BRAF: v-raf murine sarcoma viral oncogene homolog B

Background: A serine/threonine kinase in the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. Alterations in BRAF result in continuous activation of the MAPK pathway, promoting cell growth, proliferation and differentiation. BRAF mutations occur in 2% to 4% of patients with NSCLC, with about half occurring in the V600 position where a glutamic acid substitution is found (V600E). While non-V600E may coexist with KRAS mutations, other BRAF mutations are mutually exclusive from EGFR mutations and ALK rearrangements in treatment-naive patients.     

• Clinical Features Associated: smoking history, Caucasians, females, adenocarcinoma histology

Detection Methods: RT-PCR, NGS, and Sanger sequencing. Liquid biopsy is an option for patients who cannot undergo biopsy or do not have enough tissue remaining for NGS.

Classes of BRAF Mutations:

1. Class I:
   • Most frequently identified, RAS-independent, strong activation of BRAF kinase activity, and continuous activation of MAPK pathway.
   • V600E: 1-2% of lung adenocarcinomas and 50% of BRAF-mutated NSCLC. BRAF V600E mutation occurs mutually exclusive of KRAS, EGFR and ALK alterations and is currently the only BRAF mutation with FDA-approved targeted therapy. Combination BRAF-MEK inhibitors have shown better clinical outcomes than platinum-based chemotherapy; however, acquired resistance to this combination remains a challenge.
     • Clinical Features Associated: females, not correlated with smoking history
2. Class II:
   • RAS-independent, including both high and intermediate BRAF kinase activity based on MAPK pathway activation, and constitutively active dimers.
   • The most common is G469A (35% of all BRAF mutations).
   • Other identified mutations include K601E and L597Q.
3. Class III:
   • RAS-dependent, BRAF kinase activity is low or impaired, requires upstream activation of MAPK pathway and often coexists with RAS mutations or NF1 loss.
   • Most common: D594X (10% of all BRAF mutations)
   • Other identified mutations include G466X.
4. Additional missense, deletions and mutations of unknown function have also been identified

Table 3. Current BRAF Fusion Partners Identified in NSCLC

 

FDA-Approved Targeted Therapy:

1. Dabrafenib plus trametinib (Novartis):

• This BRAF + MEK combination therapy was granted full approval by the FDA in 2017 and is the only approved treatment for patients with metastatic NSCLC with BRAF V600E mutation. The approval was based on the BRF113928 multicenter study of patients with locally confirmed BRAF V600E mutation-positive NSCLC. At time of approval, an ORR of 63% and duration of response of 12.6 months were found in patients who received prior lines of chemotherapy. For treatment-naive patients, an ORR of 61% was found, with 59% of responders having response of greater than 6 months. 
• Most Common Adverse Events: fever, fatigue, nausea, vomiting, diarrhea, dry skin, decreased appetite, swelling, rash, chills, bleeding, cough, shortness of breath

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