The Bottom Line

About 40–50% of melanomas carry a specific gene mutation called BRAF V600E. If your melanoma has this mutation, you may be a candidate for targeted therapy — daily pills that block the faulty signal driving your cancer's growth. Combining a BRAF inhibitor with a MEK inhibitor shrinks tumors in 60–75% of patients, with an average benefit lasting about 10–12 months. These drugs work fast — within weeks — but the cancer often finds a way around them over time. Immunotherapy drugs tend to produce more durable (longer-lasting) responses, so the two approaches are often used in sequence.

What Is Targeted Therapy for Melanoma?

Targeted therapy uses drugs designed to attack a specific molecular change in cancer cells — rather than attacking all fast-growing cells the way chemotherapy does. In melanoma, the most common targetable change is a mutation in a gene called BRAF.

BRAF is a gene that normally helps cells grow and divide in a controlled way. In about 40–50% of melanomas, a specific BRAF mutation — called V600E — locks this gene in the "on" position permanently, causing cancer cells to multiply without stopping. BRAF inhibitor drugs turn this switch back off.

Do You Need BRAF Testing?

Yes. BRAF mutation testing is standard of care for all stage IIIC and stage IV (advanced) melanomas. It is a simple molecular test done on a sample of your tumor tissue. The result — BRAF mutant or BRAF wild-type — determines whether targeted therapy is an option for you.

About 40–50% of patients with advanced melanoma test positive for BRAF V600E or the related V600K mutation. If your test is negative, BRAF inhibitors will not help — your oncologist will focus on immunotherapy or other approaches.

How Do BRAF and MEK Inhibitors Work Together?

Early BRAF inhibitors (used alone) worked well initially — shrinking tumors in 40–50% of patients — but the cancer often developed resistance quickly (median time to progression: 5–8 months). The reason: blocking BRAF alone causes the cancer to activate alternative bypass signals through a protein called MEK.

Adding a MEK inhibitor blocks this bypass route. Combination BRAF + MEK inhibitor therapy achieves:

  • Response rates of 60–75% (partial or complete tumor shrinkage)
  • Complete response (no detectable tumor) in 10–15% of patients
  • Median progression-free survival of 10–12 months (vs. 5–8 months with BRAF alone)
  • Median overall survival of 26–27 months (vs. 9–10 months with older chemotherapy)

Which Drugs Are Available?

Three FDA-approved combinations are currently used:

  • Dabrafenib (Tafinlar) + trametinib (Mekinist) — the most widely studied combination
  • Vemurafenib (Zelboraf) + cobimetinib (Cotellic)
  • Encorafenib (Braftovi) + binimetinib (Mektovi) — the newest combination, with some evidence of improved tolerability

All three combinations are taken as oral pills, typically twice daily. You do not need to visit an infusion center.

What Side Effects Should You Expect?

Targeted therapy side effects are generally more predictable than chemotherapy and often improve over time:

  • Fatigue (30–40%): Common early in treatment, often improves after the first few weeks.
  • Fever (30–40% with dabrafenib combinations): Can be significant; usually managed with dose breaks and anti-inflammatory drugs. Less common with vemurafenib/cobimetinib.
  • Skin rash and photosensitivity: Your skin becomes much more sensitive to sunlight. Strict sunscreen use and protective clothing are essential.
  • Joint and muscle aches (20–30%): Usually mild and manageable with over-the-counter pain relievers.
  • New skin cancers (squamous cell carcinoma): BRAF inhibitors alone cause new SCCs of the skin in 20–30% of patients. Combination BRAF + MEK therapy reduces this risk substantially to 5–10%. These are usually low-grade, easily treated skin cancers — not the same as the original melanoma.
  • Heart changes (5–10%): Reduced heart pumping efficiency (reduced ejection fraction) can occur. Your doctor will monitor your heart with periodic echocardiograms or EKGs.
  • Eye inflammation (uveitis, 1–2%): Rare but requires ophthalmology referral if it occurs.

How Long Does Targeted Therapy Work?

Targeted therapy works quickly — many patients see meaningful tumor shrinkage within weeks — but it rarely provides permanent control. The cancer nearly always develops resistance within months to years. At that point (median around 10–12 months), your oncologist will transition you to another treatment, most commonly immunotherapy.

A small subset of patients — roughly 15–20% — remain in remission beyond three years on combination targeted therapy. It is not yet possible to predict reliably who will be a long-term responder.

How Does Targeted Therapy Compare to Immunotherapy?

This is one of the most common questions oncologists face for BRAF-mutant melanoma. Here is a simplified comparison:

  • Targeted therapy advantages: Works faster (response often visible within 2–4 weeks), higher initial response rate (60–75% vs. 35–45% for immunotherapy monotherapy), oral pills rather than infusions, predictable side effect profile
  • Immunotherapy advantages: More durable responses — 20–30% of patients achieve long-lasting remission or functional cure; applicable to both BRAF-mutant and wild-type tumors; when it works, it often keeps working for years

For many patients, the current approach is sequential: start with targeted therapy for its rapid effect, then switch to immunotherapy when resistance develops. Some clinical trials are exploring upfront combinations of both approaches, though they carry greater toxicity.

Targeted Therapy After Surgery: Adjuvant Treatment

For patients with stage III melanoma (cancer that reached lymph nodes) who have had surgery to remove all visible disease, adjuvant BRAF/MEK inhibitor therapy reduces recurrence risk. Clinical trials show that one year of adjuvant dabrafenib + trametinib improves recurrence-free survival by 10–15 months and reduces the risk of dying from melanoma in the years following surgery.

When to See a Dermatologist or Oncologist

  • You have been diagnosed with advanced (stage III or IV) melanoma and have not yet had BRAF testing
  • Your melanoma has returned after prior treatment
  • You are experiencing side effects from current targeted therapy
  • Your tumor is growing despite being on BRAF/MEK inhibitor therapy (possible resistance)
  • You want a second opinion on your treatment plan

Frequently Asked Questions

What if my melanoma is BRAF wild-type (no mutation)?

BRAF inhibitors will not work for you. However, this does not mean you have fewer options — immunotherapy (checkpoint inhibitors like pembrolizumab or nivolumab) is very effective for BRAF wild-type melanoma and is often the first-line treatment. Your oncologist will guide you toward the right approach.

Can I take these pills with food?

This varies by drug. Dabrafenib should generally be taken on an empty stomach. Trametinib can be taken with or without food. Encorafenib and binimetinib are also taken with or without food. Always follow the specific instructions from your pharmacy and medical team.

What happens at the point of resistance?

When targeted therapy stops working, your oncologist will reassess with new imaging and possibly re-biopsy to understand the resistance mechanism. The most common next step is checkpoint immunotherapy (anti-PD-1 drugs). Clinical trials are another option, and your oncologist can help identify trials testing new combinations.

Will targeted therapy affect my ability to have children?

BRAF and MEK inhibitors can cause fetal harm and should not be used during pregnancy. Both men and women should use reliable contraception during treatment. If you are considering having children, discuss this with your oncologist before starting therapy.

References

  1. Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014;371(20):1877-1888.
  2. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival with dabrafenib and trametinib in melanoma. J Clin Oncol. 2015;33(25):2771-2778.
  3. Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.
  4. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
  5. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107-114.

Trusted Resources

Always consult a board-certified dermatologist or medical oncologist about your individual melanoma diagnosis and treatment options. This article is for educational purposes and does not replace professional medical advice.