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General Discussions

Initial Treatment Approach in Advanced Melanoma: Factors to Consider

By Michael B. Atkins, MD, and Michael Postow, MD


Michael B. Atkins, MD:
The factors that we look at when we’re seeing a patient with metastatic melanoma and deciding an initial approach are, first, their BRAF status. Second, we also look at the type of protocols that we have available that address important questions that are yet to be answered. So, how does that work? In a patient with a BRAF mutation, we would prefer to put them on the Cooperative Group protocol, EA6134, addressing whether starting with BRAF inhibitor and giving immune therapy at the time of progression is better or worse than starting with immune therapy and switching to BRAF inhibitor if and when the patient progresses. That would be our preferred choice. And, in a patient with a BRAF mutation who wasn’t eligible for that protocol —because they couldn’t get immune therapy, because they had symptomatic brain metastases requiring steroids, had autoimmune conditions that required steroids and made them poor candidates for immune therapy, or they were hospitalized and needed to have rapid response to treatment to be able to get them out of the hospital — we start on BRAF inhibitor therapy.

For the BRAF wild-type patients, our default is to give them combination immune therapy with ipilimumab and nivolumab. And the only patients where we would consider for monotherapy are those patients who we think would not be able to tolerate combination therapy. That would include patients with autoimmune conditions that would potentially flare on more potent immune therapy, patients who were elderly and had significant comorbidities that would make us suspect they wouldn’t be able to tolerate the complications of combination immune therapy — should they happen — and patients who might have already received ipilimumab or potentially an anti-PD-1 in the adjuvant setting and had their disease progress.

Michael A. Postow, MD: Age and performance status are important considerations in taking care of patients with advanced melanoma. With age in mind, I think it’s really important to consider that age is not just a number, it’s really a functional age. So, I do get information about whether or not patients are a certain age. But, I really try to use that in the context of what is their life like? Are they working? What’s their functional status and performance of activities of daily living, travel, and how their family support is? I think that’s all important in setting the patient in the context of their entire environment. I’ll have older patients in their 80s or 90s sometimes that I think about as if they were in their 50s or 60s, depending on their functional status.

If I have a patient that’s in their 80s or 90s, even if they have an excellent functional status and a much younger functional age, it is still important to not completely forget about that they’re in their 80s or 90s. If they have a really significant side effect, they may have less resilience in coming back from that type of a side effect. But, I wouldn’t withhold the opportunity to treat older patients just because of the number of their age in and of itself, and I really try to incorporate their functional status within that. If I have a patient with a very sick or very bad melanoma disease burden and a very impaired functional status — at any age — and I think their functional status is impaired due to their melanoma, that’s a patient I’ll treat aggressively for their melanoma because I believe that if they have a nice response against their melanoma, their functional status could really dramatically improve. And we see that with BRAF and MEK inhibitors all the time — we see that with ipilimumab and nivolumab. So, those are the aggressive types of treatments. And if I have a patient of any age really that’s really functionally impaired from their melanoma, that’s a patient I would still think about treating aggressively, if the patient wants to be aggressive and that’s in line with their goals of care. If I have a patient that has really bad functional status impairment from other medical comorbidities, bad congestive heart failure, cardiopulmonary disease, renal failure, those are the kinds of patients I may think about treating their melanoma less aggressively, particularly if their melanoma disease burden is not that bad. I may think about a single-agent PD-1 type drug in those types of patients. So, I really use performance status more so than age, keeping in mind you can’t completely ignore age, but it’s really functional age that’s most important.

Brain metastases are unfortunately a common problem in patients with advanced melanoma. It’s really unfortunate that there are so many patients with brain metastases, and that’s really a reason why we need to obtain a brain MRI in all patients that we have that are newly diagnosed with stage IV melanoma and even on treatment at certain intervals. So, when you encounter a patient with brain metastases from melanoma, I think the most important issue is if you know if they have a BRAF mutation, yes or no, how many brain metastases they have, and how are you able to handle them. If I have a patient with many, many brain metastases or what’s called “leptomeningeal melanoma,” which is a neurologic complication of melanoma cells in the cerebrospinal fluid, that’s a patient I’ll treat with a BRAF and a MEK inhibitor because I don’t think that there’s any single drug combination or single drug that’s more effective in the brain than BRAF and MEK inhibitors. So, really bad brain metastases or leptomeningeal disease, treat those patients with BRAF and MEK inhibitors. If I have a patient with a few brain metastases that are amenable to stereotactic radiosurgery, I may give that patient stereotactic radiosurgery with my radiation oncology colleagues and treat that patient with immune therapy, such as PD-1 single-agent treatment. There are emerging data of the efficacy of PD-1 alone and ipilimumab in combination with PD-1 in treating brain metastases. We know that PD-1 alone and ipilimumab/PD-1 can shrink brain metastases in some patients. We don’t yet really quite know officially what the response rate is because we don’t have as much data on that topic as we would like. But, PD-1 can work in the brain and ipilimumab/PD-1 can work in the brain.

Transcript Edited for Clarity
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