Melanoma KnowledgeBase | BRAF

The BRAF gene makes a protein that is involved in cell division. BRAF is mutated in 50% to 60% of people with melanoma, making it the most commonly mutated gene in this group of aggressive skin cancers. BRAF mutations can occur in all melanoma subtypes, but are most common in skin with intermittent sun exposure. Most tumors with this abnormal gene can be treated with vemurafenib (Zelboraf™). Vemurafenib is often used in combination with other drugs that inhibit a protein called MEK.

Testing

Melanomas can be tested for BRAF abnormalities by a laboratory procedure called polymerase chain reaction or PCR. This process makes many copies of DNA fragments so that even a small amount of DNA from a person can be tested for genetic abnormalities. The most common BRAF mutation is called V600E; this abnormality can be targeted with a drug called vemurafenib.

There are several manufacturers of genetic tests that can detect BRAF mutations in melanoma tumor samples. Testing may be performed onsite at a medical facility or at a specialized laboratory. Your doctor can recommend which tests are appropriate for you.

Molecular explanation

BRAF is an oncogene. When mutated, oncogenes can cause or contribute to tumor growth. Like many genes, the BRAF gene provides instructions for making a protein. Normally, the BRAF protein helps transmit signals that regulate cell growth, division, and movement.  However, when the BRAF gene is mutated, it makes an abnormal BRAF protein that is too active. This abnormal protein makes cells divide abnormally fast, potentially leading to tumor formation.

The BRAF protein is a serine-threonine protein kinase. This protein is regulated by signals received by cells. When activated, the BRAF protein in turn activates a cellular process called the MAP kinase pathway. This pathway is involved in cell division. The only protein known to be directly activated by the BRAF protein is another kinase, which is called MEK. This means that MEK inhibitors also have the potential to counteract the effects of BRAF mutations.

Other instances

BRAF mutations are infrequently found in non-small cell lung cancer, or NSCLC, as well as in cancers of the colon and rectum, ovary, and thyroid gland.

Further reading

Melanoma Molecular Model

My Cancer Genome

Genetics Home Reference

The U.S. Food and Drug Administration (FDA) has approved three treatments specifically for melanomas with BRAF mutations. Vemurafenib and dabrafenib directly target a mutated form of the BRAF protein, and trametinib inhibits a protein called MEK. Ongoing clinical trials are testing the effectiveness of other targeted therapies, as well as drug combinations that inhibit several different protein targets at once.

FDA-approved targeted treatments and immunotherapies

Vemurafenib:

The FDA has approved treating melanomas that have BRAF mutations with vemurafenib. This drug is also known as PLX4032, or Zelboraf, and is made by Roche. In clinical trials with Zelboraf, melanoma tumors stopped growing for several months. In addition, during the course of the trials, melanoma patients treated with Zelboraf were 63% more likely to survive than those treated with conventional chemotherapy. The latter treatment kills rapidly dividing cells rather than targeting specific genetic abnormalities. Vemurafenib is a BRAF inhibitor that blocks only the most common mutated form of the BRAF protein, which is called BRAF V600E.

Dabrafenib:

In May 2013, the FDA approved dabrafenib for all melanoma patients with the BRAF V600E mutation. The drug was developed by GlaxoSmithKline as Tafinlar. Its approval was based on the results of randomized clinical trials in which patients who took dabrafenib showed significantly improved progression-free survival compared to patients who received chemotherapy with dacarbazine.

Trametinib:

Trametinib is a drug that inhibits a protein called MEK, which is, in turn, activated by mutant BRAF. It is made by GlaxoSmithKline as Mekinist. In a large clinical study, trametinib significantly prolonged progression-free survival in patients with metastatic melanoma. In May 2013, the FDA approved Mekinist as a single-agent oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600E or V600K mutations. The FDA did not recommend that Mekinist be given to patients who have previously been treated with BRAF inhibitors.

