FDA Approval: Dabrafenib + trametinib for Melanoma

Why one drug was not enough

Melanoma taught oncology an uncomfortable lesson about targeted therapy.

About half of advanced melanomas carry a mutation at a spot called V600 in the BRAF gene. NCI explains that the mutation jams a growth signal permanently on. Block BRAF with a drug and tumors shrink, often dramatically.

Then, usually within six to seven months, they start growing again. NCI describes why: the tumor reroutes around the block by switching on a neighboring part of the same circuit, the MAP kinase pathway, through a protein called MEK.

So researchers tried blocking both ends at once. Dabrafenib, sold as Tafinlar, inhibits BRAF. Trametinib, sold as Mekinist, inhibits MEK. The FDA approved each drug on its own on 29 May 2013, and approved the combination through an efficacy supplement on 9 January 2014.

The two trials

NCI summarizes two phase 3 trials, both published in the New England Journal of Medicine in November 2014.

The larger one, led by Caroline Robert at Institut Gustave Roussy, randomized 704 people with BRAF V600-mutated metastatic melanoma to dabrafenib plus trametinib or to vemurafenib, another BRAF inhibitor, alone. Twelve-month survival was 72% with the combination against 65% with vemurafenib. Median progression-free survival, the time before the cancer grew again, was 11.4 months against 7.3 months.

The second, led by Georgina Long at Melanoma Institute Australia, randomized 423 previously untreated people to dabrafenib plus trametinib or dabrafenib plus placebo. Tumors shrank measurably in 67% against 51%. Six-month survival was 93% against 85%. Median progression-free survival was 9.3 months against 8.8 months.

Our explainer on clinical trial phases covers what a randomized phase 3 comparison establishes.

The surprise in the side effects

Adding a second drug usually adds harm. Here one specific harm went down.

BRAF inhibitors given alone can trigger a second skin cancer, cutaneous squamous cell carcinoma, because blocking BRAF in normal skin cells can paradoxically switch the same pathway on. Adding a MEK inhibitor closes that door.

In the larger trial, 1% of the combination group developed squamous cell carcinoma against 18% of those on vemurafenib alone. In the second trial it was 2% against 9% with dabrafenib alone.

The common side effects were fever, fatigue, nausea, headache and chills. Discontinuation rates because of side effects were similar between groups, at 13% versus 12% in the larger trial. Our overview of targeted therapy explains why this drug class needs a biomarker test first.

What the test result has to say

None of this applies without a BRAF result. The mutation has to be present in the tumor, found by testing tissue from a biopsy. A person whose melanoma is BRAF wild type, meaning unmutated, gets no benefit from either drug and will be steered toward immunotherapy instead.

That is the whole logic of precision treatment: the drug is chosen by what the tumor is made of, not by where it sits.

The wider picture

The American Cancer Society projects 112,000 new US melanoma diagnoses and 8,510 deaths for 2026; SEER publishes that projection. Five-year relative survival across all stages, for 2016 to 2022, is 94.7%.

Stage explains that. Localized melanoma, still confined to the skin, carries 100.0% five-year relative survival, and 77% of US cases are found at that point. Regional disease carries 76.0%. Distant disease, the group these trials studied, carries 34.0%. Each of those rates tracks people diagnosed from 2016 through 2022. These are group figures over past years and are not a prediction for any individual. More detail sits in our page on melanoma.

When to get checked

NCI says the first sign of melanoma is often a change in the shape, color, size or feel of an existing mole. It sets out the ABCDE rule:

• Asymmetry. One half does not match the other.
• Border that is irregular, ragged, notched or blurred.
• Color that is uneven, with shades of black, brown and tan, sometimes white, gray, red, pink or blue.
• Diameter. A change in size, usually bigger. Most melanomas are wider than 6 millimeters, though they can be tiny.
• Evolving. The mole has changed over the past few weeks or months.

NCI notes that many melanomas show all five features, but some show only one or two. A new colored or unusual patch of skin counts too.

What this does not mean

• These trials enrolled people with BRAF V600-mutated melanoma. Without that mutation, neither drug is expected to help.
• Median progression-free survival gains in the second trial were modest, 9.3 months against 8.8 months. The response rate and early survival differences were larger than the progression measure.
• Both trials compared the combination with a BRAF inhibitor. They do not rank it against immunotherapy, which has since reshaped melanoma care.
• Fewer squamous cell carcinomas is a real advantage, not a claim that the combination is gentle. Fever and fatigue were common.
• Approval sets who is eligible in general terms. Whether it fits one person is a clinical decision.

Sources

• NCI, Dabrafenib Plus Trametinib for Advanced Melanoma — https://www.cancer.gov/types/skin/research/dabrafenib-trametinib
• FDA Drugs@FDA (openFDA API), TAFINLAR NDA 202806: original approval 29 May 2013, efficacy supplement 9 January 2014 — https://api.fda.gov/drug/drugsfda.json?search=application_number:%22NDA202806%22
• NCI, Dabrafenib Mesylate — https://www.cancer.gov/about-cancer/treatment/drugs/dabrafenib
• NCI, Trametinib Dimethyl Sulfoxide — https://www.cancer.gov/about-cancer/treatment/drugs/trametinib
• NCI, Common Moles, Dysplastic Nevi, and Risk of Melanoma — https://www.cancer.gov/types/skin/moles-fact-sheet
• NCI PDQ, Melanoma Treatment (Patient Version) — https://www.cancer.gov/types/skin/patient/melanoma-treatment-pdq
• SEER Cancer Stat Facts, Melanoma of the Skin — https://seer.cancer.gov/statfacts/html/melan.html

How this article was prepared

An AI-assisted editorial system helped prepare this page. No named medical reviewer has reviewed it unless one is listed.

The National Cancer Information Foundation publishes Cancer Explained. This page is for learning. It is not medical advice and does not suggest a test or treatment.

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