Dr. Omid Hamid:
Welcome to The ASCO Post Roundtable Series on Updates in Melanoma. I'm Dr. Omid Hamid, Chief of Translational Research and Immunooncology at The Angeles Clinic and Research Institute, and Co-Director of Cutaneous Malignancies at Cedar Sinai Medical Center. Joining me today are two of my colleagues, Dr. Sapna Patel, and Dr. Ryan Sullivan.
Dr. Sapna Patel:
Hi, I'm Dr. Sapna Patel. I'm a medical oncologist, and Associate professor and Director of the Uveal Melanoma Program at MD Anderson Cancer Center in Houston, Texas.
Dr. Ryan Sullivan:
And I'm Ryan Sullivan. I'm also a medical oncologist, and the Associate Director of the Melanoma Program at the Mass General Cancer Center, and Associate Professor at Harvard Medical School.
Dr. Omid Hamid:
Our third installment will focus on first-line therapy for metastatic malignant melanoma.
Melissa is our 32-year-old female who was recently diagnosed with a BRAF V600E mutation–negative melanoma that has metastasized to her liver. She received her staging scans and an MRI of the brain was negative. Her ECOG performance status was 1 and she has no contraindications to targeted therapy or immune checkpoint inhibitors, and her past medical history is benign. At this point, which therapy would be appropriate for her first-line therapy being a BRAF V600E mutation–negative melanoma. We’ll also discuss the options for first-line therapy given the newer developments in BRAF-positive melanoma, and transition into a discussion about the MRI of a patient with brain metastases and how we would make therapeutic decisions moving forward.
To begin, the therapy for metastatic and unresectable melanoma has changed significantly over the last decade. Pre-1998 there were approvals but without randomized trials, and at this point we have multiple single-agent PD-1 approvals, we have combination with anti–PD-1, anti–CTLA-4 and combination with anti–PD-1, anti-LAG therapy. In addition, we have three different combinations of BRAF/MEK targeted agents. What this has done, it has moved the overall survival bar for metastatic melanoma from 6 to 8 months, median overall survival to median overall survivals near and over 6 years. That makes the decision-making in the first line slightly difficult with a couple of caveats to be considered. At this point, I'd like to bring in Dr. Patel to tell us about how she thinks of her primary metastatic melanoma patients.
Dr. Sapna Patel:
Thank you, Dr. Hamid. I think paramount for most medical oncologists treating metastatic melanoma in the first line is to think about which combination immunotherapy they'd like to use. This particular case of a BRAF wild-type patient, those combination immunotherapies are either nivolumab plus relatlimab based on the RELATIVITY-047 study or nivolumab plus ipilimumab based on the CheckMate 067 study. And not to be outdone would be the option of clinical trials in the front-line setting, with the hope that we eventually get a front-line therapy that is such a blockbuster that it becomes hard to put a therapy up against that. So starting with the RELATIVITY-047 study, this is the newest combination immunotherapy approved for the front-line treatment of metastatic melanoma. And this study randomized participants to the combination of nivolumab plus relatlimab, which is an anti–LAG-3 inhibitor and a fixed dose combination.
Importantly, that's nice for patients because that means both drugs are in one bag as opposed to say other combinations where it's sequential infusion. So participants received a fixed-dose combination of nivolumab plus relatlimab, vs nivolumab monotherapy every 4 weeks flat dosing with a primary endpoint of progression-free survival by blinded independent central review. And this study met its primary endpoint with a significant improvement in PFS in the combination arm of approximately 10.2 months estimated vs 4.6 months in the nivolumab monotherapy. And as of yet, the overall survival data is not yet fully mature to show a benefit in the combination, but in this important first step of improving progression-free survival and with the very manageable toxicity profile, it has emerged as the front-line combination immunotherapy to be contended with. Most investigators will be familiar with the CheckMate-067 study, which randomized metastatic melanoma patients in the front-line setting to either combination immunotherapy using what we call the standard dose in melanoma, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, the combination given every 3 weeks for four doses, and then fixed-dose nivolumab for up to 2 years compared to nivolumab monotherapy, truly both of those arms were compared statistically to ipilimumab monotherapy.
