Sequencing Debate for Frontline BRAF-Mutant Melanoma in Full Force

Geoffrey T. Gibney, MD

Now that BRAF/MEK combination regimens and immunotherapeutic approaches have demonstrated significant benefit in patients with BRAF-mutated melanoma, efforts are being focused on addressing the question of sequencing and determining biomarkers for optimal patient selection, according to Geoffrey T. Gibney, MD.

Research such as the COMBI-d and COMBI-v trials have demonstrated that durable responses can be achieved with BRAF/MEK combinations, and many patients who receive these regimens have proven to be long-term survivors, according to Gibney. Pooled data from the 2 trials indicated that patients who received the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) experienced a 5-year PFS rate of 19% and a 5-year overall survival (OS) rate of 34%.¹

Now, efforts like the EA6134 trial (NCT02224781) are examining whether it is more beneficial to utilize a BRAF/MEK combination or an immunotherapy combination first in a patient who presents with BRAF V600-mutated disease. Specifically, the phase 3 trial will examine initial treatment with ipilimumab (Yervoy) and nivolumab (Opdivo) followed by dabrafenib and trametinib versus initial treatment with dabrafenib/trametinib followed by ipilimumab/nivolumab in patients with unresectable disease.²

“Currently, in patients who have active stage IV disease or unresectable stage III disease, we debate whether patients should start with BRAF-targeted therapy or anti–PD-1–based immunotherapy, if their tumor harbors a BRAF mutation,” said Gibney. “This is 1 [aspect] that we struggle with in academic and community practices.”

The biomarker component of the research is also generating excitement, according to Gibney. In the trial, investigators will examine molecular features in the tumor, both the genetics and the immune phenotype, to understand whether these factors are associated with outcomes.

“Perhaps, it really is not an all-comers type of approach, where all patients should start with 1 therapy versus the other,” noted Gibney. “Ideally, we would have a biomarker strategy that allows us to select patients, so that if we performed did a test prior to the start of treatment, we could meet with the patient and tell them which regimen they are most likely to benefit from, whether it's an anti–PD-1 strategy or a BRAF/MEK inhibitor strategy.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer (IPC) webinar on Melanoma, Gibney, co-leader of the Melanoma Disease Group and a member of the Developmental Therapeutics (Phase I) program at the Lombardi Comprehensive Cancer Center and MedStar Cancer Network, MedStar Georgetown University Hospital, provided an update on the evolution of frontline treatment in metastatic melanoma.

OncLive^®: What are some of the factors to consider when navigating among the many BRAF/MEK combination regimens available for frontline therapy in melanoma?

Gibney: We have 3 regimens that are FDA approved. We have dabrafenib/trametinib, encorafenib (Braftovi)/binimetinib (Mektovi), and we have vemurafenib (Zelboraf)/cobimetinib (Cotellic). The efficacy of the regimens is about the same, at least based on the data that we've seen presented and published. The toxicity profiles have slight differences but overall, it's about the same number of serious grade 3 or 4 adverse effects (AEs), and about the same number of patients who will permanently discontinue these drugs due to toxicity, which is around 15%.

As such, you start looking at the individual safety profiles for the regimens, as well as the way they're dosed; that is where many providers do decide on 1 versus the other. It’s up to the treating provider and patient to make the decision based on that information.

Could you further discuss the what was seen in both the COMBI-d and COMBI-v trials?

What we wanted to see in these studies was the long-term follow-up in the patients being treated with the combination therapy. The key question that we are still debating is: Are the responses that we've seen with dabrafenib/trametinib and encorafenib/binimetinib going to be durable? Or, will all patients eventually progress after having a good or deep response?

What we see from these studies and long-term follow-up is that around 20% of patients are progression free pretty far out from their treatment; by that, I mean that they are in the 4- or 5-year range. Also, some patients come off [treatment] for various reasons, either by choice or because of toxicity, and then don't progress, as well. Some of these patients will still be on treatment and some of them will not. What we've learned from these studies is that durable responses can be achieved with BRAF/MEK combinations [and some of these patients] are long-term survivors.

Multivariate analyses also revealed factors that were associated with improved progression-free survival (PFS) and OS for those trials. Could you expand on those findings and how that information is being applied to practice?

We know that across most subgroup analyses that the combination of a BRAF inhibitor and a MEK inhibitor does improve outcomes. The more impressive results have been seen in patients who have lower disease burden. Those are patients who have a normal baseline lactate dehydrogenase and a low number of tumor sites, usually classified at 3 or less. Then, in some analyses, we've actually added up the sum of diameters for the total disease burden. However, when you look at those patients who have a lower disease burden, the chances of a complete response (CR) are much higher than what we see in these studies, in general. We see the PFS being much higher. In patients who have low disease burden, you might actually see a lot more benefit with BRAF/MEK inhibitor combinations.

Shifting over to the EA6134 trial, could you discuss the objectives of this research and how this will help with sequencing? What did the biomarker data show?

EA6134 is addressing a very important question that we have in the clinic today: If you have a patient with advanced BRAF-mutant melanoma, is it best for that patient to start off with immunotherapy or a BRAF/MEK combination? We still debate this; we don't quite know which is the best route for a patient as first-line therapy. If you look at the current guidelines, patients can start with either strategy. We have seen superior survival in the nivolumab (Opdivo)/ipilimumab studies. The tail of the curve for the survival rates was a bit higher with [the immunotherapy combination] compared with BRAF/MEK inhibitors, which in this case, is dabrafenib/trametinib. However, they have not been compared directly head-to-head.