Immunotherapy

Immunotherapy is a treatment approach in which drugs or cells are used to redirect a patient’s own immune system to recognize and kill tumor cells. Recently, great successes were seen with antibody-based drugs that work by releasing the molecular “brakes” that prevent immune cells from eliminating tumor cells. These antibodies work either by unleashing the activity of the immune cells directly, or by removing obstacles from the tumor cells. The three remaining treatments in this section are all examples of immunotherapies.

Interleukin-2:

High-dose bolus interleukin-2 (IL-2) was approved by the FDA for the treatment of metastatic melanoma in 1998. IL-2 is a so-called “immunomodulatory agent” that stimulates the immune system to attack cancer cells. IL-2 has been shown to achieve rates of tumor reduction of about 10-15%, but about half the patients who respond to IL-2 have a complete response—disease remission for more than 10 years. However IL-2 is among the most toxic of cancer treatments, with marked side effects and a significant risk of life-threatening adverse events. IL-2 treatment can be considered only for patients who are in otherwise excellent health and only after extensive discussion of the risks and benefits of this treatment.

Interferon alfa-2b:

Interferon alfa-2b—which, like IL-2, is an immunotherapy agent—is approved by the FDA as an adjuvant treatment for patients with stage II melanoma and primary tumors more than 4-mm thick, or with stage III melanoma. (An adjuvant treatment is given after a primary treatment to keep the cancer from returning.) Interferon alfa-2b has been shown to delay recurrence in these patients, but in most clinical studies it has not improved overall survival durations.

Ipilimumab:

The FDA has approved ipilimumab for all patients with advanced melanoma, regardless of whether BRAF is mutated. This drug is made by Bristol-Meyers Squibb as Yervoy. In clinical trials, ipilimumab has increased survival in a small subset of melanoma patients. Ipilimumab is an immunotherapy drug that inhibits a protein called CTLA-4, which normally helps control immune system cells called T cells. By blocking CTLA-4, ipilimumab stimulates T cells and thus boosts the immune system response against melanoma cells in the body. However, ipilimumab does not specifically target tumors with BRAF mutations.

Experimental targeted treatments and immunotherapies

BRAF and MEK Inhibitors:

Clinical trials are underway to test treating melanomas that have BRAF mutations by combining a BRAF inhibitor (vemurafenib or dabrafenib) with drugs that inhibit the MEK protein. This is because many tumors that are initially sensitive to vemurafenib eventually become resistant to it, sometimes as a result of their MEK proteins becoming more active. A clinical trial testing the combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib showed superior effects for this combined treatment compared to treatment with either drug alone. Similar trials are still in progress (See “Clinical Trials” tab). In addition, new inhibitors of BRAF (RO5185426, RO5212054) and MEK (GDC-0973, MEK162, pimasertib and more) are also in clinical testing.

Other Targeted Drugs:

Some melanoma tumors with BRAF mutations also have abnormalities or activation of other genes, including PTEN, AKT, CCND1, or others. Clinical trials are underway to test combinations of drugs to treat melanomas that have BRAF mutations as well as mutations in other genes. Among investigational drugs that are tested in trials in combination with inhibitors of BRAF or MEK are inhibitors of PI3K and/or AKT (MK2206 and BKM120, PX-866, SAR260301), inhibitors of HSP90 (STA-9090), inhibitors of CDK4 (LEE011), and many others.

Immunotherapy

Immunotherapy is a treatment approach in which drugs or cells are used to redirect a patient’s own immune system to recognize and kill tumor cells. Recently, great successes were seen with antibody-based drugs that work by releasing the molecular “brakes” that prevent immune cells from eliminating tumor cells. These antibodies work either by unleashing the activity of the immune cells directly, or by removing obstacles from the tumor cells. The treatments listed below are all examples of immunotherapies.

