BRAF V600 melanoma: targeted or immunotherapy first

A 61-year-old lawyer comes to the emergency department with pain on the right side of her abdomen and fatigue that has worsened over three weeks. She had a melanoma on her arm removed four years earlier. The CT scan shows several lesions in the liver and two in the lungs. The liver biopsy confirms metastatic melanoma, and molecular testing of the tumor finds the BRAF V600E mutation. Lactate dehydrogenase is four times the upper limit. The brain MRI shows no metastases. The team must decide where to start: targeted therapy or immunotherapy. The scene is fictional and was written for teaching.

This text uses the case as a clinical reasoning scenario for students and health professionals. The topic is the combination of encorafenib with binimetinib in advanced BRAF V600-mutant melanoma, based on the COLUMBUS study, and the question Dr. Alexei proposed for the series: how to choose and sequence targeted therapy and immunotherapy considering symptoms, speed of progression and the need for a rapid response? The text does not replace your country's guideline or your service's protocol. If you play the case of the day on NEXO, you will recognize the challenge: the same disease can call for different answers depending on the pace at which it advances.

Key points

• COLUMBUS compared encorafenib with binimetinib against vemurafenib or encorafenib alone in 577 patients with advanced BRAF V600 melanoma.
• At 5 years, the combination had more patients alive and without progression than vemurafenib.
• The label dose is encorafenib 450 mg once a day with binimetinib 45 mg twice a day.
• DREAMseq showed that starting with combination immunotherapy led to more patients alive at 2 years than starting with targeted therapy.
• Targeted therapy remains important when the disease is symptomatic, fast or bulky and the response needs to come soon.
• The COLUMBUS data are from advanced disease and should not be extended to adjuvant treatment.

Why this is a reasoning scenario

Metastatic melanoma with a BRAF mutation has two families of effective treatment, and the two work in very different ways. Targeted therapy blocks the signaling pathway that the mutation keeps switched on, and the response usually appears within a few weeks. Immunotherapy releases the immune system against the tumor, takes longer to act, but can produce responses that last for years. The choice of first line, therefore, is not just a choice of drug. It is a choice about time.

Dr. Alexei's question goes straight to this point. Symptoms, speed of progression and the need for a rapid response are precisely the variables that change the order. A patient with few lesions and no symptoms can wait for immunotherapy to act. A patient like the one in the scene, with a liver full of lesions and high lactate dehydrogenase, perhaps cannot. Clinical reasoning here consists of reading the pace of the disease, beyond the test result.

The series has already covered team organization in melanoma in the post about dermatology, surgery and oncology in melanoma. This post stays with advanced disease and the order of treatments.

A common anchoring error

When the report says BRAF V600E, the temptation is to conclude that targeted therapy is the answer. The molecular result seems to decide on its own. But the mutation says that targeted therapy will work, not that it should come first. The post about heuristics in clinical reasoning describes how a strong clue can close the investigation too early.

BRAF V600: the molecular clue

The BRAF V600 mutation appears in a significant share of cutaneous melanomas and keeps the MAPK pathway active, which stimulates cell proliferation. Blocking BRAF alone produces rapid responses, but resistance emerges early, partly because the pathway is reactivated downstream. That is why combining a BRAF inhibitor with a MEK inhibitor became the standard of targeted therapy. Encorafenib with binimetinib is one of three available combinations, alongside dabrafenib with trametinib and vemurafenib with cobimetinib (Heinzerling and colleagues, 2019).

The test must be available before the first-line decision. The ESMO guideline lists the combination of BRAF and MEK inhibitors as a first-line option for patients with a BRAF mutation, with the highest level of evidence (Amaral et al., 2025). Without the result, one of the options does not even enter the conversation.

What COLUMBUS tested

COLUMBUS was an open-label phase III study in patients with unresectable or metastatic advanced melanoma with a BRAF V600 mutation. In the first part, 577 patients were randomized: 192 to encorafenib plus binimetinib, 191 to vemurafenib and 194 to encorafenib alone (Dummer et al., 2022). The main comparator was vemurafenib, which at the time was a standard BRAF inhibitor monotherapy.

This design matters for interpretation. COLUMBUS showed that the combination beats BRAF inhibitor monotherapy. It did not compare targeted therapy with immunotherapy, and it did not answer which of the two should come first. That question required other studies.

Who was in the study

The patients were treatment-naive or had progressed after first-line immunotherapy, and were enrolled between December 2013 and April 2015 (Dummer et al., 2022). At the time, combination immunotherapy was not yet the first-line standard. This means the COLUMBUS population differs from the patient who comes to the clinic today, often already treated with anti-PD-1 in the adjuvant setting.

