Approximately 2.1% of men and women in the United State will be diagnosed with melanoma in their lifetime, with about 4% of cases metastatic at diagnosis.1 Approximately 40%-60% of metastatic melanomas have a BRAF mutation2, and this, along with checkpoint inhibitor therapy, have dramatically changed the survival rates of metastatic melanoma.
Choice of therapy depends on multiple clinical factors, not only including mutation status, but also comorbidities, performance status, prior therapies and patient preference. This article will focus primary on BRAF mutations; however, it is important to note that a small percentage of cutaneous melanomas have also shown alterations in NRAS, TRK and KIT genes as well.2 Studies are underway looking into alterations in these pathways.
Assessment of the BRAF Mutation and the MAPK Pathway
Inhibition of the mitogen-activated protein kinase (MAPK) has changed the landscape of treatment for cutaneous melanoma. The MAPK pathway contains three sequentially activated protein kinases that, when activated, are key components to cell proliferation, differentiation and cell death.3 [See Figure 1.]
An understanding of this pathway led to the development of BRAF and MEK inhibitor combination therapy. The two most common mutations are BRAF V600E (80%-90% of BRAF mutations) and V600K (15%).4 Overall, BRAF V600E mutations have higher response rates to BRAF/MEK inhibition compared to other BRAF V600 mutations.5
It is therefore recommended that all cutaneous melanoma is evaluated for the presence of the BRAF mutation. Mutational analysis is preferred on distant metastatic sites when possible. If this is unable to be obtained, however, it can be performed on the primary site of disease or locoregional lymph nodes.
BRAF V600 mutations are generally evaluated via singe gene polymerase chain reaction (PCR) assays that generally have a faster turnaround time than a full next generation DNA sequencing (NGS) panel, which is recommended if the specimen is BRAF V600 negative.
BRAK/MEK Inhibition in De Novo Metastatic Melanoma
Several clinical factors determine the choice of first-line agents for de novo metastatic disease, most important being the tempo of disease, the patient’s symptoms and related performance status and their medical history of comorbidities, specifically whether they are eligible for checkpoint inhibitor immunotherapy. New data is now emerging showing the benefit of immunotherapy in the first-line setting compared to BRAF/MEK inhibitors.
In the DREAMseq randomized phase III trial, 265 treatment-naïve BRAF mutant melanoma patients were randomized to either nivolumab plus ipilumumab followed by nivolumab maintenance versus dabrafenib plus trametinib targeted therapy. Upon progression, they were offered the alternate regimen.
Preliminary results at a median follow up of 28 months showed a two-year overall survival (OS) benefit of 72% in the immunotherapy followed by targeted therapy arm compared to 52% in the targeted therapy followed by immunotherapy arm. Because of an OS benefit of 20%, the trial was stopped early for benefit.
This trial also suggested that immunotherapy is less effective given after disease progression with targeted therapy. Objective response rates (ORRs) were lower for patients who received immunotherapy following targeted therapy (30%), compared with those who received initial immunotherapy (46%). However, ORR were similar for targeted therapy whether given as initial therapy (43%) or following disease progression on immunotherapy (48%).6 Additional studies are still ongoing, and an NCCN update is in progress.
There are, however, several circumstances when targeted therapy should be considered over immunotherapy. Patients who are ineligible for immunotherapy, such as those with a history of autoimmune disease or those who have medical comorbidies that would make immune-related adverse events difficult to manage, should received BRAF/MEK inhibitor therapy upfront. In addition, in patients with rapidly progressing signs of organ failure, targeted therapy should be considered first. BRAF/MEK combination therapy is recommended over single-agent therapy.
Three combinations are FDA approved and are category 1 recommendations per the NCCN guidelines: dabrafenib plus trametinib, encorafenib plus binimetinib and vemurafenib plus cobimetinib. They have not been directly compared in clinical trials, but all appear to have similar efficacy (ORR in the 70%).
The choice between regimens should be based on side effect profiles, patient comorbidities and sites of metastatic disease. For patients with brain metastases, the preferred combination is dabrafenib plus trametinib as this has been evaluated in patients with brain metastases in clinical trials. Otherwise encorafenib plus binimetinib may be preferred, as this combination has the most favorable toxicity profile and can be taken with or without food and stored at room temperature. In contrast trametinib requires refrigeration. Vemurafenib and cobimetinib likely have the most toxicities compared to the other two combinations.