Lambrolizumab (MK3475):

Lambrolizumab is an antibody drug that promotes the function of the immune system, helping the body fight cancer. It is made by Merck. In May 2013, the FDA granted a breakthrough therapy designation for lambrolizumab to fast-track its development, review, and approval. In a clinical trial, lambrolizumab prolonged survival in more than half of patients with metastatic inoperable melanoma. Lambrolizumab blocks a protein called PD-1, which is found on the surface of immune cells known as T cells. PD-1 usually inhibits the function of T-cells, so blocking it can increase T cell activity, thereby promoting immune system function.

Nivolumab:

Nivolumab, developed by Bristol-Myers Squibb, is an antibody-based drug that is very similar to lambrolizumab. It has also shown very promising results in clinical trials, and has been reported to produce even better results in combination with the drug ipilimumab.

MPDL3280A/BMS-936559:

MPDL3280A is an antibody drug that targets a protein called PD-L1. PD-L1 is found on tumor cells and protects them from being killed by immune cells. MPDL3280A is being tested in clinical trials, and preliminary results are promising for melanoma, as well as other cancer types.

Adoptive cell transfer:

Another immune system-based approach, adoptive T cell therapy, makes use of immune system cells called T cells, which can target and kill tumor cells. First, T cells are harvested from a patient’s tumor. Many copies of the T cells are produced in the laboratory, and then billions of the cells are transferred intravenously back into the patient’s bloodstream. These T cells specifically target and kill tumor cells, but are not numerous or strong enough to eradicate the entire tumor. To help the body make even more copies of these tumor-specific T cells in the bloodstream, the patient is given chemotherapy to deplete ordinary T cells prior to the tumor-specific T cells’ reintroduction, and then given a high dose of the protein IL-2 to stimulate T cell growth after the T cells’ reintroduction. This therapy is still highly experimental.

