BRAF inhibitor therapy treats cancers that carry a BRAF mutation, most often V600E, with two tablets taken together at home, a BRAF inhibitor such as dabrafenib and a MEK inhibitor such as trametinib. It is used in melanoma after surgery and when spread, and in lung, bowel and thyroid cancer. Our oncologists arrange the mutation test, the first weeks of treatment under close watch and follow-up once you are back home.
About This Department
Medical oncology
Half of melanomas carry a single spelling error in one gene, BRAF, that locks the cell into growth. Two tablets taken together switch it off. The mutation test decides whether they will work.
BRAF inhibitor therapy treats cancers that carry a mutation in the BRAF gene, most often the one called V600E, with a tablet that blocks the faulty BRAF protein, almost always paired with a second tablet, a MEK inhibitor, that blocks the next step in the same pathway. The combination is taken at home, every day. In melanoma that had spread, a third of patients treated with dabrafenib and trametinib were alive at five years, and among those whose cancer disappeared completely, 71 percent were (Robert and colleagues, New England Journal of Medicine, 2019). After surgery for stage III melanoma, a year of the same tablets raised the share of patients alive without relapse at five years from 36 to 52 percent (Dummer and colleagues, New England Journal of Medicine, 2020). The same approach now treats BRAF-mutated lung, bowel and thyroid cancers and several others. This page explains what BRAF is, how the mutation is found, why two drugs work better than one, the results in melanoma and beyond, how BRAF tablets compare with immunotherapy, how the treatment is taken and its side effects, and how patients from abroad arrange it at Biruni Hospital in Istanbul.
34
Percent of patients with BRAF-mutated melanoma that had spread alive at five years on dabrafenib plus trametinib
52
Percent alive without relapse at five years after a year of the same tablets following surgery, against 36 percent
71
Percent alive at five years among patients whose melanoma disappeared completely on the combination
Free
Review of your pathology and mutation report by the medical oncology team
BRAF is a gene that makes a switch inside cells, part of a relay called the MAPK pathway that passes growth signals from the surface of the cell to its nucleus. A single change in one letter of the gene, at position 600, turns the switch permanently on. The commonest version is called V600E. The cell no longer waits for a signal to grow. It grows.
The drugs
BRAF and MEK inhibitor pairs
BRAF inhibitor
MEK partner
Main uses
Dabrafenib
Trametinib
Melanoma before or after surgery and when spread, lung cancer, anaplastic thyroid cancer, glioma, other solid tumors with V600E
Encorafenib
Binimetinib
Melanoma that has spread, lung cancer. Encorafenib with cetuximab for bowel cancer
Vemurafenib
Cobimetinib
Melanoma that has spread, and vemurafenib alone for some rare blood and histiocytic diseases
First-line treatment with dabrafenib plus trametinib led to long-term benefit in approximately one third of the patients who had unresectable or metastatic melanoma with a V600E or V600K mutation (Robert and colleagues, 2019).
Finding the mutation
How is the BRAF mutation found?
On the tumor tissue, from the biopsy or the surgical specimen. A quick test on a single gene gives an answer in a few days. A broader panel, next-generation sequencing, reads BRAF along with dozens of other genes and takes one to three weeks. Where tissue is scarce or old, a blood test can find tumor DNA circulating in the plasma, though a negative blood result does not rule the mutation out. Every patient with melanoma that is stage III or beyond should have the test, as should every patient with lung adenocarcinoma, bowel cancer that has spread and anaplastic thyroid cancer.
The result names the exact change. V600E and V600K respond to the approved drugs. Mutations elsewhere in the gene, called non-V600 mutations, behave differently and in most cases do not respond, and a report that says only BRAF positive should be read in full before a prescription is written.
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Why the answer is needed early
A patient with BRAF-mutated melanoma that is growing fast, with many symptoms, may need the tablets within days, since they shrink tumors faster than any other treatment. The test is ordered at diagnosis so that the choice is ready when it is needed.
Why two drugs
1
Alone, a BRAF inhibitor works fast and fails fast
The first BRAF inhibitors shrank melanomas in half of patients within weeks, then the cancer found a way round the block within months, typically by reactivating the next step of the same pathway, MEK. Adding a MEK inhibitor closes that detour and doubles the time the response lasts.
The pair also has fewer of one side effect than either drug alone. A BRAF inhibitor on its own switches on the pathway in normal skin cells, and some patients developed new skin growths and even small skin cancers. The MEK inhibitor blocks that paradoxical effect. A BRAF inhibitor without its partner is now used only where the partner cannot be tolerated or in a few rare diseases.
