Dabrafenib and trametinib are oral medications used together as a targeted cancer treatment. This combination therapy acts on specific molecular characteristics within cancer cells. It is prescribed for cancers that have a specific genetic profile, which is identified before starting the therapy.
The Targeted Mechanism of Action
Targeted therapy is an approach to cancer treatment that focuses on specific molecules involved in cancer cell growth. Dabrafenib and trametinib are examples of this approach, as they interfere with signals that drive tumor development. Their effectiveness is linked to a genetic alteration in the BRAF gene.
In some cancers, a V600E or V600K mutation occurs in the BRAF gene. This mutation causes the BRAF protein to become permanently active, leading to constant signaling that promotes uncontrolled tumor growth through the MAPK pathway. Dabrafenib is a BRAF inhibitor that works by directly blocking the activity of this mutated BRAF protein, cutting off the abnormal signal.
Cancer cells can develop resistance to a BRAF inhibitor alone, often by reactivating the signaling pathway through a different protein. Downstream from BRAF in the MAPK pathway is another protein called MEK. Trametinib is a MEK inhibitor, meaning it blocks the activity of the MEK1 and MEK2 proteins.
Using dabrafenib and trametinib together provides a dual blockade of the MAPK pathway. Inhibiting this pathway at two distinct points—BRAF and MEK—is more effective at shutting down cancer-driving signals than either drug alone. This dual action also helps to delay or overcome the development of resistance.
Cancers Treated With This Combination
The combination of dabrafenib and trametinib is approved for treating several types of cancer, but only when the tumor cells have a BRAF V600E or V600K mutation. This makes genetic testing of the tumor a necessary step before a patient can be considered for this regimen.
A primary use for this combination is in the treatment of melanoma. It is approved for patients with unresectable or metastatic melanoma that has a BRAF V600E or V600K mutation. It is also used as an adjuvant treatment for melanoma with these mutations after surgery to reduce the risk of the cancer returning.
The therapy is also an option for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a BRAF V600E mutation. Another approved use is for locally advanced or metastatic anaplastic thyroid cancer with a BRAF V600E mutation when there are no other satisfactory treatment options.
The application of dabrafenib and trametinib has expanded to include certain pediatric patients with low-grade glioma, a type of brain tumor, that has a BRAF V600E mutation. It also has a tumor-agnostic approval to treat any unresectable or metastatic solid tumor with a BRAF V600E mutation that has progressed on prior treatment and has no other good options.
Potential Side Effects
Treatment with dabrafenib and trametinib can cause a range of side effects that vary in frequency and severity. The most common effects include fever, fatigue, nausea, headache, and skin rashes. Fever (pyrexia) can be accompanied by chills, dizziness, or dehydration. Patients may also experience diarrhea, high blood pressure, and mild bleeding.
Serious Side Effects
Less frequent but more serious reactions can occur and require prompt medical attention.
- Heart problems: A decrease in the heart’s pumping ability can occur. Symptoms include new or worsening shortness of breath, swelling in the ankles, or an irregular heartbeat.
- Eye problems: Patients should report any vision changes, eye pain, or redness to their healthcare team, as these could signal conditions like uveitis.
- Severe skin reactions: These can include blistering, peeling skin, or a rash accompanied by fever and swollen lymph nodes. There is also an increased risk of developing new skin cancers, so regular skin examinations are important.
- Other serious events: These include bleeding in the brain or stomach and inflammation of the lungs or colon. Any signs of significant bleeding, such as coughing up blood, black stools, severe stomach pain, or difficulty breathing should be reported immediately.
This list is not exhaustive, and patients are advised to communicate any new or concerning symptoms to their medical team.
Treatment Administration and Monitoring
Patients take dabrafenib and trametinib at home on a specific schedule. Dabrafenib is taken as capsules twice a day, approximately 12 hours apart. Trametinib is a tablet taken once a day on an empty stomach, at least one hour before or two hours after a meal. The daily trametinib dose can be taken at the same time as either the morning or evening dose of dabrafenib.
If a dose of dabrafenib is missed, it should be skipped if the next scheduled dose is less than six hours away. For a missed dose of trametinib, the dose should be skipped if the next one is due in less than 12 hours. Patients should not take an extra dose to make up for a missed one. The capsules and tablets should be swallowed whole with water and not crushed or opened.
Regular monitoring is required to manage potential side effects and check the therapy’s effectiveness. Before starting and during treatment, patients will undergo regular check-ups. These include blood tests to monitor blood counts, liver function, and kidney function.
Targeted monitoring for specific organs is also performed. Skin examinations are conducted before, during, and for several months after treatment to check for any new or changing skin lesions. Eye exams are also recommended to screen for ocular issues. Heart function is assessed with tests like an electrocardiogram (ECG) or an echocardiogram (ECHO) at baseline and then at regular intervals.