Further reading

Melanoma Molecular Model

Overview of Melanoma Treatments

Genes and Development Melanoma Targeted Treatments Paper

CollabRx Therapy Finder

Cancer.org Guide to Cancer Drugs

BRAF

TRIAL NAME TRIAL ID Phase
A Phase III Study Comparing GDC-0973, a MEK Inhibitor, in Combination with Vemurafenib Vs. Vemurafenib Alone in Patients with Metastatic Melanoma NCT01689519 Phase III
Dabrafenib Plus Trametinib Vs. Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-v) NCT01597908 Phase III
A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects with BRAF-Mutant Melanoma NCT01682083 Phase III
A Study of the BRAF Inhibitor Dabrafenib in Combination with the MEK Inhibitor Trametinib in the Adjuvant Treatment of High-Risk BRAF V600 Mutation-Positive Melanoma after Surgical Resection (COMBI-AD) NCT01682083 Phase III
Open-Label Phase II Trial of the BRAF Inhibitor (Dabrafenib) and the MEK Inhibitor (Trametinib) in Unresectable Stage III and Stage IV BRAF-Mutant Melanoma; Correlation of Resistance with the Kinome and Functional Mutations NCT01726738 PhaseII
Dabrafenib Alone and in Combination with Trametinib before Surgery in Treating Patients with Locally or Regionally Advanced Melanoma That Can Be Removed by Surgery NCT01701037 Phase II
GSK2118436 (Dabrafenib) and GSK1120212 (MEK162) NCT01619774 Phase II
Selumetinib and Akt Inhibitor MK2206 in Treating Patients with Stage III or Stage IV Melanoma Who Failed Prior Therapy with Vemurafenib or Dabrafenib NCT01519427 Phase II
BKM120 (PI3Ki) Combined with Vemurafenib (PLX4032) in BRAFV600E/K Mutant Advanced Melanoma NCT01512251 Phase I/II
Study of PX-866 (PI3Ki) and Vemurafenib in Patients with Advanced Melanoma NCT01616199 Phase I/II
A Study of Vemurafenib and GDC-0973 in Patients with BRAF Mutation-Positive Metastatic Melanoma NCT01271803 Phase I
A Study of MEK162 (Trametinib) and AMG 479 (IGF1-R hu-ab) in Patients with Selected Solid Tumors NCT01562899 Phase II
Study of XL888 (HSP90 Inhibitor) with Vemurafenib for Patients with Unresectable BRAF-Mutated Stage III/IV Melanoma NCT01657591 Phase I
A Phase I/Ib Trial for the Evaluation of SAR260301 in Monotherapy or in Combination with Vemurafenib in Patients with Various Advanced Cancers NCT01673737 Phase I
Safety, Pharmacokinetics, and Pharmacodynamics of BKM120 Plus MEK162 in Selected Advanced Solid Tumor Patients NCT01363232 Phase I
Safety, Pharmacokinetics, and Pharmacodynamics of BEZ235 Plus MEK162 in Selected Advanced Solid Tumor Patients NCT01337765 Phase I
Trial of MEK Inhibitor and PI3K/mTOR Inhibitor (MSC1936369B/Pimasertib) and SAR245409 in Subjects with Locally Advanced or Metastatic Solid Tumors NCT01390818 Phase I
Cediranib Maleate (AZD2171, VEGFRi) and Selumetinib in Treating Patients with Solid Malignancies NCT01364051 Phase I
Phase Ib Study of PI3 (Phosphoinositol 3)-Kinase Inhibitor BAY80-6946 with MEK (Mitogen-Activated Protein Kinase) Inhibitor BAY86-9766 in Patients with Advanced Cancer NCT01392521 Phase I
Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Combination with Cisplatin, Vinblastine, and Temozolomide in Treating Patients with Recurrent or Metastatic Melanoma NCT01196416 Phase I/II
Vemurafenib (R05185426) in Poor Performance Status Patients with Unresectable Locally Advanced or Metastatic Melanoma Harboring a V600E/K Mutation NCT01474551 Phase II
A Study of RO5185426/Vemurafenib in Patients with Metastatic Melanoma NCT01307397 Phase I
A Study of RO5212054 (PLX3603) in Patients with BRAF V600-Mutated Advanced Solid Tumours NCT01143753 Phase I
A Study of GSK2118436 (Dabrafenib) in BRAF-Mutant Metastatic Melanoma to the Brain (Break MB) NCT01266967 Phase II
STA-9090/Ganetespib (HSP90i)) in Patients with Unresectable Stage III or Stage IV Melanoma NCT01551693 Phase II
Aurora A Kinase Inhibitor MLN8237 in Treating Patients with Unresectable Stage III-IV Melanoma NCT01316692 Phase II
RO4929097 (Gamma-Secretase/Notch Signalling Pathway Inhibitor) in Treating Patients with Stage IIIb, Stage IIIc, or Stage IV Melanoma That Can Be Removed by Surgery NCT01216787 Phase II
A Phase I/II Trial of Vemurafenib and Metformin to Melanoma Patients NCT01638676 Phase I/II
Safety and Efficacy of LEE011 and LGX818 in Patients with BRAF-Mutant Melanoma NCT01777776 Phase I/II not open yet
Dinaciclib in Treating Patients with Advanced Melanoma NCT01026324 Phase I/II
C-KIT, BRAF/NRAS Mutations in Advanced Melanoma: Clinical Outcome in Response to Tyrosine-Kinase Inhibitors—KitMel Project NCT01543113 Phase I
LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma (LOGIC) NCT01820364 Phase II (not open yet)
A Phase 1b Open Label, Dose Escalation Study of PLX3397 in Combination With Vemurafenib in V600-mutated BRAF Melanoma NCT01826448 Phase I
A Phase I Trial of Vemurafenib and Hydroxychloroquine in Patients With Advanced BRAF Mutant Melanoma NCT01897116 Phase I
Cabozantinib-S-Malate and Vemurafenib in Treating Patients With Melanoma That is Metastatic or That Cannot Be Removed By Surgery NCT01835184 Phase I
Study of an Oral Cdk Inhibitor Administered With an Oral BRAF Inhibitor in Patients With Advanced or Inoperable Malignant Melanoma With BRAF Mutation NCT01841463 Phase I
BRAF Inhibitor, LGX818, Utilizing a Pulsatile Schedule in Patients With Stage IV or Unresectable Stage III Melanoma Characterized by a BRAFV600 Mutation NCT01894672 Phase II
Leflunomide+Vemurafenib in V600 Mutant Met. Melanoma NCT01611675 Phase I/II

