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BRAF/MEK: Phase II study to test first BRAF combination for metastatic melanoma

Melanoma has one of the fastest rising rates of human cancer. Metastasis develops in 10 to 15 percent of patients. About 15 percent of people with late-stage disease survive five or more years, but most die within the year. Clinical studies were the standard of care for the last two decades, although until recently there was only marginal evidence of a survival benefit from any metastatic melanoma treatment tested in randomized controlled phase III studies.

Advanced melanoma has multiple genetic mutations that corrupt many signaling pathways, but about half of melanomas are “addicted” to the single mutated gene known as BRAF. Overactivated BRAF turns on a critical cell proliferation pathway in people. Last year, a selective inhibitor of BRAF reversed radiology signs and clinical symptoms in 81 percent of 32 people with late-stage BRAF-mutant melanomas, reported Keith Flaherty, MD (MGH), and his colleagues in the New England Journal of Medicine.The regression lasted two to twenty months before the tumors developed resistance to the single inhibitor.

Objectives and importance of this trial

The first part of this phase I open-label, dose escalation trial began last June to test the safety and efficacy of combining a selective BRAF inhibitor with an inhibitor of the downstream molecule MEK. (Mutant BRAF causes unrestrained signaling to MEK). The MEK inhibitor is the first agent to be combined with a BRAF inhibitor in a clinical trial. The experimental combination (GSK2118436 and GSK1120212, GlaxoSmithKline) has been tested in 93 patients, and Flaherty will present preliminary phase I results at the June ASCO meeting.

The study has entered its second stage, which aims to further explore the safety, tolerability and clinical activity of the recommended dose. It will accrue the last of about 150 patients with advanced BRAF mutant melanoma in the next several months. Patients will be randomized to one of three arms – one with the BRAF inhibitor alone and two with different doses of the combination of the BRAF and MEK inhibitors.

The BRAF inhibitor selectively shuts down the activity of mutant BRAF kinase, blocking the growth of tumors with the mutations. The MEK inhibitor also showed a clinical effect on its own (a 44 percent response rate in 29 patients at the end of the phase I trial, Flaherty said) in other phase I studies. In combination with a BRAF inhibitor, a MEK inhibitor may help keep the pathway shut down and may delay the emergence of resistance.  Additionally, the BRAF/MEK combination may reduce side effects of mutant BRAF inhibition. Paradoxically, in non-cancerous cells lacking the mutation, the inhibitor activates downstream signaling of the pathway, promoting growth. This may explain squamous cell carcinoma, a frequent complication that can arise from normal skin cells during treatment with a BRAF inhibitor alone. Although squamous cell skin cancers are usually manageable and not life-threatening, the BRAF/MEK inhibitor combination may prevent the activation of signaling in non-cancerous cells and may reduce the incidence of squamous cell skin cancers.

In addition to melanoma, BRAF mutation also occurs in a small percentage of cases in other cancer types. The clinical trial will also examine the BRAF/MEK inhibitor combination in a group of patients with colon cancer harboring BRAF mutation. This will help determine whether the results in melanoma are applicable to other tumors with BRAF mutation as well.

Principal investigator
Keith Flaherty, MD (MGH)

Co-principal investigators
Daniel Cho, MD (BIDMC); Geoffrey Shapiro, MD (DFCI)

More information
For eligibility criteria search for NCT01072175 on ClinicalTrials.gov. To refer a melanoma patient to the trial, contact Diane Gaucher, 617 643 2427, dlgaucher@partners.org (MGH), or Megan Lynch, RN, DFCI Melanoma Center, 617 632 5906, megan_lynch@dfci.harvard.edu (DFCI).