Melanoma that has spread
Dabrafenib plus trametinib, five-year results
Measure
Result
Meaning
Alive at five years
34 percent of 563 patients
A third of patients alive long-term
Alive without progression at five years
19 percent
Durable control for about one in five
Complete response
19 percent
The cancer disappeared on scans
Alive at five years after a complete response
71 percent
The best predictor of long survival
What the trials showed
A complete response occurred in 109 patients, 19 percent, and was associated with an improved long-term outcome, with an overall survival rate of 71 percent at five years (Robert and colleagues, 2019).
Who does best
Patients who start in good general health, with a normal level of the blood test LDH, with the cancer in fewer than three organs and without spread to the brain. Those factors predicted long survival in the pooled trials. Patients with a high LDH and widespread disease still respond. Fast, too. The response lasts less long in this group, and it is here that the order of treatment matters most.
When the tablets stop working
Resistance develops in nearly every case. Sooner or later, in the majority, a melanoma that has spread grows again on the tablets.
The cancer finds new routes around the block. Some cells pick up a second mutation further down the same pathway, others switch on a parallel pathway through a different receptor, and a few change their identity altogether so that the growth signal no longer depends on BRAF at all. Progression can appear in a single spot while everything else stays controlled, and in that case the lone growing deposit can be removed by surgery or treated with focused radiation while the tablets continue, because the rest of the disease is still responding and there is no reason to give up a drug that is working almost everywhere. With widespread growth, the next step is immunotherapy if it has not been given, a clinical trial, or chemotherapy. A second course of the same tablets after a break sometimes works again, since resistant cells can lose their advantage once the pressure of the drug is removed. Where possible, the oncologist biopsies the tumor again. The new sample shows what changed and may point to a different drug.
Nobody did anything wrong. Stopping the tablets reflects the biology of the cancer.
Melanoma after surgery
The COMBI-AD trial randomized 870 patients with stage III melanoma and a BRAF V600E or V600K mutation, after surgery, to a year of dabrafenib and trametinib or to placebo. At five years, 52 percent of the treated group were alive without relapse against 36 percent on placebo, and 65 percent against 54 percent were free of distant spread. No long-term toxic effects appeared after the year ended (Dummer and colleagues, 2020).
Tablets or immunotherapy after surgery?
Both are standards for stage III melanoma with a BRAF mutation. No trial has compared them head to head. The tablets act faster, are taken at home and stop after a year. Their side effects fade when they stop. Immunotherapy runs for a year by infusion and can leave a permanent side effect, such as an underactive thyroid. The choice depends on the patient's other illnesses, preference and, in some centers, on which drug is available. The oncologist sets out both.
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A year, then watching
Twelve months of tablets, then scans every three to six months for several years. A relapse after the year can be treated with the same tablets again or with immunotherapy.
Relapse-free survival at five years was 52 percent with dabrafenib plus trametinib and 36 percent with placebo, a reduction in the risk of relapse or death of almost half (Dummer and colleagues, 2020).
Other cancers
Lung, bowel, thyroid, brain and blood
BRAF mutations appear in one to two percent of lung adenocarcinomas. In 36 previously untreated patients with BRAF V600E lung cancer that had spread, dabrafenib and trametinib shrank the cancer in 64 percent (Planchard and colleagues, Lancet Oncology, 2017). For these patients the tablets are a first treatment in their own right.
BRAF treatment beyond melanoma
Cancer
Combination
Notes
Lung adenocarcinoma, V600E
Dabrafenib and trametinib, or encorafenib and binimetinib
First treatment or after chemotherapy
Bowel cancer, V600E, spread
Encorafenib and cetuximab, with or without binimetinib
After earlier chemotherapy, and in newer regimens earlier
Anaplastic thyroid cancer, V600E
Dabrafenib and trametinib
Fast responses in an aggressive cancer, sometimes making surgery possible
Low-grade glioma in children, V600E
Dabrafenib and trametinib
Liquid form for young children
Hairy cell leukemia and histiocytic diseases
Vemurafenib or dabrafenib
When standard treatment fails
Other solid tumors with V600E
Dabrafenib and trametinib
Approved in the United States when no better option exists
The median overall survival was 9.0 months with encorafenib, binimetinib and cetuximab and 5.4 months with standard therapy in BRAF V600E bowel cancer that had progressed, and the response rate was 26 percent against 2 percent (Kopetz and colleagues, New England Journal of Medicine, 2019).
Bowel cancer shows why the cancer's origin matters. A BRAF inhibitor alone barely works in the bowel, because bowel cells answer the block by switching on another receptor, EGFR, which restarts the pathway. Adding cetuximab, an antibody against EGFR, closes that route. The same mutation in two organs needs two different partners.
Tablets or immunotherapy first
For BRAF-mutated melanoma that has spread, which should come first?
A randomized trial of the sequence found that patients who started with immunotherapy and switched to BRAF and MEK tablets on progression lived longer than those who started with the tablets, and the standard since has been immunotherapy first for most patients. The tablets come first when the cancer is growing so fast, or causing such symptoms, that the weeks immunotherapy needs to act cannot be spared, or when immunotherapy cannot be given. Both are used in the end, in one order or the other.
