Selumetinib (AstraZeneca), an investigational MEK 1/2 inhibitor, has received orphan drug status from the FDA for the adjuvant treatment of patients with stage III or IV differentiated thyroid cancer (DTC). In July 2015, selumetinib failed to meet its goal in a late-stage trial for uveal melanoma, a rare eye cancer.
Orphan drugs are intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States.
Selumetinib is an oral, selective inhibitor of MEK, part of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is often activated in cancers, including those with the KRAS mutation, which is present in 20% of human cancers and in 20% to 30% of tumors in non–small-cell lung cancer (NSCLC). MAPK activation also inhibits the expression of thyroid hormone biosynthesis genes, including the sodium/iodine symporter (NIS), which facilitates iodine uptake into cells. Preclinical studies suggested that iodine uptake by thyroid tumor cells is regained after MAPK inhibition.
DTC is diagnosed in approximately 60,000 people in the U.S. each year, and radioactive iodine (RAI) is recommended for those with known or suspected metastases at diagnosis and for those at high risk of recurrence. Some patients do not benefit from currently available treatment with RAI because they do not express sufficient NIS, which is important for RAI uptake into thyroid cells. Selumetinib is being tested for its ability to increase the expression of NIS in DTC patients who do not respond well to RAI.
An ongoing phase 3, double-blind, randomized trial is comparing complete remission rates after a five-week course of selumetinib or placebo plus single-dose adjuvant RAI therapy in patients with DTC who are at high risk of recurrence. In a phase 2 study of selumetinib in patients with advanced thyroid cancer, clinically meaningful increases in iodine uptake and retention were seen in patients with disease that was refractory to RAI.
Approximately 5% to 15% of patients with DTC do not respond to RAI. The 10-year survival rate in patients who fail to take up RAI into tumor cells is 10% compared with nearly 60% in those with normal RAI uptake. Traditional chemotherapy has minimal efficacy in patients with metastatic DTC.
In addition to DTC, selumetinib is being tested in a phase 3 trial of patients with KRAS-mutant advanced NSCLC and in a phase 2 registration trial of pediatric and adolescent patients with neurofibromatosis type 1 in collaboration with the National Cancer Institute.
Selumetinib is viewed by market analysts as less important commercially than AstraZeneca’s recently launched cancer therapies osimertinib (Tagrisso) and olaparib (Lynparza), and its experimental product durvalumab.