Dr. Eroglu: Turning our focus then to patients with metastatic melanoma, where obviously considerations for delaying treatment is a lot more challenging, Ari, I wanted to ask, for patients you see for BRAF wild-type metastatic melanoma, how has this impacted your decision-making with regards to the types of immunotherapy regimens, single-agent, combinations? I just wanted to see what your thoughts were on that.
Dr. VanderWalde: Sure, and thank you for asking that, Zeynep. I think that you've kind of hit the nail on the head, which is that in metastatic therapy, we really don't want to delay therapy; the question really becomes about choice of therapy. I want to echo what has been said earlier, which is we’re in a very fluid situation, and by saying that, at least in the United States, we’ve all…most of us have been under stay-\at-home recommendations or orders now for a little bit over a month. In cancer, we have just sort of a sense of there’s a certain amount of time that it’s okay to wait, there’s a certain amount of time that it’s not okay to wait, but we’re really kind of all in this together in that we don't really know what the right answer is, and that applies to choice in metastatic therapy in BRAF wild-type patients as well.
We are always, as physicians, trying to make a risk-benefit analysis about the efficacy versus safety issues having to do with therapy, and the safety issues are somewhat more unknown than usual. So there are really two questions about immunotherapy that need to be asked under the COVID pandemic. The first is, does the safety issues of giving combination immunotherapy, which in this case would be ipilimumab plus nivolumab, are those outweighed by…are those safety considerations considered to be more severe than what we would do from single-agent nivolumab or pembrolizumab, especially given that there has yet to be an overall survival benefit that’s been demonstrated with combination immunotherapy, and yet at the same time, there’s also the duration of therapy, and again, we don't know how long that’s going to be. More than half of patients who get combination immunotherapy don't go on to getting the full year afterward of single-agent nivolumab therapy, so to some extent it might be like ripping off the band-aid. Many patients don't go on to having to have all of those visits, but that’s at the cost of having severe adverse events. I would recommend at this point, and this is what we do recommend, is that patients who are getting immunotherapy combination we go with a lower dose of ipilimumab, and this is something that we’ve doing since before the COVID epidemic, but I think it’s even more important to follow that now. That decreases the risk of grade III or higher side effects by approximately 40%. While we don't know for sure about the relative efficacy, because safety considerations are considered to be so much more concerning in patients who become immunosuppressed or who end up even becoming overly immunocompetent under the COVID conditions, we don't know if either of those conditions are actually more dangerous in patients who have COVID. I recommend that patients go on to lower-dose ipilimumab therapy with regular-dose nivolumab therapy, as per the CheckMate 511 study.
We’ve run into a couple of interesting situations in which patients are finishing up a year or 2-year checkpoint inhibitor therapy in the metastatic setting, and the question becomes whether or not we want to continue bringing them in and treating them with checkpoint inhibitor therapy after a year or 2 years, and we’re actually now erring on the side of holding therapy after they’ve completed a year or 2 years if they’ve had a good response. There haven’t been great data on whether or not you should continue nivo or pembro forever after…in metastatic disease, or whether you can stop at 2 years or stop at 1 year, whether that makes a difference, whether or not you have a complete response versus a partial response or stable disease over that period of time, but what we’ve been doing is we’ve really kind of put a hold on continuation of therapy in patients who have had a good response after a year at this point, and we’ve had a few patients who have hit that year mark.
We’re in somewhat of a data-free zone as to if the COVID and when the COVID pandemic lifts and these risks do go down, whether or not to restart therapy, whether to restart therapy if these patients do progress, and when they progress, so there’s a lot of unknowns right now, and again, they mostly have to do with the unknown safety concerns that go together with it. In patients who are determining whether or not to go onto nivolumab as a single agent, pembrolizumab as a single agent, versus combination therapy I’m more inclined to try to recommend a single-agent therapy at the current time in patients who you think can get away with that, mostly because the rate of grade III or higher toxicity is so much lower, even than low-dose ipi, regular-dose nivo, and because so many of the severe grade III, IV toxicities that can occur with combination therapy are...at least able to be overlapping with some of the COVID symptoms, including diarrhea. Some of the endocrine abnormalities can really kind of look like illness—fatigue, potentially low-grade fevers—and so, when you can get away with it, I think single-agent PD-1 therapy is still something that we recommend despite the fact that in the pre-COVID pandemic setting, a lot of people were moving toward lower-dose combination therapy.
Dr. Eroglu: Would you say then for patients who have BRAF V600 mutant metastatic melanoma, let’s say newly diagnosed, have you tended to favor the BRAF MEK inhibitor therapy for those or give it more consideration over immunotherapy, or has that not really made a difference in your decision-making?
Dr. VanderWalde: That’s really a great question, and I want to say it’s not been making a difference in my decision-making simply because we don't really know whether or not the safety is better. Currently, patients are able to come in. If they’re on checkpoint inhibitor therapy, they come in once every 3 to 4 weeks, depending on the choice, whereas when patients who are on BRAF inhibitor therapy, they’re also coming in every 3 to 4 weeks. Their visits tend to be shorter, and they don't have as many visits as they otherwise might. They don’t have to go to the infusion center as well. They mostly end up just going to the lab and seeing the doctor. I don't think that choice of therapy necessarily should favor BRAF therapy, simply because we just don't really know, and in addition, as it has been mentioned, BRAF MEK inhibitor therapy is very likely to cause a relatively high-grade fever. Without bringing the patients in, it can be very difficult to be able to determine whether or not that’s due to COVID versus the toxicities of those agents.
That said, it’s a little bit hard to know when I see a patient with BRAF mutant disease whether or not I am subconsciously favoring the oral therapy versus the immune therapy, and I think that that’s a challenge for most practicing oncologists to try to take COVID out of the equation for those patients simply because we really don't know which one is better and which one isn’t. I also want to very quickly just address the issue of number of visits because I think that that really is at the heart of that determination between oral therapy versus IV therapy. I think it’s important to recognize that decreasing the number visits is to one extent a very important part of the safety of both the patients and the healthcare providers, and whatever can be done via telemedicine should be done via telemedicine, if at all possible. [I think] that gratuitous scans shouldn't be done, generally speaking, and metastatic melanoma scans every 12 weeks remain appropriate in the absence of symptoms, and I think that in metastatic disease that remains true, if not even less commonly than that, and we’ll have to see how the COVID pandemic continues to play out. If you can do a scan on the same day that the patient is visiting, and bring them in for their scan, and have them go back out to their car or their mode of transportation, or a room that is appropriately socially distanced from others while you wait, and the patient can have all of their visits on the same day, I think that that is also something that would be favorable.