BRAF Inhibitor Therapy
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
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.
What BRAF is
The drugs
| 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?
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.
Why two drugs
Melanoma that has spread
| 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
Tablets or immunotherapy after surgery?
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
| 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).
Tablets or immunotherapy first
For BRAF-mutated melanoma that has spread, which should come first?
| 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.
| 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
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
| Item | Usually included | Priced separately |
|---|---|---|
| The tablets | A month's supply of both drugs | Cetuximab in bowel cancer |
| The visit | Consultation, blood tests, blood pressure, symptom review | Admission for a side effect |
| Tests and imaging | Routine blood tests | Mutation testing, heart scans, eye examinations, staging scans |
| 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. Metin GÜDEN, Radiation Oncology.
Medically reviewed by
Prof. Dr. Metin GÜDEN
Radiation Oncology
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