This article is intended for primary care clinicians, oncologists, dermatologists, and other specialists who care for patients with metastatic or unresectable melanoma.
The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.
Upon completion of this activity, participants will be able to:
As an organization accredited by the ACCME, Medscape, LLC, requires everyone who is in a position to control the content of an education activity to disclose all relevant financial relationships with any commercial interest. The ACCME defines "relevant financial relationships" as financial relationships in any amount, occurring within the past 12 months, including financial relationships of a spouse or life partner, that could create a conflict of interest.
Medscape, LLC, encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.
Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Medscape, LLC designates this enduring material for a maximum of 0.25
AMA PRA Category 1 Credit(s)™
. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
This enduring material activity, Medscape Education Clinical Briefs has been reviewed and is acceptable for up to 260 Prescribed credits by the American Academy of Family Physicians. AAFP accreditation begins September 1, 2012. Term of approval is for 1 year from this date. Each Clinical Brief is approved for .25 Prescribed credits. Credit may be claimed for 1 year from the date of each Clinical Brief. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Note: Total credit is subject to change based on topic selection and article length.
Medscape, LLC staff have disclosed that they have no relevant financial relationships.
AAFP Accreditation Questions
Medscape, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Medscape designates this continuing education activity for 0.25 contact hour(s) (0.025 CEUs) (Universal Activity Number 0461-0000-13-031-H04-P).
For questions regarding the content of this activity, contact the accredited provider for this CME/CE activity noted above. For technical assistance, contact [email protected]
There are no fees for participating in or receiving credit for this online educational activity. For information on applicability
and acceptance of continuing education credit for this activity, please consult your professional licensing board.
This activity is designed to be completed within the time designated on the title page; physicians should claim only those
credits that reflect the time actually spent in the activity. To successfully earn credit, participants must complete the
activity online during the valid credit period that is noted on the title page. To receive AMA PRA Category 1 Credit™, you must receive a minimum score of 70% on the post-test.
Follow these steps to earn CME/CE credit*:
You may now view or print the certificate from your CME/CE Tracker. You may print the certificate but you cannot alter it.
Credits will be tallied in your CME/CE Tracker and archived for 6 years; at any point within this time period you can print
out the tally as well as the certificates from the CME/CE Tracker.
*The credit that you receive is based on your user profile.
CME/CE Released: 7/16/2013
Valid for credit through: 7/16/2014, 11:59 PM EST
processing....
Melanoma is the leading cause of death from skin disease. Approximately half of melanomas arising in the skin have a mutation in the BRAF gene. Dabrafenib acts as a BRAF inhibitor, whereas trametinib is a mitogen-activated, extracellular signal–regulated kinase inhibitor (MEK inhibitor).
In addition to approving dabrafenib and trametinib for treatment of metastatic melanoma associated with the V600E or V600K BRAF mutation, the US Food and Drug Administration (FDA) also approved the THxID BRAF test to help detect the V600E or V600K BRAF mutation in melanoma cells.
Two new drugs have been approved by the FDA for use in certain patients with metastatic or unresectable melanoma, along with a diagnostic test to identify patients who are suitable for treatment.
The new products, dabrafenib (Tafinalar) and trametinib (Mekinist), are orally available tablets, but they have slightly different mechanisms of action.
Dabrafenib acts as a BRAF inhibitor and is approved for use in patients with melanoma whose tumors express the BRAF V600E gene mutation. It is seen as being a next-generation product but is in the same class as the first BRAF inhibitor to reach the market, vemurafenib (Zelboraf).
Trametinib has a related but slightly different mechanism and acts as a MEK inhibitor. It is the first drug in this class to be approved and is indicated for use in patients whose tumors express the BRAF V600E or V600K gene mutations.
Approximately half of melanomas arising in the skin have a BRAF gene mutation, the FDA notes in its approval notice. Alongside the new drugs, the agency also approved a genetic test, the THxID BRAF test, a companion diagnostic that will help determine whether a patient's melanoma cells have the V600E or V600K mutation in the BRAF gene.
