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Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers.
- Source :
-
Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2011 Jun 10; Vol. 29 (17), pp. 2357-63. Date of Electronic Publication: 2011 Apr 25. - Publication Year :
- 2011
-
Abstract
- Purpose: Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC.<br />Patients and Methods: This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations.<br />Results: Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response.<br />Conclusion: Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.
- Subjects :
- Adult
Aged
Benzimidazoles adverse effects
Biliary Tract Neoplasms mortality
Biliary Tract Neoplasms pathology
Extracellular Signal-Regulated MAP Kinases metabolism
Female
Humans
Male
Middle Aged
Mutation
Neoplasm Metastasis drug therapy
Phosphorylation
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins c-akt metabolism
Proto-Oncogene Proteins p21(ras)
ras Proteins genetics
Benzimidazoles therapeutic use
Biliary Tract Neoplasms drug therapy
MAP Kinase Kinase 1 antagonists & inhibitors
MAP Kinase Kinase 2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1527-7755
- Volume :
- 29
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of clinical oncology : official journal of the American Society of Clinical Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 21519026
- Full Text :
- https://doi.org/10.1200/JCO.2010.33.9473