Transcript:Robert H.I. Andtbacka, MD, CM: The next patient is a 50-year-old male who has lung, liver, and bone metastases. The LDH is slightly elevated, 1.4 times of the upper limit of normal. ECOG performance status is 1, and the patient has a BRAF V600E mutation. Georgina, what is the frontline therapy for this patient in Australia?

Georgina Long, MD: In Australia, we have funding rules, which means for BRAF-mutant patients, we have to give a BRAF and MEK inhibitor in the frontline setting no matter what their disease status is in terms of volume, LDH, etc. We actually don’t agree with that. Things may be changing in some respects in the next few months, and I tend to try and find immunotherapy for my patients via clinical trials. If I had the situation—which I hope does change—where I could choose whatever I like in the frontline setting, the frontline immunotherapy I would choose for this patient would be a combination immunotherapy. They’ve got a slightly elevated LDH, they’ve got multiple metastases, and the ECOG is 1. You would like to be more reassured about a response, and we do know that, numerically, the response rate is higher with ipilimumab combined with nivolumab—with all the other caveats we mentioned in case 1 in terms of overall survival.

Robert H.I. Andtbacka, MD, CM: So, Mike, what are the data then saying that doing nivolumab and ipilimumab is better than a BRAF/MEK combination for this patient in terms of response and in terms of durability of that response?

Michael A. Davies, MD, PhD: At this point, we’re really in a data-free zone. At this point, we really don’t have any trials that have said, head-to-head for a patient with metastatic BRAF-mutant melanoma, what the right initial therapy is. If you start with a BRAF/MEK inhibitor combination or you start with an immunotherapy combination, which of those strategies is most likely to result in long-term survival is really unknown at this point. And this is actually being tested in prospective clinical trials, where patients like this are being randomized to start with combination targeted therapy with a BRAF and MEK inhibitor versus combination immunotherapy with ipilimumab and nivolumab. And if and when the patients progress, they cross over to the other therapy. This is really going to provide us with the definitive information about which of those therapeutic approaches is the right one to start with. That being said, there is a third option. There are multiple clinical trials that are going on right now that are testing the safety and efficacy of combining targeted therapy and immunotherapy together, which is another intriguing hypothesis about how to treat a patient, particularly one like this, which, as Georgina mentioned, is a patient who has certain adverse or high-risk features that do make you concerned about their likelihood of progressing with our currently available therapies.

Robert H.I. Andtbacka, MD, CM: Tony, outside of the clinical trial that Mike is talking about, what do we know about starting with immunotherapy first and then if the patient progresses, switching over to a targeted therapy versus the other way around: starting with the BRAF and MEK and then switching over to immunotherapy? Are the responses similar or are they different in these patients?

Antoni Ribas, MD, PhD: Well, all we have is biased reports. If in a center, patients with a certain percent in characteristics are given immunotherapy or targeted therapy, and then you look back and ask, “How did those patients do?” Well, the initial decision, which was not randomized, means it will likely skew the results. But there is evidence that patients who have progressed on primary immunotherapy can still respond to a BRAF inhibitor-based therapy. There’s also evidence of the other way around: patients who progressed on a BRAF inhibitor or a BRAF plus MEK inhibitor can respond to a PD-1—blocking antibody. Actually, in the first trials, the registration of pembrolizumab and nivolumab in the United States was first used in patients who had previously progressed on ipilimumab, but also in patients who had BRAF-mutant melanoma and had to have received and progressed on a BRAF inhibitor. We know that when we do that, responses are lower, which makes us think that either having more advanced disease is less likely to respond or that maybe there is some overlap between the patients who respond to both kinds of therapies. Those are things that, obviously, without a randomized trial, we will not be able to tell.

But I would argue that for an individual patient, we may not need a randomized trial. Because if I go back to this patient, a 50-year-old male with the LDH slightly high and a BRAF-mutant melanoma, we can explain the data both with BRAF plus MEK inhibitors or with PD-1 alone or ipilimumab/nivolumab. And after explanation of the data, we get into the conversation with the patient and we start seeing how these things resonate—because there’s pros and cons for all these therapies. Yes, we all want to have a response in the majority of patients; we want it to be durable. But we can have a durable response with maybe life-threatening toxicities, which we can have with the PD-1 and CTLA4 combination, but which would be unlikely to happen with a BRAF and MEK inhibitor combination.

And then we have the patients who may say, “Well, I want to have the least toxic of all. I have my life as it is. Let’s try to see if I can get a response.” And you would go with a single agent anti—PD-1. So, I think that even with randomized data, we can tell in a group of 100 patients what would happen to the majority. But the data will never tell us what will happen to an individual patient. I think we’ll all continue to discuss and personalize therapy.

Michael A. Davies, MD, PhD: So, remember, one of the things just to explain here is, again, the significance of the elevated LDH.

Robert H.I. Andtbacka, MD, CM: Yes, so tell me about it, Mike.

Michael A. Davies, MD, PhD: LDH, again, this is a serum assay for lactate dehydrogenase. And historically, we’ve known that patients with stage IV melanoma who have elevated LDH levels have a worse prognosis for overall survival from the diagnosis of stage IV disease. What has been seen consistently across clinical trials, with both targeted therapies and immunotherapies, is that patients with high LDH have worse outcomes than patients with low LDH. In a patient like this, I think the scenario that we’re looking at is we know that their chance of responding to immunotherapy is lower than a patient with a normal LDH.

However, there are also very good data that if they do respond to immunotherapy, those responses can be quite durable. For patients with a high LDH, we actually know the targeted therapies do have very high response rates, probably higher than what we can achieve with immune therapy. But what we’ve seen over time is that the overwhelming majority of those responses are short in duration. And this patient is a patient who has very slightly elevated LDH and is not highly symptomatic. This is a patient where I think you have some time in order to get a response.

I think the other place that we have this debate is for patients who come in with markedly elevated LDH, high disease burden, and high symptomatology. There is that question of, do you want to go with targeted therapy, which has a higher chance of actually providing symptomatic benefit even if it’s going to be short-lived, or try to use the immune therapy, where maybe your chance of getting the disease under control is initially shorter but there is potentially a chance for much more durable benefit if that’s achieved? Those, again, are some of the concepts that we think about when we’re seeing these patients with a BRAF mutation, particularly with the high LDH and other high-risk features.

Transcript Edited for Clarity