IMMUNOTHERAPY and BRAF inhibitors

TRIAL NAME TRIAL ID Phase
Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects with V600 BRAF-Mutated Advanced Melanoma NCT01673854 Phase II
Vemurafenib and White Blood Cell Therapy for Advanced Melanoma NCT01585415 Phase I
Combined BRAF-Targeted Therapy & Immunotherapy for Melanoma (Vemurafenib +Aldesleukin=IL2) NCT01754376 Phase II
Vemurafenib with Lymphodepletion Plus Adoptive Cell Transfer & High-Dose IL-2 Metastatic Melanoma NCT01659151 Phase II
Systemic Therapy with Interferon, Interleukin-2, and BRAF Inhibitor (Vemurafenib) NCT01603212 Phase I/II
A Study of the Safety and Pharmacology of MPDL3280A (Anti-PD-L1 hu ab) Administered in Combination with Vemurafenib (Zelboraf®) in Patients with Previously Untreated BRAFV600 Mutation-Positive Metastatic Melanoma NCT01656642 Phase I
Safety and Efficacy Study of BMS-908662 (Pan RAF Inhibitor) in Combination with Ipilimumab in Subjects with Advanced Melanoma NCT01245556 Phase I
Study of Dabrafenib +/- Trametinib in Combination with Ipilimumab for V600E/K Mutation-Positive Metastatic or Unresectable Melanoma NCT01767454 Phase I
Ph I/II Ipilimumab Vemurafenib Combo NCT01400451 Phase I/II
The Effects of Vemurafenib on Immunity in Patients With Melanoma NCT01813214 Phase II

