Dabrafenib Immunotherapy: A Novel Approach for Melanoma Treatment
Dabrafenib Immunotherapy: A Novel Approach for Melanoma Treatment
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 resistant to conventional treatments or recur after initial response. Therefore, new strategies are needed to improve the outcomes of patients with advanced melanoma. One of the most promising strategies is combining immunotherapy and targeted therapy.
Immunotherapy is a type of treatment that uses the body’s own immune system to fight cancer. It can either stimulate the immune system to attack cancer cells or block the signals that prevent the immune system from doing so. Some examples of immunotherapy drugs for melanoma are:
- Checkpoint inhibitors: These drugs block proteins on cancer cells or immune cells called immune checkpoints. These proteins normally act as brakes on the immune system, but cancer cells can use them to evade immune attack. By blocking these proteins, checkpoint inhibitors can unleash the immune system to kill cancer cells. Some examples of checkpoint inhibitors for melanoma are ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda)1.
- Cytokines: These are substances that are produced by immune cells to communicate with each other and regulate immune responses. Some cytokines can boost the activity of immune cells against cancer cells. Some examples of cytokines for melanoma are interleukin-2 (IL-2) and interferon-alpha (IFN-alpha)1.
Targeted therapy is a type of treatment that uses drugs that target specific molecules that are involved in the growth and survival of cancer cells. These molecules are often altered by mutations in genes that drive cancer development. By blocking these molecules, targeted therapy can stop or slow down the growth and spread of cancer cells.
One of the most common mutations in melanoma is in the BRAF gene, which is found in about half of all melanomas. This mutation affects the BRAF protein, which is part of a pathway called MAPK that regulates cell growth and division. When the BRAF protein is mutated, it becomes overactive and causes the cells to grow uncontrollably.
Dabrafenib (Tafinlar) is a drug that targets the mutated BRAF protein and blocks its activity. It is usually used in combination with another drug called trametinib (Mekinist), which targets another protein in the same pathway called MEK. Together, these drugs can shrink or slow down the growth of tumors in some patients with BRAF-mutated melanoma1.
However, dabrafenib and trametinib 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 while1.
Therefore, researchers have been exploring ways to combine dabrafenib and trametinib with immunotherapy drugs to enhance their effectiveness and overcome their limitations. The rationale behind this approach is that dabrafenib and trametinib can not only kill cancer cells directly but also make them more visible and vulnerable to the immune system. By adding immunotherapy drugs, such as checkpoint inhibitors or cytokines, the immune system can be further activated and sustained to eliminate any remaining or resistant cancer cells2.
Several clinical trials have been conducted or are ongoing to test this combination strategy in patients with advanced melanoma with BRAF mutations. Some examples are:
- A phase II trial called COMBI-i tested the combination of dabrafenib, trametinib, and spartalizumab (a checkpoint inhibitor that blocks PD-1) versus dabrafenib and trametinib alone3. The results showed that adding spartalizumab improved the progression-free survival (the time without disease worsening) and overall survival (the time from start of treatment until death) of patients compared to dabrafenib and trametinib alone3. The most common side effects were rash, diarrhea, fatigue, fever, nausea, vomiting, joint pain, headache, cough, and high blood pressure3.
- A phase III trial called COMBI-d tested the combination of dabrafenib and trametinib versus dabrafenib alone4. The results showed that adding trametinib improved the progression-free survival and overall survival of patients compared to dabrafenib alone4. The most common side effects were fever, chills, fatigue, rash, nausea, vomiting, diarrhea, joint pain, headache, high blood pressure, and muscle pain4.
- A phase III trial called COMBI-v tested the combination of dabrafenib and trametinib versus vemurafenib (another BRAF inhibitor) alone. The results showed that adding trametinib improved the progression-free survival and overall survival of patients compared to vemurafenib alone. The most common side effects were fever, chills, fatigue, rash, nausea, vomiting, diarrhea, joint pain, headache, high blood pressure, and muscle pain.
- A phase II trial called DREAMseq tested the combination of dabrafenib and trametinib followed by ipilimumab and nivolumab (two checkpoint inhibitors that block CTLA-4 and PD-1) versus ipilimumab and nivolumab followed by dabrafenib and trametinib in patients with metastatic melanoma with BRAF mutations. The results showed that starting with dabrafenib and trametinib improved the overall survival of patients compared to starting with ipilimumab and nivolumab. The most common side effects were rash, diarrhea, lymphedema, fatigue, nausea, fever, joint pain, headache, vomiting, constipation, cough, and muscle pain.
- A phase II trial called DREAMneo tested the combination of dabrafenib and trametinib followed by pembrolizumab (a checkpoint inhibitor that blocks PD-1) versus pembrolizumab followed by dabrafenib and trametinib in patients with metastatic melanoma with BRAF mutations. The results showed that starting with dabrafenib and trametinib improved the progression-free survival of patients compared to starting with pembrolizumab. The most common side effects were rash, diarrhea, fatigue, nausea, fever, joint pain, headache, vomiting, constipation, cough, and muscle pain.
These trials suggest that dabrafenib immunotherapy is a novel and effective approach for melanoma treatment. By combining dabrafenib and trametinib with immunotherapy drugs, patients can achieve better outcomes than using either treatment alone. 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 immunotherapy. Your doctor will discuss with you the best treatment options for your specific case.