Results: Patient with lung cancer (non-small cell) and a somatic (tumour) BRAF variant

A 68-year-old female smoker is diagnosed with metastatic lung cancer (non-small cell). Somatic (tumour) testing on tumour-derived DNA via a multi-target massively parallel sequencing (sometimes called next-generation sequencing) panel reveals a variant in BRAF: c.1799T>G (p.Val600Gly), (V600E).

The BRAF gene

• Activating variants in the BRAF tyrosine kinase gene occur in around 1%–3% of lung cancer (non-small cell) cases, with a preponderance for adenocarcinoma.
• Variants are grouped into three classes, contingent upon their effect on kinase activity:
  • class-one variants result in autonomous kinase activity (monomers) (RAS independent) (for example, V600E);
  • class-two variants form kinase-activating homodimers (RAS independent) (for example, L597Q) ; and
  • class-three variants form kinase-inactivating heterodimers with CRAF (RAS dependent) (for example, D594A).
• The majority (50%–60%) of variants occur at the V600 position. The vast majority of those are V600E (a class-one variant).
• Non-V600 variants are functionally heterogenous. Examples of recurrent BRAF variants in lung cancer (non-small cell) include G469A (increased kinase activity) and D594G (impaired kinase activity) variants.

Clinical characteristics

• Patients with BRAF variants appear to have similar clinicopathological features to wild-type NSCLCs, including PD-L1 expression, although there may be more frequent pleural metastases.
• Most patients with non-V600 variants are smokers. The percentage of smokers is lower in the V600E cohort.
• A number of studies have reported a lack of chemo-sensitivity and worse prognosis in patients with a BRAF V600E variant treated with platinum chemotherapy.

BRAF V600E variants: targeted therapies

• BRAF V600E variants render tumours sensitive to combined inhibition of BRAF and MEK.
• The combination of dabrafenib and trametinib is approved by NICE as a first-line treatment option for BRAF V600E-positive metastatic lung cancer (non-small cell).
• Targeted treatment of patients with metastatic BRAF-V600–mutated NSCLC using BRAF/MEK-inhibitors is effective but limited by acquired resistance, similarly to other oncogene-addicted NSCLCs. For dabrafenib and trametinib, response rates of 64% and median progression free survival of 10.2 months have been seen in an upfront cohort of a phase 2 trial. Five-year OS has been reported to be 19% (pre-treated) and 22% (upfront) cohorts of this trial.

Non-V600 variants: targeted therapies

• This is a heterogenous group.
• Differing effects on the kinase activity of BRAF means that these patients do not benefit from BRAF and MEK inhibition. They were not included in many trials investigating BRAF and MEK inhibitors.
• These patients may be eligible for clinical trials.

BRAF variants and immunotherapy

• Patients with BRAF-mutant NSCLC may derive long-lasting benefit from immune checkpoint inhibition with programmed death-1/programmed death-ligand 1 (PD-L1) antibodies, however this is mainly extrapolated from unselected studies. Response rate and median progression-free survival are numerically lower (ORR 24%. mPFS 3.1months) than BRAF/MEK targeted therapies, and immunotherapy-chemotherapy combination approaches are preferred. Immunotherapy plus chemotherapy versus targeted therapy approaches have not been directly compared.

BRAF variants and constitutional genomic testing

• The identification of a somatic BRAF variant does not have any implications for constitutional (germline) genomic testing.

For clinicians

• European Society for Medical Oncology: Metastatic non-small cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up (PDF, 71 pages)
• NHS England: National Genomic Test Directory
• NICE: Dabrafenib plus trametinib for treating BRAF V600 mutation-positive advanced non-small cell lung cancer
• NICE: Guidance relevant to lung cancer

References:

• Noeparast A, Teugels E, Giron P and others. ‘Non-V600 BRAF mutations recurrently found in lung cancer predict sensitivity to the combination of trametinib and dabrafenib‘. Oncotarget 2016: volume 8, issue 36, pages 60,094–60,108. DOI: 10.18632/oncotarget.11635
• Planchard D, Smit EF, Groen HJM and others. ‘Dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic non-small-cell lung cancer: An open-label, phase 2 trial‘. The Lancet Oncology 2017: volume 18, pages 1,307–1,316. DOI: 10.1016/S1470-2045(17)30679-4
• Mazieres J, Drilon A, Lusque A and others. ‘Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry‘. Annals of Oncology 2019: volume 30, issue 8, pages 1321–1328. DOI: 10.1093/annonc/mdz167

For patients

• Macmillan Cancer Support: Lung cancer information and support
• Macmillan Cancer Support: Targeted therapies for lung cancer