Format

Send to

Choose Destination
See comment in PubMed Commons below
J Clin Endocrinol Metab. 2011 Apr;96(4):997-1005. doi: 10.1210/jc.2010-1899. Epub 2011 Feb 2.

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.

Author information

1
Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. dshong@mdanderson.org

Erratum in

  • J Clin Endocrinol Metab. 2012 Apr;97(4):1399.
  • J Clin Endocrinol Metab. 2011 Jul;96(7):2286. Busaidy, Naifa L [added]; El Naggar, Alder K [corrected to El Naggar, Adel K].

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.

PMID:
21289252
PMCID:
PMC3070247
DOI:
10.1210/jc.2010-1899
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Supplementary concept, Grant support

Publication types

MeSH terms

Substances

Supplementary concept

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems Icon for PubMed Central
    Loading ...
    Support Center