Here is the data related to approval for each combination and most common toxicities:
Dabrafenib plus Trametinib. In a combined analysis of COMBI-d and COMBI-v, the combination of dabrafenib and trametinib compared to single-agent BRAF inhibition showed a median progression free survival (PFS) estimated to be 11 and 26 months respectively. Factors associated with a favorable outcome included good performance status, normal LDH and less than three organs containing metastatic disease. The most common toxicities included diarrhea, pyrexia and chills. Of note, dabrafenib can trigger hemolysis in G6PD-deficient patients.7
Encorafenib plus Binimetinib. The phase III COLUMBUS trial performed in 577 patients with BRAF V600-mutated melanoma compared combination encorafenib plus binimetinib to single agent vemurafenib. At approximately four years follow-up, median PFS was improved with the combination (15 months versus 7), and OS improved as well (34 months versus 17). The combination had lower rates of pyrexia and photosensitivity compared to vemurafenib. However, the combination was noted to have higher rates of retinopathy.8
Vemurafenib plus Cobimetinib. The coBRIM study was a randomized phase III trial evaluation comparing the combination vemurafenib plus cobimetinib to vemurafenib alone. At median follow-up of 14 months, compared with vemurafenib alone, the combination improved both OS (22 versus 17 months) and PFS (12 versus 7 months). Toxicities with the combination included diarrhea, photosensitivity, elevation in LFTs and pyrexia.9
A Glimpse Into the Future
Combination immunotherapy and BRAF inhibition was recently studied and approved for treatment of BRAF mutated metastatic melanoma. However overall survival data is not mature, therefore the treatment has generally not been recommended in the first-line setting.10 Additional trials investigating pembrolizumab plus lenvantinib are underway, as well as the use of VEGF inhibitors such as bevacizumab and axitinib. Adoptive cell therapy (ACT) is an investigational therapy that has shown some promise in patients with metastatic melanoma who have progressed on immunotherapy and targeted therapies. ACT approaches include tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T-cell therapy, which has shown much promise in other cancer subtypes.
Due to the addition of targeted therapy to the treatment of metastatic melanoma, the overall prognosis for BRAF mutated metastatic melanoma has improved dramatically, with five-year OS rates up to 34% and 60% (previously 10% or less in studies prior to the availability of these therapies).1
As we continue to learn more about the mechanism of growth and tailor therapies to target additional enzymes in the MAPK pathway, it is expected that survival rates will continue to improve.
Dr. Nikita Amin is a board-certified medical oncologist and hematologist at the Piedmont Cancer Institute. She graduated cum laude from the University of Michigan and earned her medical degree at Ohio State University. She completed internal medicine residency and hematology/oncology fellowship at Emory University. Dr. Amin has co-authored publications for national meetings and has written clinical trials in lung cancer and thyroid cancer. She practices general oncology and sees patients both in Atlanta and Newnan.
- National Cancer Institute. Surveillance Epidemiology and End Results. 2008. Available at: http://seer.cancer.gov/statfacts/html/melan.html#ref11. Accessed June 14, 2022
- Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29(10):1239-1246. doi:10.1200/JCO.2010.32.4327
- Morrison DK. MAP kinase pathways. Cold Spring Harb Perspect Biol. 2012;4(11):a011254. Published 2012 Nov 1. doi:10.1101/cshperspect.a011254
- Rubinstein JC, Sznol M, Pavlick AC, et al. Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med. 2010;8:67. Published 2010 Jul 14. doi:10.1186/1479-5876-8-67
- Menzer C, Menzies AM, Carlino MS, et al. Targeted Therapy in Advanced Melanoma With Rare BRAFJ Clin Oncol. 2019;37(33):3142-3151. doi:10.1200/JCO.19.00489
- Atkins MB, Lee SJ, Chmielowski B, Ribas A, Tarhini A, Truong TG, Davard DREAMseq (Doublet, Randomized Evaluation in Advanced Melanoma Sequencing): A phase III trial—ECOG-ACRIN EA6134. J Clin Oncol. 2021;36S
- Robert C, Grob JJ, Stroyakovskiy D, et al. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019;381(7):626-636. doi:10.1056/NEJMoa1904059
- Ascierto PA, Dummer R, Gogas HJ, et al. Update on tolerability and overall survival in COLUMBUS: landmark analysis of a randomised phase 3 trial of encorafenib plus binimetinib vs vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Eur J Cancer. 2020;126:33-44. doi:10.1016/j.ejca.2019.11.016
- Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. doi:10.1016/S1470-2045(16)30122-X
- Gutzmer R, Stroyakovskiy D, Gogas H, et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2020 Aug 15;396(10249):466]. Lancet. 2020;395(10240):1835-1844. doi:10.1016/S0140-6736(20)30934-X