This study was designed by my colleague Michael B. Atkins, MD, of Georgetown Lombardi Comprehensive Cancer Center, and is currently an active protocol in the ECOG-ACRIN Cooperative Group system. We’re still enrolling patients. We want to accrue a total of 300 patients for the primary end point, which is examining 2-year OS difference. Currently, the statistical design is to detect a 20% difference. With data that we've seen, it may be a negative study; however, it certainly could be positive, especially since there are quite a lot of long-term survivors with nivolumab/ipilimumab.

What’s most interesting to me is the biomarker aspect of this research. We know patients can do quite well with either strategy, some patients would do really well with 1, and others won't do well with either strategy. To this end, our biomarker work is looking at molecular features in the tumor, both the genetics and the immune phenotype, and trying to sort out whether they are associated with outcomes. If that holds true, then this will be the first step to potentially developing prospective studies using a biomarker-driven approach.

Other trials are examining combining the 2 approaches. Are triplet regimens showing promise?

Three different studies—KEYNOTE-022, IMspire150, and COMBI-i—[have examined] a BRAF/MEK inhibitor combined with either an anti–PD-1 or an anti–PD-L1 agent. The PD-1 drugs were pembrolizumab plus dabrafenib/trametinib and the PD-L1 [agent] was atezolizumab (Tecentriq) plus vemurafenib/cobimetinib and then the third one is spartalizumab, which is not technically FDA approved, but we've seen [its use] in clinical trials in combination with dabrafenib/trametinib. Among the 3 studies, what we've seen is a marginal improvement in the objective response rate; this is modest but does look like it's higher when you have the triplet therapy. We've also seen an increase in the toxicity profile, meaning that there's a higher number of grade 3 or 4 AEs, as you would expect. Obviously, with the addition of the anti–PD-1 or PD-L1 drug, we see the immune-related AEs that you wouldn't see with the standard BRAF/MEK inhibitor combinations. However, the triplet regimen does look like it's tolerated well enough to be considered in the clinic, as long as it's monitored very closely.

How much is being gained by adding the immunotherapy agent to the mix?

That is the part that has become more hotly debated. In the KEYNOTE-022 study, it was a modest gain in terms of PFS; we haven't seen long-term OS yet. In the IMspire150 study with vemurafenib/cobimetinib plus atezolizumab, we saw a statistically significant improvement in PFS, and that was the primary end point. We do have an FDA approval for that regimen currently, but we haven't seen an improvement in OS statistically yet, and this is partly because the data are still not mature enough. We'll have to see if there is an improvement in OS; this is yet to be determined.

The third regimen did show some higher numbers in terms of PFS, but it didn't meet its statistical end point. There was a press release, and we've now seen data subsequently published, where it has not met its primary end point. We will eventually see more data and there may be other aspects of the efficacy analyses that look very impressive. It's still to be determined whether these regimens will improve the long-term outcomes for patients and their survival.

Currently, we now have another regimen, the triplet therapy of vemurafenib/cobimetinib plus atezolizumab, that will start being fitted into our discussions for frontline therapy. This is currently a hotly-debated topic. We are still waiting for some of the data to come out of EA6134 in terms of sequencing and other studies are overlapping with that type of approach. Currently, we don’t have a standard approach in patients with BRAF-mutant melanoma.

What remaining questions with anti–PD-1 therapy? What is known with regard to treatment discontinuation?

This is a very important topic. When we first started developing anti–PD-1 drugs, this was not something that we really considered. We wanted to ensure that these drugs worked in patients, that they were safely administered, and that we could manage the toxicities. What we didn't define well was the duration of therapy. Many of the studies that led to the FDA approvals of nivolumab (Opdivo), pembrolizumab (Keytruda), as well as other agents, did not have a hard stop in patients who were tolerating the drug well and responding. This really has left the following question open to debate: How much drug does an individual need in this scenario?

In 2 studies with pembrolizumab, there was a hard stop, or at least a stop that was offered, in KEYNOTE-006; it was 2 years of treatment. In the KEYNOTE-001 study, patients [who achieved] a CR could stop treatment after 2 subsequent scans showing CR. However, this didn't really fine tune the total duration of treatment. It's not really well-defined, so some providers still would consider going beyond that, but what we think is that 2 years is certainly enough in many cases; it is probably more than enough, and we can potentially stop early. This has some very significant cost implications. If you could offer a patient 1 year versus 2 years of therapy, that's a huge cost savings. Late AEs can occur during a second year of treatment that might not be needed. We also need to be mindful of the burden on the patient and the healthcare system of coming in for the frequent treatments; in a year, that may not be necessary.

We have moved forward with a Cooperative Group study called EA6192 or the PET-Stop trial, which I'm the study chair of. This is based on data that we have presented from Georgetown University where after 1 year of treatment in patients who are tolerating therapy with a clinical response or disease control, if you do a PET scan to look for active disease or biopsy, if patients show no active disease, it may be safe to discontinue therapy at that time. We saw a very low progression rate off-treatment in that scenario and, hopefully, this will save patients both the financial burden and potential late toxicities. This is now the framework for a prospective Cooperative Group study.

References

1. Robert C, Grab JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N Engl J Med. 2019;381:626-636. doi:10.1056/NEJMoa1904059
2. Dabrafenib and trametinib followed by ipilimumab and nivolumab or ipilimumab and nivolumab followed by dabrafenib and trametinib in treating patients with stage III-IV BRAF V600 melanoma. ClinicalTrials.gov. Updated October 8, 2020. Accessed October 8, 2020. https://clinicaltrials.gov/ct2/show/NCT02224781.