New Treatment Paradigms for Advanced Melanoma - Episode 19
Merrick I. Ross, MD: When making decisions about adjuvant therapy for patients with high-risk melanoma, several things have to be considered. First of all, we have to determine what the predicted risk for relapse is in the given patient. We also have to look at the toxicities of the therapies that are being discussed and at the efficacy of the different therapies. It’s a bit of a challenging time right now, because predicting the risk for relapse is somewhat in flux. There’s a new AJCC staging system, that was just published in January of 2018, where the stage 3 patient population is doing much better because they’re mostly patients with microscopic sentinel lymph node-positive disease. So, their risk profile is not as great. The need for adjuvant therapy is not as universally accepted, particularly for the lower-risk stage 3 patient population. Then there’s the issue of whether or not they have a BRAF mutation. Certainly, if they don’t have a BRAF mutation, they are only eligible for immunotherapy as adjuvant therapy. That would be nivolumab and then, likely, pembrolizumab, after it gets approved by the FDA.
Because the trials included completion lymph node dissection for patients who had microscopic positive sentinel lymph nodes, that becomes an issue. Recent trials looking at the role for completion lymph node dissection in patients with positive sentinel lymph nodes shows no benefit for performing the completion lymph node dissection. So, that’s another issue, in making decisions about adjuvant therapy for patients—whether or not they should undergo a completion lymph node dissection after positive sentinel lymph node. Given that there’s no apparent survival difference in patients who underwent the completion dissection, it’s not likely that that dissection contributed to any survival improvement in the adjuvant therapy trials. It’s probably safe, in selected situations, to not recommend the completion lymph node dissection for this patient population.
After the surgery is completed, there has to be a decision about using adjuvant therapy. The surgeon usually identifies the patients who are eligible and then refers these patients to a medical oncologist. On a personal level, because the BRAF/MEK trial showed such an amazing reduction in the number of events, in terms of disease-free survival, and because the therapy is relatively well tolerated, my personal first choice, if they are BRAF-mutated, would probably be the BRAF/MEK combination. Most of my medical oncology colleagues, however, like to start with immunotherapy, but I’m pretty impressed with the adjuvant therapy results using the BRAF/MEK targeted therapy option.
In terms of toxicity, there was a higher number of events of patients discontinuing the BRAF/MEK therapy compared to nivolumab or pembrolizumab. But, on the other hand, for patients who do have side effects, they are mostly immune-related. They’re usually life-lasting, particularly if it’s adrenal insufficiency or hypothyroidism. The worst possible event would be diabetes. These events are immune-related and probably don’t go away after stopping the drug. So, you kind of have to weigh the risks and benefits when you’re making decisions about targeted therapy versus immunotherapy. There may be a higher toxicity, in terms of discontinuation of targeted therapy. The side effects for the immune-related events are very long-lasting, probably for the entire life of the patient. So, particularly for patients in the adjuvant setting, where many patients are cured with surgery, alone, these are very challenging decisions to make, in terms of establishing risk and looking at toxicity.
Then we have to worry about what happens when patients are taking adjuvant therapy and they relapse. What do we do in that situation? Is it possible that they’ve already received immunotherapy and that they would not respond if they developed distant disease? The same thing may be true for targeted therapy. With immunotherapies, if patients relapse and have surgically resectable disease, they probably will then receive ipilimumab in the adjuvant setting. But that may have a higher toxicity.
When we’re looking at toxicities, particularly when we’re looking at ipilimumab, it’s probably pretty well tolerated in the stage 4 setting. But interestingly enough, in the adjuvant setting, it seems to be a little more toxic. It’s not clear as to what the mechanism of that is. The ipilimumab that was initially approved in the stage 4 setting was a 3-mg dose. The 10-mg dose was also tested in the stage 4 setting and it had a higher toxicity profile. In the adjuvant setting, the 10-mg dose is what’s approved, and those patients have a pretty tough time. As a matter of fact, there were 8 deaths on the ECOG 1609 trial, which looked at high-dose interferon versus low-dose ipilimumab, versus high-dose ipilimumab. The toxicity profile for the 10-mg dose was very high in the adjuvant setting. In terms of the BRAF/MEK combination, it looks like the tolerability is pretty much the same in the adjuvant setting as it is in the stage 4 setting. Pembrolizumab or nivolumab—they probably have similar toxicity profiles in the stage 4 setting as in the stage 3 setting.
Transcript Edited for Clarity