Melanoma: Speed and Durability of Therapeutic Response
MICHAEL A. POSTOW, MD, AND MICHAEL B. ATKINS, MD
Saturday, March 11, 2017
Michael A. Postow, MD: In thinking about responses to targeted therapy with BRAF/MEK inhibitors and immune therapy, there are a few important considerations that you have to have once you start these patients on these treatments. You’re following them, you’re monitoring their symptoms, you’re checking out their CAT scans, and trying to think about, “How is my patient doing with one of these approaches?” So, when we think about dual-targeted therapy with BRAF and MEK inhibitors, I think the key to know is that almost everyone will have an initial, really tremendous response and this response can be literally within hours or days. We’ve had patients that come in really sick with pain in their side or some tumor that they see on their skin. If they have a BRAF mutation and they start a BRAF/MEK inhibitor, literally the next day, even before that, or hours or days after starting treatment, they’ll initially start to say, “I’m feeling better. I’m having more energy. My tumor is shrinking. This is really wonderful stuff.” That’s just incredibly remarkable to see with these BRAF and MEK inhibitors, how rapid that response can happen.
Importantly, there’s this notion that has been out there that everyone with BRAF and MEK inhibitors has this wonderful initial response, but over time, everyone progresses. That’s just really not true. There is a group of patients that have this wonderful response with BRAF and MEK inhibitors, and there’s a group of patients, not everyone—we wish it were everyone—that will have retention of that response very long term, and by long term, I mean years. So, this notion that targeted therapy with BRAF and MEK inhibitors works in everyone, but then everyone progresses, I just think that’s a little bit incorrect. There is a group of people that will have long-term responses with BRAF and MEK inhibitors.
We’re trying to figure out who these patients are, and generally, they’re patients with normal LDH or only a few sites of tumor burden involvement, so that’s something we can think about. If we have a patient with an excellent performance status, few sites of disease, and a normal LDH, that may be a patient that we could expect to do well with BRAF and MEK inhibitors for a very long time because those are good prognostic features of patients that are getting BRAF and MEK inhibitors. But I think the key is very rapid initial responses with BRAF and MEK inhibitors.
When we think about immune therapy, it is a little bit different than BRAF and MEK inhibitors. However, I would caution against some generalizations that have been out there in the conversation. And what are those generalizations that we sometimes hear? Well, sometimes people will say, “BRAF and MEK inhibitors, you get this immediate, immediate response,” and that’s true. “Immune therapy, you get this delayed response. You may have atypical patterns of disease response.” That is a little bit true to immune therapy in part. However, I will say that a lot of what we initially learned about immune therapy responses—this delayed immune therapy response and these atypical responses—came from the ipilimumab era, and that was the first immune therapy drug that was approved in metastatic melanoma. And it’s true that with ipilimumab, you may have these delayed responses and you may have slower onset. You may have atypical responses of apparent progression and then ultimate disease response in approximately 10% of patients.
But as we move now from ipilimumab to PD-1 treatments with either nivolumab or pembrolizumab as single agents or the combination of ipilimumab and nivolumab, we are seeing incredibly rapid responses with either PD-1 alone or the combination of ipilimumab and PD-1 right away with immune therapy also. It’s not quite as rapid as the BRAF and MEK inhibitors, so you may start a patient on immune therapy. It may not be hours that they’re feeling immediately better versus if they would have started with the BRAF and MEK inhibitor, but often within weeks, they’ll be starting to feel immediately better. And usually when you get a CAT scan, the very first CAT scan that you obtain, which is anywhere up to about 3 months after starting immune therapy, the patients that are going to be responding will already be responding by that first CAT scan. So, immune therapy responses can also happen very, very quickly, particularly with PD-1 alone and the combination of ipilimumab and PD-1. I would caution against the generalization that ipilimumab/PD-1 and PD-1 alone have these delayed responses and that it doesn’t work right away. These can work very, very early as well. Maybe a little later than the targeted therapy approaches, but still very early.
Michael B. Atkins, MD: Our goals of therapy when we’re treating patients with metastatic melanoma have really changed dramatically. In 2017, our goals are to induce a long-term durable response that allows for the patient to be able to stop treatment and get back to their normal lives. And we’re finding that we can do this with a multidisciplinary approach to treatment that involves all the different tools that we have available used in the right sequence, which we’re still experimenting with. We can produce durable treatment-free responses in 50% to 70% of our patients. So, both BRAF/MEK inhibitors and immune therapies can produce dramatic and quick early responses. There is a tendency to think that the responses related to immune therapy are more durable and that we can more likely be able to stop treatment and have the response continue. But you can also see dramatic responses with BRAF/MEK inhibitors; patients can tolerate these pills very well. They go on therapy and stay on therapy for long periods of time. We’re seeing some patients whose disease has gone away, and we may be able to successfully stop treatment in those as well.
We’re also finding that some patients have isolated sites-of-disease resistance to either immune therapy or sometimes to targeted therapy. In those cases, we can successfully treat those with either radiation or surgery and have patients do well without other disease recurring. We’re seeing that in some patients whose disease has stopped responding to BRAF/MEK inhibitors, that we can induce durable responses with immune therapy. And we’re seeing patients whose disease has stopped responding to immune therapy, where we can add on BRAF/MEK inhibitors and see dramatic responses that at least appear to have some component of immune response related to it that’s allowing us to actually stop the treatment.
So, there’s a lot to learn. We’re working on all these things. We have a multidisciplinary team that addresses the complicated cases together, and we’re figuring out not only how to get to that endpoint of having the patient’s disease gone and being able to stop treatment, but how to do so leaving the patient as functional as possible.