IMMUNOTHERAPY

TRIAL NAME TRIAL ID Phase
Concurrent Ipilimumab and Stereotactic Ablative Radiation Therapy (SART) for Oligometastatic but Unresectable Melanoma NCT01565837 Phase II
Ipilimumab or High-Dose Interferon Alfa-2b in Treating Patients with High-Risk Stage III or Stage IV Melanoma That Has Been Removed by Surgery NCT01274338 Phase III
Biochemotherapy and Bevacizumab Followed by Consolidation Therapy with Ipilimumab for Metastatic Melanoma (BBI) NCT01743157 Phase I/II
Granulocyte Macrophage-Colony Stimulating Factor and Ipilimumab as Therapy in Melanoma (GIPI) NCT01363206 Phase II
Ipilimumab with or without Talimogene Laherparepvec in Unresectable Melanoma NCT01740297 Phase I/II
Autologous TriMix-DC Therapeutic Vaccine in Combination with Ipilimumab in Patients with Previously Treated Unresectable Stage III or IV Melanoma (TriMix-Ipi) NCT01302496 Phase II
Phase II Randomized Trial of Ipilimumab Versus Ipilimumab and Radiotherapy in Metastatic Melanoma NCT01689974 Phase II
Addition of Ipilimumab (MDX-010) to Isolated Limb Infusion (ILI) with Standard Melphalan and Dactinomycin in the Treatment of Advanced Unresectable Melanoma of the Extremity NCT01323517 Phase II
Laboratory-Treated T Cells and Ipilimumab in Treating Patients with Metastatic Melanoma NCT00871481 Phase I/II
Dose-Escalation Study of Combination BMS-936558 (MDX-1106) and Ipilimumab in Subjects with Unresectable Stage III or Stage IV Malignant Melanoma NCT01024231 Phase I
A Study of Intratumoral Injection of Interleukin-2 and Ipilimumab in Patients with Unresectable Stages III-IV Melanoma NCT01672450 Phase I
Phase II Safety Study of Vemurafenib Followed by Ipilimumab in Subjects with V600 BRAF-Mutated Advanced Melanoma NCT01673854 Phase II
Yervoy with Sylatron (Interferon A) Unresectable Stage III or IV Melanoma NCT01496807 Phase I
Ipilimumab with Lymphodepletion Plus Adoptive Cell Transfer and High-Dose IL-2 in Melanoma Mets Pts NCT01701674 Phase I
A Phase II Study to Evaluate Safety and Efficacy of Combined Treatment with Ipilimumab and Intratumoral Interleukin-2 in Pretreated Patients with Stage IV Melanoma NCT01480323 Phase II
RADVAX: A Stratified Phase I/II Dose Escalation Trial of Stereotactic Body Radiotherapy Followed by Ipilimumab in Metastatic Melanoma NCT01497808 Phase I/II
Tumor-Infiltrating Lymphocytes After Combination Chemotherapy in Treating Patients With Metastatic Melanoma NCT01807182 Phase II (not open yet)
Aldesleukin Imaging in Viewing Tumor Growth in Patients With Stage IV Melanoma Receiving Ipilimumab Therapy NCT01789827 NA (not open yet)
NY-ESO-1 Vaccine in Combination With Ipilimumab in Patients With Unresectable or Metastatic Melanoma NCT01810016 Phase I (not open yet)
Dendritic Cell Vaccines + Dasatinib for Metastatic Melanoma NCT01876212 Phase II
Phase II Study of Abraxane Plus Ipilimumab in Patients With Metastatic Melanoma NCT01827111 Phase II
Tumor-Infiltrating Lymphocytes And Low-Dose Interleukin-2 Therapy Following Cyclophosphamide And Fludarabine In Patients With Melanoma NCT01883323 Phase II
Re-Stimulated Tumor-Infiltrating Lymphocytes And Low-Dose Interleukin-2 Therapy in Patients With Melanoma NCT01883297 Phase I
Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab Alone in Previously Untreated Advanced Melanoma (CheckMate-067) NCT01844505 Phase III
Study of Nivolumab Given Sequentially With Ipilimumab in Subjects With Advanced or Metastatic Melanoma (CheckMate 064: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 064) NCT01783938 Phase II
Study of Vaccination With Poly-ICLC and Peptide-pulsed Dendritic Cells NCT01783431
A Phase 1/2 Randomized, Blinded, Placebo Controlled Study of Ipilimumab in Combination With INCB024360 or Placebo in Subjects With Unresectable or Metastatic Melanoma NCT01604889 Phase I/II
Safety Study of IL-21/Ipilimumab Combination in the Treatment of Melanoma NCT01489059 Phase I
Safety Study of IL-21/Anti-PD-1 Combination in the Treatment of Solid Tumors NCT01629758 Phase I
High-dose Interleukin-2 (HDIL-2), Combined With recMAGE-A3 + AS15 ASCI NCT01266603 Phase I

IMMUNOTHERAPY WITH ADOPTIVE CELL TRANSFER

TRIAL NAME TRIAL ID Phase
Ipilimumab with Lymphodepletion Plus Adoptive Cell Transfer and High-Dose IL-2 in Melanoma Mets Pts NCT01701674
Cell Therapy for Metastatic Melanoma Using CD8 Enriched Tumor Infiltrating Lymphocytes NCT01236573 Phase I/II
Treating Metastatic Cancer with Anti-VEGFR2 Gene Engineered CD8+ Lymphocytes NCT01218867 Phase I/II
Lymphodepletion Plus Adoptive Cell Transfer with or without Dendritic Cell Immunization NCT00338377 Phase II
Study of Gene Modified Immune Cells in Patients with Advanced Melanoma (F5) NCT00910650 Phase II
Laboratory-Treated T Cells and Ipilimumab in Treating Patients with Metastatic Melanoma NCT00871481 Phase I/II
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