Choosing the first treatment in spread melanoma
Situation
First choice
Reason
Well, slow-growing disease, normal LDH
Immunotherapy
Longer survival when given first
Rapid growth, many symptoms, high LDH
BRAF and MEK tablets
Responses within days to weeks
Brain metastases with symptoms
Tablets or combination immunotherapy, with steroids and local treatment
Both have activity in the brain
Autoimmune disease or transplant
BRAF and MEK tablets
Immunotherapy carries high risk
The tablets shrink more tumors, faster. Immunotherapy produces more long survivors. The order tries to give each patient both advantages.
Taking the tablets
Dabrafenib, twice a day. 150 milligrams, on an empty stomach, an hour before or two hours after a meal, twelve hours apart.
Trametinib, once a day. 2 milligrams at the same time each day, also on an empty stomach, taken with one of the dabrafenib doses.
Every three to four weeks. Blood tests, blood pressure and a review of symptoms, and an eye check if vision changes.
Every eight to twelve weeks. A scan to measure response.
Fever, with or without chills, the commonest side effect of dabrafenib and trametinib, which stops treatment for a day or two and is managed by pausing the tablets at the first sign.
Rash and dry skin.
Blurred vision, from fluid under the retina, which settles with a pause.
Swelling, high blood pressure, raised liver enzymes and, rarely, a fall in heart pumping function.
Common side effects and what helps
Side effect
How often with the combination
What to do
Fever
Around half of patients on dabrafenib and trametinib
Stop both tablets at the first rise, take paracetamol, call the unit, restart when fever-free for a day
Rash and skin changes
A third or more
Moisturizers, sun protection, creams, a skin check every few months
Diarrhea and nausea
A quarter to a third
Simple remedies, food timing, dose change if persistent
Eye changes
A few percent
Eye examination, short pause
Heart pumping function
A few percent
Heart scan at baseline and during treatment
Treatment for patients from abroad
BRAF treatment is a tablet taken at home, which suits patients from abroad well. The usual pattern is one visit of one to two weeks for the consultation, the mutation test if it has not been done, the baseline blood tests, heart and eye checks, and the first weeks of tablets under close watch, since fever and other early side effects appear in that window. The patient then returns home with a supply and a protocol, with blood tests at home every few weeks sent to the oncologist here, and scans reviewed here every two to three months. What the team needs is the pathology report and the mutation result, or the tumor blocks for testing, the staging scans as image files, the list of medicines and any treatment so far.
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Length of stay and fitness to fly
One to two weeks for the first visit. Patients are fit to fly as soon as the first weeks pass without significant fever, and the supply for the journey and the first months is dispensed before departure.
One coordinator from the international patients office handles arrangements from the first message through discharge and answers the same WhatsApp number once you are back home. The office works in English, Arabic, French, Russian, Serbian, Romanian and Spanish and books interpreters for other languages, and it arranges the visa invitation letter, airport transfers, daily transport and accommodation near the hospital. Halal, vegetarian and diabetic meals, a prayer room on site, and a female physician on request wherever the rota allows.
Living on the tablets
Daily life continues. Patients work, travel and look after family while taking dabrafenib and trametinib, and the main rule to learn is the one about fever.
A thermometer at home, a reading whenever chills or tiredness appear, and both tablets paused at 38 degrees. That single habit prevents most admissions. Sun protection matters on vemurafenib and is sensible on all three pairs. Grapefruit and some herbal remedies change the level of the drugs in the blood, so every new medicine, including those bought without a prescription, is checked with the oncology pharmacist first.
Pregnancy has to be avoided, by both women and men on treatment, and dabrafenib can make hormonal contraception less reliable, so a barrier method is added as well.
Cost
The tablets are priced by the month, and the figure depends on the combination and the country of dispensing. A year of treatment after surgery, or open-ended treatment for spread disease, is a long commitment, and the plan for obtaining the tablets at home is settled at the first visit.
Compare quotes for the same combination and the same number of months, and ask how the tablets will be supplied once you are home.
Monitoring during treatment
Test
How often
Why
Blood tests and blood pressure
Every three to four weeks at first, then monthly
Liver, kidney, sugar and blood pressure changes
Heart scan
Before starting and every three months in the first year
Rare fall in pumping function
Skin check
Every two to three months
New skin growths, especially without the MEK partner
References
Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381(7):626-636.
Dummer R, Hauschild A, Santinami M, et al. Five-year analysis of adjuvant dabrafenib plus trametinib in stage III melanoma. N Engl J Med. 2020;383(12):1139-1148.
Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632-1643.
Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer. An open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307-1316.
Editor's note
Written by the Biruni Hospital medical editorial team. Reviewed by Prof. Dr. Özcan YILDIZ, Medical Oncology.
