Phase I and II clinical trial evaluating the combination of dabrafenib and trametinib for the treatment of patients with metastatic melanoma

This paper presents results from phase I and II clinical trials evaluating the safety and efficacy of two targeted therapies – dabrafenib and trametinib – given in combination for metastatic melanoma patients with BRAF mutations.

BRAF is a protein that plays a role in cell division and growth. About 50% of melanomas arise because of a genetic defect which causes the BRAF protein to malfunction (BRAF mutation). As a result, the pigmented cells of the skin (the melanocytes) start multiplying and growing abnormally, forming a melanoma. Metastatic melanoma means that the cancer has spread to distant lymph nodes or other parts of the body such as the liver, lungs or brain. In metastatic melanoma patients with BRAF mutations, the cancer actually becomes addicted to this protein. Therefore, it can be treated with drugs that block this specific protein (targeted therapies). As a result, targeted therapies can help stop the cancer's growth, relieve symptoms and prolong survival for patients with metastatic disease. Dabrafenib and Trametinib are two experimental drugs that target BRAF which have shown promising results in clinical trials for patients with metastatic melanoma.

The study included 247 metastatic melanoma patients with BRAF mutations. After evaluating the safety and side effects of progressive doses of dabrafenib (75 mg and 150 mg twice daily) plus trametinib (1, 1.5 and 2 mg once daily) – phase I trial, patients were separated into 3 groups for the phase II trial.

One group received 150 mg of darafenib twice daily plus 1 mg of trametinib once daily (150/1 group).

A second group received 150 mg of darafenib twice daily plus 2 mg of trametinib once daily (150/2 group).

The third group received 150 mg of dabrafenib monotherapy (a single drug treatment) twice daily (DM group).

The main outcomes evaluated were progression-free survival or PFS (defined as the period of time without cancer progression), overall survival, melanoma response rate (defined as the percentage of patients whose cancer stops growing or shrinks following treatment), as well as side effects such as cutaneous squamous-cell carcinoma or SCC (a form of skin cancer caused by an abnormal growth of the cells from the most superficial layer of the skin – the epidermis) which is common with dabrafenib therapy.

During follow up, 19% of patients in the DM group developed SCC compared to 7% patients in combination 150/2 group and 2% in combination 150/1 group. Fever was more common in the 150/2 group than in the DM group (71% versus 26%). After approximately 14 months of follow up, the median PFS for patients in the 150/2 group was 9.4 months compared to 5.8 months in the DM group. The response rate was higher in the 150/2 group compared to the DM group (76% versus 54%). Also, the overall survival was higher in the 150/2 group (79%) than in the DM group (70%). However, 80% of patients in the DM group switched to the combination 150/2 group when the melanoma progressed. 

In summary, dabrafenib and trametinib were safely combined at full monotherapy doses and PFS and overall survival were significantly improved. Compared to the DM group, patients receiving combination therapy had more side effects such as fever and chills. However, these side effects were not severe and were manageable. Also, there were fewer cases of SCC in the combination therapy group.

Despite these promising results, this drug combination has only passed through the phase I and II clinical trials. Larger trials are needed to further establish this combination’s therapeutic potential.