What COLUMBUS showed at 5 years

In the 5-year update, progression-free survival was 23 in 100 patients with the combination, versus 10 in 100 with vemurafenib. Overall survival was 35 in 100 with the combination and 21 in 100 with vemurafenib (Dummer et al., 2022). In patients with normal lactate dehydrogenase, the numbers were better: 31 and 45 in 100 with the combination (Dummer et al., 2022).

The median duration of response was 18.6 months with the combination and 12.3 months with vemurafenib, and disease control was achieved in about 92 in 100 patients with the combination (Dummer et al., 2022). The control rate shows the strength of targeted therapy: almost everyone responds or stabilizes. The duration shows the limit: most end up progressing.

How to read these numbers

• The combination is better than BRAF inhibitor monotherapy, in progression and in survival.
• Lactate dehydrogenase is a strong prognostic marker, and results are worse when it is high.
• A smaller group of patients stays alive and progression-free for many years with targeted therapy.
• The data do not say how the combination compares with first-line immunotherapy.

Study	Comparison	Main finding	What it does not answer
COLUMBUS	Encorafenib plus binimetinib versus vemurafenib	More survival at 5 years with the combination	Whether targeted therapy should come before immunotherapy
DREAMseq	Starting with nivolumab plus ipilimumab or with dabrafenib plus trametinib	More patients alive at 2 years starting with immunotherapy	Patients with untreated brain metastases
SECOMBIT	Three sequences, including short induction with targeted therapy	Higher 5-year survival in the short-induction arm, without a formal comparison	Which sequence is superior, because it is non-comparative
EBIN	Immunotherapy straight away or 3-month induction with targeted therapy	No overall gain, possible gain with very high lactate dehydrogenase	Confirmation of the subgroup

The sequencing question: DREAMseq and SECOMBIT

DREAMseq randomized 265 patients with advanced BRAF V600 melanoma, with no prior treatment, to start with nivolumab plus ipilimumab or with dabrafenib plus trametinib, switching on progression (Atkins et al., 2023). Overall survival at 2 years was about 72 in 100 patients who started with immunotherapy, versus about 52 in 100 who started with targeted therapy (Atkins et al., 2023). The study was stopped early by the monitoring committee because a clinically significant outcome was reached.

Two details of DREAMseq change the interpretation. The response rate was similar between the initial arms, about 46 and 43 in every 100, but median response duration was not reached with immunotherapy and was 12.7 months with targeted therapy (Atkins et al., 2023). In addition, only about half of the patients with progression went on to switch treatment. In real life, those who progress quickly do not always manage to get second-line therapy.

SECOMBIT and short induction

SECOMBIT, a non-comparative phase II study, tested three sequences with encorafenib and binimetinib and with ipilimumab and nivolumab. One of the arms used 8 weeks of targeted therapy before switching to immunotherapy. The 5-year survival rates were 45, 52 and 57 in every 100 patients across the three arms, the highest in the arm with short induction (Amaral et al., 2025). Because it is non-comparative, the study does not prove superiority, but it supports the idea that targeted therapy can serve as a bridge.

The ESMO guideline summarizes this line of evidence as follows: combined immunotherapy is the preferred first-line choice when it can be given safely in the first months, that is, when the disease is not aggressive or symptomatic enough to require a rapid response (Amaral et al., 2025). Real-world data point in the same direction. In a retrospective series of 567 patients, median survival with first-line targeted therapy was 13.2 months, versus 39.5 months with anti-PD-1, and was not reached with the immunotherapy combination (Moser et al., 2019). These numbers carry selection bias, because more severe patients tend to receive targeted therapy.

When a rapid response matters more

The ESMO guideline considers induction of 8 to 12 weeks with BRAF and MEK inhibitors, followed by ipilimumab and nivolumab, as an option, mainly for patients with high lactate dehydrogenase or liver metastases (Amaral et al., 2025). The basis comes from EBIN, a phase II study with 271 patients that showed no overall gain with induction, but suggested benefit in those with lactate dehydrogenase above twice the upper limit (Amaral et al., 2025). The guideline itself notes that induction with targeted therapy is not approved by the FDA or the EMA.

Signs that favor targeted therapy first

• Significant symptoms caused by the tumor, such as pain, shortness of breath or decline in general condition.
• Rapid progression between two close imaging scans.
• Large disease burden, mainly in the liver.
• Lactate dehydrogenase far above normal.
• Temporary or permanent contraindication to combined immunotherapy.
• Need for a response within weeks, for example before a predictable complication.

Signs that favor immunotherapy first

Low-volume disease, without symptoms and with normal lactate dehydrogenase gives immunotherapy time to act. In this scenario, the chance of a durable response matters more than speed. The patient in the scene is at the other extreme: liver lesions, symptoms and a high marker. For her, the discussion of induction with targeted therapy is reasonable, with a plan already defined to switch to immunotherapy.