Melanoma is the leading cause of death from skin disease, the FDA adds. The National Cancer Institute estimates 76,690 Americans will be diagnosed with melanoma and 9480 will die from the disease in 2013.
Clinical Trial Data
Dabrafenib was approved on the basis of data from the BREAK 3 study, conducted in 250 patients with previously untreated BRAF V600 mutation–positive metastatic melanoma. It showed that in such patients, dabrafenib significantly improved the median progression-free survival compared with chemotherapy with dacarbazine (5.1 vs 2.7 months; P < .0001). These results were published in July 2012 issue of the Lancet (2012;380:358-365).
The FDA notes that the most serious adverse effects reported in patients receiving dabrafenib included an increased risk for cutaneous squamous cell carcinoma, fevers that may be complicated by hypotension, severe rigors, dehydration, kidney failure, and increased blood sugar levels requiring changes in diabetes medication or the need to start medicines to control diabetes.
The most common adverse effects reported in patients receiving dabrafenib included hyperkeratosis, headache, fever, joint pain, noncancerous skin tumors, hair loss, and hand–foot syndrome.
The pivotal study for trametinib, the METRIC study, was a little different in that it was conducted in 322 patients who had already tried a prior regimen of chemotherapy. In this study, compared with chemotherapy, trametinib significantly improved progression-free survival as well as overall survival duration. The results were published in the July 12, 2012, issue of the New England Journal of Medicine (2012;367:107-114).
The FDA notes that the most serious adverse effects reported in patients receiving trametinib included heart failure, lung inflammation, skin infections, and loss of vision. Common adverse effects included rash, diarrhea, tissue swelling (peripheral edema), and skin breakouts that resemble acne.
The agency also noted that women of childbearing years should be advised that dabrafenib and trametinib carry the potential to cause fetal harm. Men and women should also be advised that both drugs also carry the potential to cause infertility.
Being Investigated in Combination
Dabrafenib and trametinib have been approved for use as monotherapy, and not as a combination treatment, the FDA has emphasized. However, there is a lot of interest from clinicians in using both drugs together, and indeed the manufacturer is conducting a clinical trial with the combination.
Preliminary results from a clinical trial with the combination suggest that use of the 2 drugs together resulted in less toxicity, and specifically in fewer secondary skin cancers, than has been seen with vemurafenib used alone.
A phase 3 study is now being conducted (known as COMBI-AD) of the combination of dabrafenib and trametinib in patients with BRAF V600 melanoma that has been completely removed by surgery. Such patients are at high risk for relapse, and the combination of drugs is being tested to see whether it can delay or prevent the recurrence of melanoma.
Problem: Responses Are Short-Lived
The new dabrafenib appears to be similar to the already-marketed vemurafenib, but there are important differences between the 2 BRAF inhibitors in their toxicity profiles, noted Kim Margolin, MD, from the Seattle Cancer Care Alliance in Washington, commenting in a recent Medscape videoblog.
Skin toxicities, particularly the emergence of low-grade squamous cancers and keratoacanthomas, which occurred in a substantial number of patients taking vemurafenib, appear to be quite unusual with dabrafenib, Dr. Margolin noted. However, a systemic "pyrexia reaction," which is almost never seen with vemurafenib, has been seen in a substantial percentage of patients taking dabrafenib. "We don't know yet about the off-target mechanisms of these differences and how much may be due to the vehicle or the formulation for each of these oral agents," she added.
However, the biggest problem with the BRAF inhibitors in the treatment of melanoma has been the lack of durable response: These drugs "tend to work for an average of 5 to 6 months," Dr. Margolin noted. What to do when patients fail on these drugs remains a challenge, she added.
Ultimately, combination therapy with a BRAF inhibitor (such as vemurafenib or dabrafenib) plus a MEK inhibitor (such as trametinib) is "likely to be most valuable for improved and lasting results," according to Dr. Margolin, commenting on dabrafenib last year.
More information on dabrafenib and trametinib for metastatic melanoma is available on the FDA Web site.