BRAF Mutations in Lung Cancer

by Matthew Cecchini, MD PhD FRCPC
March 20, 2026

BRAF is a gene that encodes a protein kinase — an enzyme that acts as a relay in a signalling chain called the MAPK pathway, which controls cell growth and division. In normal cells, BRAF passes signals from activated surface receptors (including RAS proteins) downstream to the rest of the cell in a tightly regulated way. When the BRAF gene carries a mutation, this relay switch can become constitutively active, continuously driving cell proliferation without the normal controls. BRAF mutations are found in approximately 2–4% of non-small cell lung cancers. Unlike in melanoma — where a single BRAF mutation (V600E) accounts for the vast majority of cases — lung cancers carry a broader spectrum of BRAF mutations, and not all of them have the same treatment implications. The most important subset, BRAF V600E-mutated lung cancers, can be targeted with a combination of drugs called BRAF and MEK inhibitors, which together achieve high response rates and have transformed outcomes for patients with this specific alteration.

What the test looks for

The BRAF protein sits within the RAS-RAF-MEK-ERK signalling cascade, also called the MAPK pathway. This pathway is one of the cell’s primary mechanisms for translating external growth signals into cell division. BRAF receives an activation signal from an upstream protein (RAS), then activates MEK, which activates ERK, which enters the nucleus and switches on genes involved in cell growth. In BRAF-mutated cancers, BRAF remains active even without upstream RAS signaling, keeping the downstream pathway constitutively activated.

BRAF mutations in lung cancer occur at several different positions in the gene and are divided into functional classes with distinct biological behaviours and therapeutic implications:

BRAF V600E (Class I). A mutation at codon 600 in which valine is replaced by glutamic acid. This is the most common BRAF mutation in lung cancer, accounting for approximately 50% of all BRAF mutations in NSCLC. The V600E change produces a BRAF protein that is highly active as a monomer — independently of RAS — and that drives strong, continuous ERK signalling. This is the only BRAF mutation in lung cancer for which combination targeted therapy is currently approved. BRAF V600E-mutated lung cancers are found more commonly in women, in never-smokers or light smokers, and are almost exclusively adenocarcinomas.
Non-V600 BRAF mutations (Class II and Class III). A range of other BRAF mutations occur at different codons, including G469A (Class II) and D594G (Class III), among others. These mutations activate the MAPK pathway through mechanisms distinct from those of V600E. Some signal as dimers rather than monomers, and some have reduced or absent kinase activity but activate the pathway through alternative means. They do not respond to the same drugs used for V600E and are generally not currently targetable with approved therapies, though clinical trials are investigating new approaches. Non-V600 BRAF mutations in lung cancer are more strongly associated with a history of tobacco smoking than V600E.

Why is the test done

To identify BRAF V600E and determine eligibility for BRAF/MEK inhibitor combination therapy. The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) — a BRAF inhibitor paired with a MEK inhibitor — is approved for BRAF V600E-mutated advanced NSCLC. Response rates in clinical trials exceeded 60% and demonstrated meaningful durability. Identifying the specific mutation is the only way to determine who qualifies for this treatment.
To distinguish actionable from non-actionable BRAF mutations. Because BRAF V600E and non-V600E mutations have completely different therapeutic implications, knowing the specific mutation — not just that BRAF is mutated — is essential. A report stating only “BRAF mutation detected” without specifying the variant is insufficient for treatment planning.
To characterise the full molecular landscape of the tumour. Comprehensive molecular profiling identifies all actionable alterations simultaneously. BRAF testing is part of this broader picture alongside EGFR, ALK, KRAS, ROS1, MET, RET, and others.
To guide immunotherapy decisions. Some BRAF-mutated lung cancers exhibit meaningful PD-L1 expression and may respond to immune checkpoint inhibitors, particularly non-V600 BRAF-mutated tumours for which targeted therapy is not available. PD-L1 testing is performed alongside BRAF testing as part of the standard workup.
To support clinical trial eligibility. Trials investigating BRAF inhibitors for non-V600 mutations, next-generation BRAF inhibitors, and combination strategies are ongoing. Knowing the specific BRAF mutation opens potential clinical trial options.