Brain metastases

The brain changes the reasoning. An Australian analysis showed intracranial response in 12 of 16 patients with first-line ipilimumab and nivolumab, with median progression-free survival of 41.6 months (Lau et al., 2021). When the combination was used after brain progression with BRAF and MEK inhibitors, intracranial response fell to 1 of 21 patients, and median progression-free survival was 1.3 months (Lau et al., 2021). The order of treatments, in this scenario, can decide whether second-line therapy still works.

Targeted therapy also has brain activity. In the E-BRAIN study, with 48 patients with brain metastases, including symptomatic ones, encorafenib plus binimetinib produced an intracranial response in about 71 out of every 100 patients after 2 months (Márquez-Rodas and colleagues, 2024). In a series of 24 previously treated patients, most of them with BRAF and MEK inhibitors before, the intracranial response was 33 out of every 100 (Holbrook and colleagues, 2020). Responses tend to be shorter than those of immunotherapy.

Indirect comparisons

Before studies such as DREAMseq, comparing the strategies depended on indirect analyses. One of them compared individual data from CheckMate 067 with the trials of targeted therapy combinations, adjusting the populations (Tarhini and colleagues, 2021). This type of analysis helps generate hypotheses, but it does not replace randomization, and it is worth remembering that when reading any chart that places different studies side by side.

Dose, toxicity and monitoring

The encorafenib label states 450 mg orally once a day, as six 75 mg capsules, in combination with binimetinib, until progression or unacceptable toxicity (Braftovi label). The binimetinib label states 45 mg orally twice a day, about 12 hours apart, together with encorafenib (Mektovi label). The encorafenib dose is different in other indications, such as colorectal cancer, and must not be confused.

The binimetinib label lists the precautions that guide monitoring: new cutaneous and noncutaneous neoplasms, cardiomyopathy, venous thromboembolism, ocular toxicity with serous retinopathy and retinal vein occlusion, interstitial lung disease, hepatotoxicity and rhabdomyolysis (Mektovi label). The same label calls for assessment of ejection fraction before starting, after one month and every 2 to 3 months.

Fever and other effects

In COLUMBUS, fever was less common with encorafenib plus binimetinib than with dabrafenib plus trametinib, in a comparison between trials of 21 versus 53 out of every 100 patients, with dose adjustment or interruption for fever in about 6 out of every 100 (Dummer and colleagues, 2022). The review by Heinzerling and colleagues describes the profile of each combination and proposes assessment routines for the most common and most serious events, including ocular, cardiac and cutaneous ones (Heinzerling and colleagues, 2019).

Oral medicine, daily routine

Targeted therapy is taken at home, every day, and that changes who is responsible for care. Encorafenib is taken once a day and binimetinib twice, and the patient needs to know what to do when a dose is missed, when vomiting occurs after taking it and when fever appears. The binimetinib label advises reducing, suspending or stopping treatment according to the severity of the events, with specific tables for each toxicity (Mektovi label). When one of the two medicines is suspended, what to do with the other also needs to be reviewed, and the encorafenib label provides guidance for this adjustment (Braftovi label).

The list of medicines in use also needs review. Encorafenib interacts with strong inhibitors and inducers of liver enzymes, and the label provides dose adjustment when a strong inhibitor cannot be avoided (Braftovi label). Antifungals, some antibiotics and anticonvulsants are part of this count. For the team, this means that the first targeted therapy visit is also a medication reconciliation visit, with the pharmacist when available.

Common reasoning errors

• Concluding that mutated BRAF requires starting with targeted therapy.
• Starting immunotherapy in very symptomatic disease without a plan for rapid response.
• Using the colorectal cancer dose in melanoma, or the other way around.
• Forgetting the echocardiogram and the eye exam before and during treatment.
• Extending the COLUMBUS data to adjuvant treatment.

Adjuvant therapy is another question

Dr. Alexei's warning about not extrapolating to adjuvant treatment is well founded. The targeted therapy with phase III evidence in melanoma adjuvant treatment is dabrafenib with trametinib, in the COMBI-AD study, which showed a gain in relapse-free survival (Amaral et al., 2025). COLUMBUS studied advanced disease, and its result does not automatically transfer to the patient who has undergone surgery with no visible disease.

How NEXO helps train this reasoning

In NEXO, the case of the day is fictional, with a real clinical presentation and up to six progressive clues, and you propose the diagnosis by looking for the ICD-10 code. BRAF melanoma is a good exercise because the molecular clue is strong, but it does not decide on its own. The post on clinical decision-making helps weigh urgency and benefit, and the post on prognostic reasoning shows how markers such as lactate dehydrogenase enter the conversation.

