BRAF and MEK combined treatment in BRAF-mutant advanced melanoma

This study reviewed the effectiveness and safety of combined treatment with BRAF and MEK inhibitors in patients with advanced melanoma. Researchers suggested that combined treatment of BRAF and MEK inhibitors was associated with better responses than other treatments.

Some melanoma patients have a mutation (permanent change) in the BRAF gene. BRAF and MEK inhibitors block the BRAF and MEK proteins, reducing tumor growth. Studies have shown an improved effect of the combined treatment with BRAF and MEK inhibitors when compared with BRAF treatment alone. Despite of having lower response rates, anti-PD1 therapies have prolonged overall survival in advanced melanoma patients. These treatment target the PD-1 receptor on cancer cells, which stimulates the immune system to attack them.

The objective of this study was to review the effectiveness and safety of BRAF and MEK combined treatment when compared to BRAF or PD-1 agents alone.

One study compared the combined treatment of dabrafenib (BRAF inhibitor; Tafinlar) plus trametinib (MEK inhibitor; Mekinist) to dabrafenib alone. This study showed a 25% improvement in the odds of a better progression-free survival (PFS; time from treatment to cancer progression).

Another study showed that the combined treatment of dabrafenib plus trametinib had an improved effect when compared to vemurafenib alone (BRAF inhibitor; Zelboraf). The overall response rate was 67% in the combination group and 53% in the vemurafenib group.

A third study found that the combined treatment of vemurafenib and cobimetinib (Cotellic) had an improved effect when compared to vemurafenib alone. The combined treatment group had a 30% improvement in the odds of a better overall survival and a 42% improvement in the odds of a better PFS.

Overall survival and PFS were lower in patients with elevated lactate dehydrogenase (LDH) levels when compared to patients with normal LDH levels. LDH is an indicator of cell or tissue damage in the body.

A prior study with the PD-1 inhibitor pembrolizumab (Keytruda) showed a response rate of 38% in patients with non-BRAF mutated melanoma and 32% in BRAF-mutated patients. Therefore, this study indicates that the BRAF plus MEK combination have a higher chance of response in BRAF-mutated patients when compared to PD-1 agents.

The presence of brain metastasis (when the cancer spreads to the brain) is associated with a poor prognosis. A prior study showed that dabrafenib was active in melanoma brain metastasis achieving a response of 39.2% in patients not previously treated.

MEK inhibitors alone such as trametinib are also active in advanced melanoma. This agent showed an improved overall survival and PFS when compared with chemotherapy alone. However, trametinib alone was less active than BRAF and MEK combined treatment, showing a PFS of only 4.8 months.

The most common side effects in the dabrafenib plus trametinib combination is fever followed by fatigue (35%), nausea (30-35%), headache (30%), chills (30-31%), diarrhea (24-32%), joint pain (24%), rash (22-23%) and high blood pressure (22%). Severe side effects were detected in 11-16% of the patients. In patients receiving vemurafenib and cobimetinib, strong sensitivity to light (28%), diarrhea (56%) and increased liver levels (22-23%) were the most common side effects. 14% of the patients experienced severe side effects.

Rates of severe side effects in patients treated with PD-1 agents were lower than in the patients treated with BRAF and MEK inhibitors. 

This study suggested that the BRAF and MEK combined therapy is associated with better responses in advanced melanoma patients. Currently, there are no predictive factors to determine the treatment outcomes, however high levels of LDH are associated with poorer prognosis.