Success of Dabrafenib and Trametinib in BRAF-Positive Stage 4 Lung Cancer

In stage 4 non-small cell lung cancer, successful results of the dabrafenib and trametinib combination in the BRAF V600E mutation-positive subgroup were presented at ESMO 2017.

Subtype classification, previously performed only by examining cancer cells’ appearance under a microscope, is now done by searching for and identifying their genetic characteristics (DNA mutations). In other words, cancer medicine is becoming increasingly precise. Treatments targeting these cancer-driving mutations are called targeted drugs . BRAF mutations in lung cancer are among these cancer-driving mutations.

The BRAF V600E mutation, the most common form of BRAF mutation, is present in %1-2 of all lung adenocarcinomas.

What Is a BRAF Mutation?

BRAF is a human gene encoding a protein called B-Raf. The B-Raf protein participates in a signaling process responsible for growth inside the cell (see the figure below). In 2002, faulty B-Raf proteins resulting from BRAF gene mutations were first identified in some human cancers. Vemurafenib and dabrafenib, targeting BRAF mutations in malignant melanoma, an aggressive skin cancer, had previously received FDA approval. Subsequent studies showed BRAF mutations also occur at certain rates in colorectal cancer, thyroid cancer and non-small cell lung cancers, in addition to melanoma.

Intracellular growth mechanisms include the Ras/Raf/MEK/ERK signaling pathway; previous studies had shown that blocking this pathway at multiple points is more effective than blocking it at a single point.

ESMO 2017 presented a phase-2 study in which previously untreated patients with stage 4 small cell lung cancer received the BRAF inhibitor dabrafenib and MEK inhibitor trametinib; of every 4 patients, 3 achieved complete or partial response or stable disease. In the presented phase-2 study, BRAF V600E-mutated metastatic non-small cell lung cancer was present in 36 patients, who received first-line oral treatment 2 times daily at 150 mg of dabrafenib (Tafinlar) and 1 time daily at 2 mg of trametinib (Mekinist). The participants had a median age of 67; %61 were women, %83 were white and %72 were smokers.

According to the Study Results;

• In this study with a median follow-up of 16 months, %64 of patients showed a meaningful response to treatment, and among responding patients, this response lasted a median of 10.4 months. 
• For all patients, the median duration of disease control with treatment was 10.9 months and the cancer control rate was %75.
• Two patients with metastatic lung cancer receiving this combination treatment had a complete response, meaning that disease findings disappeared completely on imaging.
• Median overall survival was slightly over 2 years, at 24.6 months.

Serious side effects reported in patients receiving dabrafenib and trametinib combination treatment were elevated liver function tests (ALT and AST) (%8-14), fever (%11) and reduced cardiac ejection fraction (%8).

In conclusion, targeted drug treatments for lung cancer are advancing in small but steady steps. Another important step was taken with the results of this study presented at ESMO 2017, reporting on two combined targeted drugs in BRAF-mutant lung cancer patients. With important advances in modern medicine, chemotherapy has begun giving way to targeted therapies and/or immunotherapies in patients with lung cancer.