Three exercises with cases

Change the pace. Say what changes if the patient had two small lung lesions, no symptoms and normal lactate dehydrogenase.

Change the organ. Say how you would think if the MRI showed three asymptomatic brain metastases.

Change the heart. Say what you would do if the baseline echocardiogram showed an ejection fraction of 45.

The post on diagnostic uncertainty helps talk about choices with no definitive answer. The limits of use of the game are described on the NEXO Economy page. If you research teaching of clinical reasoning, the page for Researchers explains how to get in touch. Professionals who write or review cases find information under Curator and under Creators, and institutions can learn about the proposal on the partnerships page.

Frequently asked questions

Does encorafenib with binimetinib increase survival?

Yes, compared with vemurafenib. At 5 years, 35 out of every 100 patients were alive with the combination, versus 21 out of every 100 with vemurafenib (Dummer et al., 2022).

What is the dose?

Encorafenib 450 mg once a day and binimetinib 45 mg twice a day, per the US label (Braftovi label). Check the label in your country.

Should I start with targeted therapy if the tumor has BRAF?

Not necessarily. When the disease allows waiting, combined first-line immunotherapy led to more patients alive at 2 years in DREAMseq (Atkins et al., 2023).

When does targeted therapy come first?

When the disease is symptomatic, bulky or progressing fast and the response needs to come within weeks. The European guideline also considers short induction with high lactate dehydrogenase or liver metastases (Amaral et al., 2025).

Is this combination used after surgery?

COLUMBUS studied advanced disease. The targeted therapy with phase III adjuvant evidence is another combination, studied in COMBI-AD.

Final checklist

• I confirmed the BRAF V600 mutation in tissue before first line.
• I assessed symptoms, disease volume and speed of progression.
• I ordered lactate dehydrogenase and a brain MRI.
• I discussed combined immunotherapy and targeted therapy, with the sequence planned.
• I used the dose for the melanoma indication.
• I did an echocardiogram, an eye exam and baseline liver and creatine phosphokinase tests.
• I gave guidance on fever, visual changes and respiratory symptoms.
• I explained that the data apply to advanced disease.

Want to practice reasoning with progressive clues? Play the case of the day.

References

1. Amaral T, Ottaviano M, Arance A, et al. Cutaneous melanoma: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2025. PMID 39550033.
2. Atkins MB, Lee SJ, Chmielowski B, et al. Combination Dabrafenib and Trametinib Versus Combination Nivolumab and Ipilimumab for Patients With Advanced BRAF-Mutant Melanoma: The DREAMseq Trial-ECOG-ACRIN EA6134. J Clin Oncol. 2023. PMID 36166727.
3. Dummer R, Flaherty KT, Robert C, et al. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J Clin Oncol. 2022. PMID 35862871.
4. Heinzerling L, Eigentler TK, Fluck M, et al. Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open. 2019. PMID 31231568.
5. Holbrook K, Lutzky J, Davies MA, et al. Intracranial antitumor activity with encorafenib plus binimetinib in patients with melanoma brain metastases: A case series. Cancer. 2020. PMID 31658370.
6. Lau PKH, Feran B, Smith L, et al. Melanoma brain metastases that progress on BRAF-MEK inhibitors demonstrate resistance to ipilimumab-nivolumab that is associated with the Innate PD-1 Resistance Signature (IPRES). J Immunother Cancer. 2021. PMID 34625515.
7. Moser JC, Chen D, Hu-Lieskovan S, et al. Real-world survival of patients with advanced BRAF V600 mutated melanoma treated with front-line BRAF/MEK inhibitors, anti-PD-1 antibodies, or nivolumab/ipilimumab. Cancer Med. 2019. PMID 31677253.
8. Márquez-Rodas I, Álvarez A, Arance A, et al. Encorafenib and binimetinib followed by radiotherapy for patients with BRAFV600-mutant melanoma and brain metastases (E-BRAIN/GEM1802 phase II study). Neuro Oncol. 2024. PMID 38946469.
9. Pfizer Laboratories. BRAFTOVI (encorafenib) capsules, for oral use. Prescribing information. DailyMed. 2026. DailyMed.
10. Pfizer Laboratories. MEKTOVI (binimetinib) tablets, for oral use. Prescribing information. DailyMed. 2025. DailyMed.
11. Tarhini AA, Toor K, Chan K, et al. A matching-adjusted indirect comparison of combination nivolumab plus ipilimumab with BRAF plus MEK inhibitors for the treatment of BRAF-mutant advanced melanoma☆. ESMO Open. 2021. PMID 33556898.