Expert Highlights Impressive Long-Term Activity With BRAF/MEK Combos in Melanoma

Melissa A. Wilson, MD, PhD

Exciting long-term findings on the BRAF/MEK inhibitor combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) as treatment for patients with metastatic BRAF^V600-mutant melanoma were presented at the 2017 ASCO Annual Meeting, showcasing the impressive 4- and 5-year overall survival (OS) rates for patients.

In the open-label trial, patients with BRAFV600-mutant melanoma were randomized 1:1:1 to receive dabrafenib (150 mg twice daily) alone, with 1 mg daily of trametinib, or with 2 mg daily of trametinib (n = 54 each).

The data showed that OS with dabrafenib/trametinib continued to remain superior to dabrafenib monotherapy, with 4-year and 5-year OS rates of 30% and 28%, respectively. The progression-free survival (PFS) curve for dabrafenib/trametinib also remained stable, with 4-year and 5-year rates both at 13%. At the 5-year landmark, 1 additional patient who received dabrafenib/trametinib went from a partial response to a complete response.

“We know that targeted therapy can have results in 3 days. We physically see patients changing in 3 days after receiving targeted therapy and feeling better a couple days later. We definitely know that using combinations—a BRAF and MEK inhibitor—really provides improved PFS and OS for patients,” said Melissa A. Wilson, MD, PhD.

OncLive^®: You lectured on targeted therapies in melanoma. Can you provide some highlights?

At the 2017 ASCO Annual Meeting, we saw the 5-year follow-up data of dabrafenib/trametinib and the potential it has in patients with brain metastases. Can you comment?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Melanoma and Immuno-Oncology, Wilson, an assistant professor of medicine at Perlmutter Cancer Center at NYU Langone Medical Center, discussed the promising results with BRAF/MEK inhibitor combinations and what ongoing studies have the potential to alter the landscape again.Wilson: I talked about targeted therapy in melanoma and the origin of targeted therapy, particularly talking about BRAF-mutant melanoma and BRAF targets, and the success that we have had with these targeted therapies. It has really changed the landscape since 2011 when ipilimumab (Yervoy) and vemurafenib (Zelboraf) were FDA approved, and since then we have identified combination therapy—so BRAF plus MEK inhibitors—and we have seen a number of successes with this combination, including increased PFS, as well as OS, and so we have updated data that demonstrates that there are patients who have longer-term responses, so increased OS at 2 and 3 years, as well. The 5-year OS data really points to the fact that patients are staying on these treatments a lot longer than we initially anticipated. The thought was that the median PFS was 11.4 months in the trial, so to have 5-year data is really important to demonstrate that there are patients who are still on these targeted therapies. Our concern was that patients are going to develop resistance, so it is showing that a select population still has continued benefit using these.

How do you decide which BRAF/MEK combination to use in BRAF-mutant patients?

In the incidence of brain metastases, it is an unmet need still in the field of melanoma. We are doing a great job at controlling systemic disease, but we are seeing a number of patients actually recur with brain metastases. Some of the data show that we are able to use targeted therapy to treat brain metastases. That is actually really promising as well—something to offer patients. It is really the side effect profile. While all of the BRAF/MEK inhibitors have very similar general side effect profiles, some of them have little differences and nuances. Dabrafenib/trametinib is associated with pyrexia and the fevers that go along with it. Those are the unique characteristics of that combination.

Whereas, vemurafenib combined with cobimetinib (Cotellic) has photosensitivity associated with it. You could choose 1 regimen over the other depending on patients’ lifestyle and depending on whether patients are outside often or not.

Is adding immunotherapy part of the next steps with dabrafenib and trametinib combinations?

What are the differences in biology between BRAF-mutant, BRAF wild-type, BRAF^V600E, and BRAF^V600K melanomas?

The other differences are related to storage and taking the medication. Trametinib, the MEK inhibitor, needs to be refrigerated. Then, dabrafenib/trametinib needs to be taken on an empty stomach, whereas vemurafenib/cobimetinib have no refrigeration requirements nor any separation with food requirements. There are a lot of different things that you balance when deciding which regimen to put them on. We think that is going to be a benefit because, then, you get both medications at the same time. Right now, we are still sequencing them; we either give immunotherapy upfront and then targeted therapy second, or it’s flipped. In certain cases, you will give targeted therapy upfront followed by immunotherapy at the time of recurrence. Now, we are hoping to see some benefits by actually putting the 2 together to see if we can get more sustained responses. BRAF-mutant just means that patients have a mutation in the BRAF gene. Wild-type means that they don’t have a mutation; it is just the wild-type gene that functions normally. BRAF mutations can occur in a number of places. The most common mutation is in exon 15, and we call it being a “hot spot” mutation—where you analyze a large number of genes and most of the genes fall with mutations at that site. It is protein code 600, so that’s where the V600 [comes in]. “V” is the original protein that is there; it is valine at position 600 in the protein sequence.

What other interesting trials besides immunotherapy combined with targeted therapies are being conducted?

What happens is a number of mutations can happen at that site. Therefore, 3 nucleotides make up a protein signal, so you can get mutations in any 1 of those 3 DNA nucleotides that then codes for a protein. Depending on where the mutation occurs depends on what protein gets substituted. In the wild-type tumors, where there is no mutation, it is a valine; V600E means that it is a glutamic acid that gets substituted for that valine. V600K means there are different types of DNA mutations that protrudes a lysine as opposed to a glutamic acid, so that is what V600E versus V600K means. ECOG, our big Cooperative Group, is looking into sequencing immunotherapy versus targeted therapy because, right now, we still don’t have that answer. The way it is set up is to recruit patients with a BRAF mutation. They are randomized to receive immunotherapy upfront followed by targeted therapy at the time of resistance versus targeted therapy upfront with immunotherapy at the time of resistance.

It is a challenging study to accrue to because, with such great data and great responses with immunotherapy upfront, it is a hard trial for patients to say, “Sure, I’m going to try targeted therapy versus immunotherapy upfront.” However, it is still an important question that we really need to answer because we make [these decisions] based on our best judgment on the data that we have. Therefore, we’ll see if we get a readout from that.

The other important studies that we are waiting for data on are adjuvant therapy. We are doing a great job at treating metastatic disease but, obviously, we need to do better because we don’t have a 100% response yet. Thankfully, with some of our new therapies, our survival at 1 year is a lot higher than it ever has been.

What do you hope community oncologists took away from your lecture on targeted therapies?

Prior to 2011, our median OS was 6 months to 9 months depending upon where the site of metastasis was, and now we have an 80% 1-year OS rate. That being said, if we can prevent melanoma from coming back, it would be important and a lot of patients would be happy about treatments for that.When trying to determine what treatments are available for patients, there are a number of different options, including immunotherapy and targeted therapy. When choosing targeted therapy, there is certainly a benefit when patients are very symptomatic from their disease and need immediate relief.

Long GV, Eroglu Z, Infante JR, et al. Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600—mutant unresectable or metastatic melanoma (MM). J Clin Oncol. 2017;35 (suppl; abstr 9505).