Selumetinib in Uveal Melanoma

Study comparison of MEK inhibition vs. chemotherapy

In patients with advanced uveal melanoma, treatment with the agent selumetinib, compared with chemotherapy, resulted in an improved cancer progression-free survival time and tumour response rate, but no improvement in overall survival, according to a study in the June 18 issue of JAMA. The modest improvement in clinical outcomes was accompanied by a high rate of adverse events.

Uveal melanoma arises from melanocytes within the choroid layer of the eye. Uveal melanoma is biologically distinct from skin related melanoma. It is characterised by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation.

Selumetinib is an oral agent, a selective, non–adenosine triphosphate competitive inhibitor of MEK1 and MEK2. A subgroup analysis from an earlier trial that included 20 patients with uveal melanoma suggested favourable results with selumetinib treatment, according to background information in the article.

Dr Richard Carvajal of Memorial Sloan-Kettering Cancer Center, New York, USA and colleagues randomly assigned patients with metastatic uveal melanoma to receive selumetinib (n = 50; orally twice daily), or chemotherapy (n = 51; temozolomide, orally daily for 5 of every 28 days, or dacarbazine, intravenously every 21 days) until disease progression, death, intolerable adverse effects, or withdrawal of consent.

Progression-free survival was the primary end point in the study. After analysis of the primary outcome, 19 additional patients were registered and 18 treated with selumetinib without randomisation, to complete the planned 120-patient enrolment.

The researchers reported that the median progression-free survival time was 7 weeks in the chemotherapy group (median treatment duration, 8 weeks) and 15.9 weeks in the selumetinib group (median treatment duration, 16.1 weeks). The 4-month progression-free survival rate was 8.5% with chemotherapy, and 43.1% with selumetinib.

Median overall survival time was 9.1 months with chemotherapy and 11.8 months with selumetinib, a difference that was not statistically significant.

Tumour regression was uncommon with chemotherapy, whereas 49% of patients randomised to selumetinib achieved tumour regression.

Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction.

"In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival time and rate of response; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events." the authors conclude.

Reference

Carvajal RD, Sosman JA, Fernando Quevedo J, et al. Effect of Selumetinib vs Chemotherapy on Progression-Free Survival in Uveal Melanoma : A Randomized Clinical Trial. JAMA 2014; 311(23):2397-2405. doi:10.1001/jama.2014.6096.