ESMO V-Learning: Inhibition of MEK to Treat Cancer, focussing on Melanoma

Learning Objectives

  • Understand the RAS-RAF-MEK-ERK pathway and related signaling, as well as oncogenic drivers within the pathway
  • Understand which driver Mutations may be affected by MEK inhibition in patients with metastatic melanoma
  • Describe novel therapeutic agents – MEK inhibitors, their mechanism of action, results from recent clinical studies and side-effects
Title Duration Content CME Points CME Test
Inhibition of MEK to Treat Cancer, focussing on Melanoma 25 min. 26 slides 1 Take Test
James Larkin
James Larkin
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Trametinib, a selective MEK inhibitor, has been shown to have a survival benefit over cytotoxic chemotherapy in patients with V600 BRAF-mutant metastatic melanoma, leading to the recent FDA approval for this patient population. MEK inhibitors have also showed activity in treatment of advanced melanoma harbouring other genetic alterations, such as NRAS and GNAQ/GNA11 Mutations.

This is a second ESMO module focusing on a molecular pathway, this time on RAS-RAF-MEK-ERK showing the pathway in an animated fashion and emphasising on effects of signalling cascade. The author starts the module with a clinical case presentation of a 59 year old female with primary melanoma excised in 2007, who relapsed 6 years later with a mass in the left breast. The biopsy has shown melanoma BRAF wild type, NRAS mutant. CT showed presence of subcutaneous and lung metastases. LDH was normal, performance status 0. The patient has been treated with immunotherapy in a clinical trial but best response was progressive disease. With a question ‘what now’, the author introduces into the world of the MAP kinase pathway and oncogenic drivers.

The author describes BRAF, NRAS and GNAQ mutations in melanoma, reviews and discusses MEK as a therapeutic target in cancer, and the currently available clinical trials data regarding MEK inhibitors and their role in the treatment of advanced melanoma. In his presentation, he shows that combined BRAF and MEK inhibition is active at full doses with less toxicity than sole BRAF inhibition, describes early signals in GNAQ and NRAS mutant melanomas, and elaborates on ongoing evaluation in appropriately defined subgroups in other tumour types. In uveal melanoma, a melanoma subtype currently without a good standard of care, MEK inhibition in a prospective randomised trial showed first ever prospective signal in this disease that provides foundation for further research. A number of MEK inhibitors are under investigation in uveal melanoma as single agents and in combination.

In this module, the author also elaborates on challenges for targeted cancer therapies, such as lack of predictive biomarkers and associated limited efficacy, resistance to therapy, chronic side effects in comparison to cytotoxic treatment, optimal scheduling, cost and access to treatment. Besides providing a comprehensive teaching on molecular pathway, this module also shows how testing of mutations is important in patients with metastatic melanomas.

Last update: 28 April 2014

The author has reported to receive research funding from Pfizer, Novartis and providing consultancy to Pfizer, Novartis, GSK and BMS.