How a Combination of Drugs Can Extend the Lives of Patients with Advanced Melanoma
How a Combination of Drugs Can Extend the Lives of Patients with Advanced Melanoma
Melanoma is a type of skin cancer that develops from the cells that control the pigment of the skin. It is caused by problems in these cells, called melanocytes, but the exact cause is unknown. Some factors that increase the risk of melanoma include exposure to UV rays, skin type, family history, and immune system weakness. Melanoma can be treated with surgery, chemotherapy, immunotherapy, targeted therapy, and radiation therapy1.
However, some melanomas are very aggressive and can spread to other parts of the body, such as the lungs, liver, brain, and bones. This is called metastatic melanoma, and it is often fatal. The average survival time for patients with metastatic melanoma is less than a year2.
One of the reasons why melanoma is so hard to treat is that it often has mutations in a gene called BRAF. This gene makes a protein that is part of a pathway that regulates cell growth and division. When the BRAF gene is mutated, it makes an abnormal protein that causes the cells to grow and divide without control. This leads to the formation of tumors that are resistant to conventional treatments.
About half of all melanomas have mutations in the BRAF gene. These mutations are usually either V600E or V600K, which affect the amino acid sequence of the BRAF protein. These mutations can be detected by a test that analyzes a sample of the tumor tissue3.
Fortunately, there are drugs that can target the abnormal BRAF protein and block its activity. These drugs are called BRAF inhibitors, and they include dabrafenib (Tafinlar) and vemurafenib (Zelboraf). These drugs can shrink or slow down the growth of tumors in some patients with BRAF-mutated melanoma3.
However, BRAF inhibitors have some limitations. They can cause serious side effects, such as skin problems, fever, joint pain, fatigue, nausea, heart rhythm problems, liver problems, kidney failure, bleeding, and increased blood sugar levels. They can also induce resistance in some cancer cells, which means that they stop working after a while3.
Therefore, researchers have been exploring ways to combine BRAF inhibitors with other drugs that can enhance their effectiveness and overcome their limitations. One of these drugs is trametinib (Mekinist), which belongs to a class of drugs called MEK inhibitors. MEK is another protein in the same pathway as BRAF, and it works together with BRAF to stimulate cell growth and division. By blocking both proteins, trametinib and dabrafenib can stop the signals that tell the cells to grow and divide uncontrollably3.
Several clinical trials have been conducted or are ongoing to test this combination strategy in patients with metastatic melanoma with BRAF mutations. Some examples are:
- The COMBI-d trial compared dabrafenib plus trametinib versus dabrafenib alone in 423 patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations4. The results showed that adding trametinib improved the median overall survival (the time from start of treatment until death) from 18.7 months to 25.1 months. This means that dabrafenib plus trametinib reduced the risk of death by 29%. The most common side effects were fever, chills, fatigue, rash, nausea, vomiting, diarrhea, joint pain, headache, high blood pressure, and muscle pain4.
- The COMBI-v trial compared dabrafenib plus trametinib versus vemurafenib alone in 704 patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations5. The results showed that adding trametinib improved the median overall survival from 17.2 months to 25.6 months. This means that dabrafenib plus trametinib reduced the risk of death by 37%. The most common side effects were rash, diarrhea, lymphedema (swelling caused by fluid buildup), fatigue, nausea, fever, joint pain, headache, vomiting, constipation, cough, and muscle pain5.
- The COMBI-i trial compared dabrafenib plus trametinib plus spartalizumab (a drug that blocks a protein called PD-1 that prevents the immune system from attacking cancer cells) versus dabrafenib plus trametinib alone in 559 patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. The results showed that adding spartalizumab improved the median overall survival from 23.5 months to 28.8 months. This means that dabrafenib plus trametinib plus spartalizumab reduced the risk of death by 23%. The most common side effects were rash, diarrhea, fatigue, fever, nausea, vomiting, joint pain, headache, cough, and high blood pressure.
These trials suggest that dabrafenib and trametinib combination therapy is a novel and effective approach for melanoma treatment. By combining dabrafenib and trametinib, patients can achieve better outcomes than using either drug alone. By adding other drugs, such as spartalizumab, the effectiveness can be further enhanced. However, more research is needed to optimize the dose, schedule, sequence, and duration of this combination therapy. Patients should also be aware of the potential side effects and monitor their health closely while receiving this treatment.
If you have melanoma that has spread beyond the skin or has come back after surgery or other treatments, you should ask your doctor if your tumor has a BRAF mutation. If it does, you may benefit from dabrafenib and trametinib combination therapy. Your doctor will discuss with you the best treatment options for your specific case.