Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers

Tanios Bekaii-Saab, Mitch A. Phelps, Xiaobai Li, Motoyasu Saji, Laura Goff, John Sae Wook Kauh, Bert H. O'Neil, Stephanie Balsom, Catherine Balint, Ryan Liersemann, Vasily V. Vasko, Mark Bloomston, William Marsh, L. Austin Doyle, Gilian Ellison, Michael Grever, Matthew D. Ringel, Miguel A. Villalona-Calero

Research output: Contribution to journalArticlepeer-review

212 Scopus citations

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. 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. 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. 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.

Original languageEnglish (US)
Pages (from-to)2357-2363
Number of pages7
JournalJournal of Clinical Oncology
Volume29
Issue number17
DOIs
StatePublished - Jun 10 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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