Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers - PubMed (original) (raw)

Clinical Trial

. 2011 Jun 10;29(17):2357-63.

doi: 10.1200/JCO.2010.33.9473. Epub 2011 Apr 25.

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

Affiliations

Clinical Trial

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

Tanios Bekaii-Saab et al. J Clin Oncol. 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.

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.

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Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Fig 1.

CONSORT diagram.

Fig 2.

Fig 2.

Kaplan-Meier plots for overall survival (OS) and progression-free survival (PFS). mOS, median OS; NA, not available; mPFS, median PFS.

Fig 3.

Fig 3.

Waterfall plot showing maximum percentage decrease in target lesions. (*) Patients with 0% change as maximum response. PD, progressive disease; SD, stable disease; PR, partial response; CR, complete response.

Fig A1.

Fig A1.

Representative immunohistochemistry results from patients 13, 7, and 17 to demonstrate the range of staining. pERK, phosphorylated ERK; pAKT, phosphorylated AKT.

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