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Published on: July 31, 2016
Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers
Tanios Bekaii-Saab1, Mitch A Phelps, Xiaobai Li
1The Ohio State University Comprehensive Cancer Center--James Cancer Hospital and Solove Research Institute, Columbus, OH 43210, USA. Tanios.Bekaii-Saab@osumc.edu
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.
Insights
Selumetinib showed activity in advanced biliary cancers (BCs), with some patients achieving stable disease. This MEK inhibitor (selumetinib) warrants further study for metastatic BC treatment.
Area of Science:
- Oncology
- Molecular Targeted Therapy
- Cancer Research
Background:
- Biliary cancers (BCs) have a poor prognosis.
- Targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is a significant therapeutic strategy.
- Selumetinib is a MEK1/2 inhibitor.
Purpose of the Study:
- To determine the safety and efficacy of selumetinib in patients with advanced biliary cancers.
- To evaluate response rate as the primary endpoint.
Main Methods:
- A multi-institutional phase II study enrolled patients with advanced BC.
- Selumetinib was administered orally at 100 mg twice daily.
- Tumor tissue was analyzed for phosphorylated ERK (pERK), phosphorylated AKT (pAKT), and BRAF/RAS mutations.
Main Results:
- Twenty-eight patients were enrolled; 12% had an objective response, and 68% had stable disease (SD), with 56% experiencing prolonged SD (>16 weeks).
- Median progression-free survival was 3.7 months, and median overall survival was 9.8 months.
- Rash and xerostomia were the most common toxicities; no BRAF V600E mutations were found, and absence of pERK staining correlated with lack of response.
Conclusions:
- Selumetinib demonstrated notable activity and acceptable tolerability in patients with metastatic BC.
- Further investigation of selumetinib for metastatic BC is warranted.
