Role of BRAF Mutations in Non-Small Cell Lung Cancer Still Emerging, Evolving

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“BRAF-mutated NSCLC represents an emerging targetable entity among the scenario of oncogene-driven NSCLC.”
“BRAF-mutated NSCLC represents an emerging targetable entity among the scenario of oncogene-driven NSCLC.”

The identification of molecular targets for treating non-small cell lung cancer (NSCLC) changed the treatment landscape of the disease. Among the more commonly seen mutations are alterations to epidermal growth factor receptor (EGFR) and chromosomal translocations of anaplastic lymphoma kinase (ALK) genes. However, mutations to BRAF are also found in between 1.5% and 3.5% of NSCLCs.

BRAF-mutated NSCLC represents an emerging targetable entity among the scenario of oncogene-driven NSCLC, another important brick to pickaxe in the molecular wall of NSCLC,” Alessandro Leonetti, MD, of University Hospital of Parma in Italy, and colleagues, wrote in a recent review of BRAF in NSCLC.1

BRAF is a protein kinase known to play a role in the MAPK/ERK pathway, involved in cell growth, proliferation, survival and differentiation. BRAF mutations have been discovered in about 8% of cancers, with a greater incidence in certain tumors including melanoma and papillary thyroid carcinoma.

In NSCLC, BRAF mutations generally occur exclusively from EGFR mutations or ALK rearrangements. The most frequent activating BRAF mutation is BRAFV600E, which occurs in about 1% to 2% of lung adenocarcinomas. Patients with BRAFV600E mutations have been found to have different clinical parameters compared with non-V600E mutations. Overall BRAF mutations commonly occur in current or former smokers, but BRAFV600E mutations are more commonly seen in light or never smokers. Additionally, BRAF mutations, including BRAFV600E mutations, occur more commonly in women. Furthermore, patients found to have BRAFV600E mutations are more likely to have shorter disease-free and overall survival rates.

“If this prognostic impact is attributable to aggressive histologic architectures, like the micropapillary one, frequently associated with BRAFV600E mutations, remains to be assessed,” Dr Leonetti and colleagues wrote in their review.

Targeting BRAF

Two potent BRAF inhibitors — vemurafenib and dabrafenib ― have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of advanced metastatic melanoma with V600 mutation. However, the majority of patients treated with the inhibitors eventually develop resistance to the drugs.

Some research is exploring the addition of a MEK inhibitor to overcome this acquired resistance to BRAF inhibition in melanoma. Specifically, two phase 3 trials combining BRAF and MEK inhibitors in untreated disease have shown response rates of about 70% and median overall survival approaching 2 years.2,3

According to Dr Leonetti and colleagues, “given the strong results observed with BRAF inhibition for the treatment of BRAF-mutated metastatic melanoma, the perspective of translating the success of BRAF inhibition for other tumor types that harbor a BRAF mutation has raised interest in clinicians.”

However, results in different solid tumors types have been mixed, with emerging positive data in NSCLC. Results from a basket study looking at BRAFV600E in non-melanoma showed that among 19 patients with NSCLC 42% had objective response with 14 patients having a reduction in tumor size.4 Similarly, a retrospective study of vemurafenib treatment in patients with BRAF-mutant NSCLC showed patients with V600E mutations had a 54% disease response rate.5

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