And what that study showed was both the combination nivolumab arm and the monotherapy nivolumab arm fared superior in terms of overall survival, objective response rate and even progression-free survival compared to ipilimumab monotherapy. CheckMate-067 has the benefit of having 6.5 to 7 years now of follow up. And so there is a comfort level with investigators and medical oncologists who know the duration of benefit, the treatment-free intervals, the median overall survivals, and the response rates that can be expected with these regimens, specifically nivolumab plus ipilimumab. And as some of that data emerges for RELATIVITY-047, given the less high rate of high-grade adverse events, I suspect we will start to see more of a shift away from nivolumab/ipilimumab towards nivolumab plus relatlimab. If people have already made that shift, it's very understandable based on RELATIVITY-047 and the progression-free survival endpoint, if other people are waiting for more mature overall survival benefit, that's also reasonable and we will be likely to see that in the next few years.
Interestingly, what happens if you have a BRAF mutation and CheckMate 067 has some interesting analysis by BRAF mutation status showing again, the combination of nivolumab plus ipilimumab has a striking benefit over single-agent ipilimumab and as an exploratory analysis of course over single-agent nivolumab. So BRAF-mutated or patients with a BRAF mutation seem to fare the most or the best from combination therapy vs single-agent therapy, but that's not the same thing in the BRAF wild-type population. So that's very intriguing and could spark a lot of interesting discussion if whether you have a BRAF wild-type, maybe even monotherapy is something to consider for those. But really I think importantly would be what to do in the BRAF population if you now also have the option of front-line BRAF/MEK. And perhaps I can invite Dr. Sullivan here to speak about things about sequencing for a BRAF patient in the front-line setting.
Dr. Sullivan:
Thanks, Dr. Patel. It's really amazing how many new drugs and combinations of drugs have been approved for this patient population, Dr. Hamid highlighted it so nicely with that diagram of where we were and where we are now and continue to go. And with this embarrassment of riches in some respects in terms of particularly for the BRAF-mutant population, there's combination BRAF/MEK, which is in four randomized phase III trials, proven to be better than single-agent BRAF inhibitors in the front-line setting. We even have a BRAF/MEK/PD-L1 combination vs BRAF/MEK showing superiority and that combination of atezolizumab/vemurafenib/cobimetinib was approved a few years back. And then all of the immunotherapy, and as that data so beautifully illustrates BRAF-mutated melanoma patients seem to really benefit from ipilimumab/nivolumab. And so what's the right thing for this patient population?
And there were, as Dr. Patel and Dr. Hamid know, many conferences where we'd get together and we'd debate whether we should start with BRAF/MEK or ipilimumab/nivolumab, or single-agent PD-1, and we'd talk about retrospective data sets that might have existed and essentially were dreaming about a sequencing trial. And then one was actually in the works for the better part of this past decade, and that's a DREAMseq study which randomized front-line patients with BRAF mutations to either receive ipilimumab/nivolumab in the standard dosing or dabrafenib/trametinib which is a BRAF/MEK combination. And then at progression were offered the opposite arm. And what's really striking about the data from this study is that clearly patients who started with ipilimumab/nivolumab had the best outcomes. And essentially, despite the fact that early on the progression-free survival and overall survival favored BRAF/MEK at about 10 months, the PFS and OS curves cross.