Who should be tested

Current guidelines recommend BRAF mutation testing for:

All patients with advanced or metastatic non-small cell lung cancer undergo comprehensive molecular profiling at diagnosis.
Patients with lung adenocarcinoma, specifically, where BRAF mutations are most commonly found, though guidelines generally support testing all NSCLC subtypes as part of a comprehensive panel.

In practice, BRAF testing is performed simultaneously with all other major lung cancer biomarker tests as part of a comprehensive NGS panel at the time of diagnosis and is not ordered in isolation.

How the test is performed

BRAF mutation testing in lung cancer uses the same molecular platforms employed for other lung cancer driver genes.

Next-generation sequencing (NGS)

Comprehensive next-generation sequencing (NGS) on tumour tissue is the preferred approach. DNA-based NGS panels sequence the relevant exons of BRAF — particularly exon 15, which contains the V600 codon — and report all detected variants with their specific amino acid changes. NGS is preferred over single-gene assays because it simultaneously characterises all other relevant lung cancer genes, identifies co-mutations that may influence treatment decisions, and avoids the need for sequential testing. The specific variant must be reported (e.g., V600E, G469A, D594G) rather than simply noting that a BRAF mutation is present.

PCR-based assays

PCR-based assays can detect specific BRAF mutations — particularly V600E — with high sensitivity and are used at some centres where NGS is not available or when a rapid result is needed. However, they typically assess only a limited number of mutations and may miss non-V600 variants. NGS is generally preferred when tissue is available.

Liquid biopsy

Cell-free circulating tumour DNA testing can detect BRAF V600E and other BRAF point mutations in blood. BRAF V600E is well-suited to liquid biopsy detection as a single-nucleotide variant. Liquid biopsy is particularly useful when tissue is unavailable or insufficient for NGS, or for monitoring disease during treatment. A negative liquid biopsy does not exclude a BRAF mutation, and tissue testing should follow when the clinical question is important and tissue is accessible.

How results are reported

BRAF results are reported using standard protein nomenclature specifying the exact amino acid change — for example, “BRAF p.V600E (c.1799T>A) detected” or “BRAF p.G469A detected.” A result confirming no mutation is reported as “BRAF wild-type” or “No pathogenic BRAF variant detected.”

Comprehensive NGS reports will also note the variant allele frequency (VAF) — the proportion of DNA copies carrying the mutation — and will list any co-mutations in other genes, which may be clinically relevant for treatment planning.

Some reports will indicate the functional class of the mutation (Class I, II, or III) or whether the mutation is predicted to be a BRAF inhibitor-sensitising variant. If this information is not included, your oncologist or a molecular tumour board can interpret the specific variant in the context of available evidence.

What each result means

BRAF V600E detected. The most actionable BRAF result in lung cancer. The cancer carries the V600E mutation, which produces a constitutively hyperactive BRAF protein that drives continuous MAPK signalling independently of upstream RAS. The combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) is approved for BRAF V600E-mutated advanced NSCLC. Dabrafenib directly inhibits mutant BRAF, while trametinib inhibits MEK — the next protein downstream — providing dual blockade of the pathway. Combining both drugs is more effective than either alone and reduces the risk of a specific resistance mechanism (paradoxical MAPK pathway reactivation) that can occur with single-agent BRAF inhibition. In the pivotal clinical trial, the response rate exceeded 60% and progression-free survival was approximately 10 months in previously treated patients, with more durable responses in some individuals. The combination is available as two oral drugs taken daily. Your oncologist will discuss whether to use this combination as first-line treatment or whether immunotherapy (with or without chemotherapy) is more appropriate given your overall clinical situation and PD-L1 expression.
Non-V600E BRAF mutation detected (Class II or Class III). A BRAF mutation is present, but it is not the V600E variant for which targeted combination therapy is approved. These mutations activate the MAPK pathway through less responsive mechanisms — and in some cases not responsive — to the dabrafenib/trametinib combination used for V600E. No approved targeted therapy currently exists specifically for non-V600E BRAF mutations in lung cancer. Treatment will be guided by PD-L1 expression and may include immunotherapy with or without chemotherapy. Clinical trial participation is worth discussing with your oncologist, as several trials are investigating approaches targeting non-V600E BRAF alterations. The specific mutation identified will be noted in the report and may be relevant to future trial eligibility.
No BRAF mutation detected (wild-type). No BRAF mutation was found in the regions tested. BRAF-targeted therapy is not indicated. The full molecular profile will guide treatment, including review of other driver mutations and PD-L1 expression.

