Selumetinib

Selumetinib is a MEK inhibitor from the class of serine/threonine kinase inhibitors. The drug was developed for the therapy of neurofibromatosis type 1 (NF1).

Selumetinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. The MEK proteins are upstream regulators of the extracellular signaling pathway (ERK), which promotes cell proliferation. In melanoma and other cancers, this pathway is often activated by mutated forms of BRAF that activate MEK. By selectively binding the drug to MEK1 and MEK2, this cascade is interrupted and uncontrolled cell growth is inhibited.

The preparation was used in children with neurofibromatosis type 1 who suffered from non-operable neurofibromas. Therapy with selumetinib led to a reduction of plexiform neurofibromas. The treatment attempts with tipifarnib, pirfenidone, sirolimus, interferon alfa-2b and imatinib were unsatisfactory in this indication. The cause of neurofibromatosis type 1 is the failure of the NF1 gene product neurofibromin, a negative regulator of the Ras signaling pathway. Treatment with selumetinib must probably be permanent. In one patient, a relapse, i.e. a renewed increase in neurofibromas, occurred promptly after discontinuing selumetinib. Shorter interruptions in therapy may be possible, however.

Other clinical trials involve the use of selumetinib in combination with a so-called platinum doublet, i.e. a combination of two platinum-based drugs, in advanced non-small cell lung cancer (NSCLC). In a Phase I study, patients who had not previously received treatment were given selumetinib orally twice daily in different doses (50, 75 or 100 mg). They also received standard chemotherapy consisting of gemcitabine or pemetrexed combined with cisplatin or carboplatin. The results are awaited here.

Nausea, vomiting, diarrhoea and skin rashes are among the most common side effects of the preparation.

1. Burki TK (2017) Selumetinib for children with plexiform neurofibromas. Lancet Oncol 18:e69.
2. Carvajal RD et al (2018) Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). J Clin Oncol 36:1232-1239.
3. Decaudin D et al (2018) Selumetinib-based therapy in uveal melanoma patient-derived xenografts. Oncotarget 9:21674-21686.
4. Dombi E et al. (2016) Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med 375:2550-2560.