And then the OS curve stabilizes for the ipilimumab/nivolumab and continues to go down for the dabrafenib/trametinib and the primary endpoint, which was 2-year overall survival, showed a not relative but absolute 20% difference in overall survival, that's stunning and a complete victory of those who were years ago arguing for front-line immunotherapy, it's also victory for patients that we know this information. So what do we do with BRAF-targeted therapy? Is there ever a role for it? Well, there are a few scenarios where we consider it patients who are about to die from their metastatic melanoma, we know they have a BRAF mutation, we might choose to give those patients that BRAF/MEK upfront. There's actually another randomized trial randomizing patients to receive either ipilimumab/nivolumab or a different BRAF/MEK combination encorafenib/binimetinib or a sandwich of encorafenib and binimetinib, then switching to ipilimumab/nivolumab after a fixed period of time on therapy and then switching at relapse.
And ultimately that study, which is called the SECOMBIT study, showed that again, front-line immunotherapy was best, but that sandwich might actually also do well. And so for patients who have terrible disease and you really don't think they have time to give them ipilimumab/nivolumab, you might give BRAF/MEK front-line for a fixed period of time, then switch those patients to ipilimumab/nivolumab. That's probably it in terms of the role of front-line BRAF-targeted therapy. However, we're also need to think about other lines of therapy.
Now, I think something that Dr. Patel mentioned earlier was that another potential option for patients in the frontline is a clinical trial. We are not there yet. We have not succeeded. We have not come to the mountaintop in terms of where we can go with front-line therapy. We still have at best 45% of patients having long-term survival, that's less than half if my math is correct. And so that's not good enough. We need to be better. And in the front-line setting is still a very good place to try and do our best. And so there are clinical trials that are out there that are beginning to show things. And so one of these trials that Dr. Hamid presented recently in Paris was a different LAG-3 inhibitor fianlimab with a different PD-1 inhibitor cemiplimab showing 70% of patients having tumor regression over a 60% response rate in the front-line setting, these responses being mostly durable and with a progression-free survival of 2 years. Now that's a subset of patients, we don't know if that's the same population of patients who are on the RELATIVELY-047, but that's exciting and is now in a randomized phase III trial to see if that's a potentially new effective regimen in a new way of blocking PD-1 and LAG-3.
I think another question that was asked, Dr. Hamid, in your early slides was, what if our patient Melissa had brain metastases, then what would we do? And I think the answer is pretty clear based on both the CheckMate-204 trial, which was an open label study for patients with brain metastases to receive ipilimumab and nivolumab. There was also a trial from the Australian Brain Consortium, the ABC study, which randomized patients to ipilimumab/nivolumab or nivolumab. And what's clear is that patients with either asymptomatic brain metastases, or even symptomatic brain metastases, that receiving ipilimumab/nivolumab is transformative and that these trials are so positive, it's amazing. So the asymptomatic patient data, now this is like over 100 patients, and we're seeing PFS rates that... PFS curves and OS curves that sort of flatten at 65 and 70% with going out to many years, that's unbelievable, literally unbelievable, but it's actually real data. It's true. These patients with asymptomatic brain metastases have incredible responses that persist. With PD-1 inhibitors for whatever reason, it doesn't work as well, in patients who have brain metastases, than in patients who don't. But ipilimumab/nivolumab works as well, maybe even slightly better. And so I think that the declarative and definitive answer of what would we do for Melissa if she presented with asymptomatic brain metastases would be to give her ipilimumab/nivolumab. I'll turn it back over to you, Dr. Hamid.
Dr. Hamid:
Wow, what a tour de force. And it shows just how far we've come within a couple of years for our patients with metastatic malignant melanoma where CTLA-4 and PD-1 combination therapy are now indicated in the first-line therapy for BRAF mutant patients. PD-1/LAG-3 combinations are available in the first line that show higher response rates and less toxicity than other combos and higher response rates in patients vs PD-1. With single-agent PD-1 becoming less and less of an option for patients, but still an option for those who haven't seen it in the adjuvant. And as we move forward, regimens that really salvage patients who present with brain metastases. So at this point in conclusion, we have a lot more to do in clinical trials, but we have a lot available to our patients. And this brings us to the end of this case. Please see the other segments for further discussion about the latest data in melanoma or visit ascopost.com. Thank you.