BRAF V600E lung cancer and immunotherapy

Immunotherapy with checkpoint inhibitors has revolutionised lung cancer treatment, and the question of whether to use immunotherapy, BRAF/MEK targeted therapy, or both comes up for patients with BRAF V600E-mutated NSCLC. The two treatment approaches are not routinely combined because the concurrent use of BRAF/MEK inhibitors with checkpoint inhibitors carries an increased risk of serious toxicity, particularly liver inflammation. The standard approach is generally to use one strategy at a time, with the sequence determined by individual patient factors including PD-L1 expression level, performance status, tumour burden, and urgency of response.

For patients with high PD-L1 expression, some oncologists may choose immunotherapy first and reserve BRAF/MEK combination therapy for subsequent lines. For patients with rapidly progressive disease or lower PD-L1 expression, starting with dabrafenib plus trametinib may be preferred. This decision should be made in discussion with a thoracic oncology specialist.

BRAF mutations in lung cancer vs. other cancers

Patients with BRAF V600E-mutated lung cancer may encounter information about BRAF-targeted therapy in the context of melanoma or thyroid cancer, where BRAF V600E is also common and where BRAF inhibitors are used. The same drugs — dabrafenib and trametinib — are approved across these cancer types, which can be reassuring. However, there are important differences in how BRAF V600E behaves across cancer types, and the treatment approach is not identical across cancer types. Patients should discuss their specific situation — lung cancer with BRAF V600E — rather than assuming that findings from melanoma or thyroid cancer trials apply directly.

BRAF mutations are somatic in the vast majority of lung cancer cases — they arise within the cancer cells and are not inherited. Germline BRAF mutations are associated with rare developmental syndromes (such as cardio-facio-cutaneous syndrome) but are entirely unrelated to the somatic BRAF mutations found in lung cancer. Patients do not need to worry that their BRAF mutation can be passed to their children, and family members do not require BRAF screening on this basis.

What happens next

If BRAF V600E is found: Your oncologist will discuss treatment options, which include the dabrafenib plus trametinib combination and potentially immunotherapy depending on PD-L1 expression and other clinical factors. Both dabrafenib and trametinib are oral medications. Your oncologist will review expected side effects — which include fever, fatigue, skin changes, and others — and the monitoring schedule. Brain imaging may be recommended given the propensity of BRAF V600E lung cancers to spread to the brain in some patients.
If a non-V600E BRAF mutation is found: No approved BRAF-targeted therapy is available for your specific mutation. Treatment will be guided by PD-L1 expression and overall molecular profile. Ask your oncologist whether any clinical trials investigating non-V600 BRAF mutations are available.
If no BRAF mutation is found, the full molecular panel will guide treatment. BRAF-targeted therapy is not indicated.
At progression on dabrafenib plus trametinib: Repeat molecular testing is recommended to identify resistance mechanisms. Options may include a clinical trial, immunotherapy, or chemotherapy, depending on prior treatment history and the molecular findings at progression.

Questions to ask your doctor

Has my tumour been tested for BRAF mutations, and what is the specific mutation — V600E or something else?
If I have BRAF V600E, is the dabrafenib plus trametinib combination recommended for me?
Should I start with BRAF/MEK targeted therapy or immunotherapy, given my PD-L1 expression level?
Can BRAF/MEK inhibitors and immunotherapy be safely combined?
What side effects should I expect from dabrafenib and trametinib, and how are they managed?
If I have a non-V600E BRAF mutation, are there clinical trials I should consider?
If my cancer progresses on BRAF/MEK inhibitor therapy, what are the options?
What other biomarkers have been tested in my tumour, and were any other actionable alterations found?