylurea Compounds
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacology)
• Proto-Oncogene Proteins c-ret (antagonists & inhibitors)
• Pyridines (administration & dosage, adverse effects, pharmacology)
• Quinolones (administration & dosage, adverse effects, pharmacology)
• Signal Transduction (drug effects)
• Sorafenib
• Thyroid Neoplasms (drug therapy, pathology)
• raf Kinases (antagonists & inhibitors)