Hackensack University Medical Center oncologist, Andrew Pecora, MD talks about a new way to treat melanoma.
Interview conducted by Ivanhoe Broadcast News in 2022.
Talk a little bit about metastatic melanoma. To this point, what has been the best treatment for patients or the available treatment for patients?
PECORA: Up until not that long ago, metastatic melanoma was a uniformly fatal disease. If you had it, you usually died of it within a few years. We now have two new avenues of therapy that are highly effective. One is immunotherapy, the second is targeted therapy. Targeted therapy is limited to patients who have a mutation in their melanoma. Immunotherapy is applicable to any patient with melanoma.
Tell me a little bit about the dream seek trial.
PECORA: The dream seat trial is a practice changing trial in that it proves if you have metastatic melanoma and it’s associated with a mutation of an oncogene called BRAF. There was a choice you could make. You could give targeted therapy, or you could give immunotherapy. We didn’t know which was better and did the sequence matter. It turned out the sequence mattered profoundly. Patients who received immunotherapy or first had a significantly better survival than patients who received targeted therapy first. We now recommend that all patients with BRAF mutated melanoma receive immunotherapy first, only to be followed by targeted therapy if the immunotherapy fails. That will result in more people being alive at five and 10 years.
So, it’s not necessarily both automatically. It depends on how you do with the immunotherapy?
PECORA: Correct. If you go into remission with immunotherapy, you don’t need targeted therapy. If, however, you receive the immunotherapy and you have a side effect and you still have active melanoma, or if the melanoma goes away incompletely, or if the melanoma goes away completely and then comes back, you will then pivot to targeted therapy in those cases.
You mentioned this is practice changing. Is this something that you’ve already instituted here at Johnson?
PECORA: Yes. At the Johnson Cancer Center, we’ve instituted the results of the trials. All patients with BRAF mutated melanoma will first receive immunotherapy only to be followed by targeted therapy if it’s needed.
When you’re talking about immunotherapy, what are you talking about? And then targeted therapy, what are you talking about?
PECORA: Immunotherapy is a broad phrase. In this context, it defines an antibody or class of antibodies that allows a person’s T cells. T cells are immune cells that we have that fend off viruses. When you get a vaccine, you develop T cells to the antigen of the vaccine or fend off cancer. Cancer cells have figured out how to turn off T cells. They do that through something called a checkpoint, like a light switch. They turn it off and the T cell goes to sleep. What immunotherapy is, that light switch so the cancer cells can no longer engage the checkpoint, turn off the light switch, the T cell stay on, and they kill the cancer. There are two classes of immunotherapy, those that affect something called PD-L1 and another that affects CTLA-4, two different light switches. Nonetheless, you cover those up. T cell stays on and you kill the melanoma. Targeted therapy goes after the molecular circuitry that has been altered in a cancer cell. Our cells have all these pathways. These pathways result in proteins being made that allow us to live and stay healthy and do what they need to do. Cancer hijacks that protein manufacturing and makes its own proteins for its own bad purposes. Sometimes we can see the pathway that was hijacked because it’s called mutated. We have been able to develop small molecules pills that you can take that go to that broken circuit and shut it off. There are two circuits in patients who have BRAF mutated melanoma. One is the BRAF circuitry, and the other is the MEK, circuitry. We give BRAF inhibitors in combination with MEK inhibitors. We shut off the two circuits, BRAF, and MEK. As a consequence, that’s what targeted therapy is. You shut off the cancer cell’s ability to grow and so it dies.
What’s the benefit of patients being able to be treated with immunotherapy first before you go to the targeted therapies?
PECORA: What the dream seek trial did was randomize patients to either start with targeted therapy or immunotherapy. Then it looked at hundreds and hundreds of patients in both of those groups. It’s shown that at three years and now out to five years, the patients who received immunotherapy first, not only had more responses, but were alive. A significantly greater percentage were alive than those that received targeted therapy first, even though the targeted therapy patients went on to receive immunotherapy later. We have some ideas why this occurred, but we’re not quite sure. What we do know is unequivocally the standard of care should be for any patient with metastatic melanoma regardless of their BRAF status. Immunotherapy first followed by targeted therapy if needed.
What percentage of metastatic melanoma patients have this BRAF mutation?
PECORA: About 50% of patients with metastatic melanoma have the BRAF mutation.
When you’re talking about oral medications, is that oral chemotherapy? Or is chemotherapy not a good term to use?
PECORA: Chemotherapy is not a good term to use. These are small molecules that specifically inhibit a certain pathway. I would call it a targeted therapy.
When did you institute this as the practice the way you treat patients here?
PECORA: The preliminary results came out a couple of years ago and we started then. The more formal results were recently published, and the most recent update was done a couple of months ago. The improvement is getting greater over time.
Is this a cancer that has been growing?
PECORA: Yes, the incidence of melanoma is on the rise, particularly in some parts of the world. Excess sun exposure can lead to skin cancers of which melanoma is one. We see melanoma more commonly in fair-skinned people who don’t have a lot of pigment to protect themselves from the ultraviolet radiation of the sun. People who live in the Southern Hemisphere around the equator and people that live in the lower states of the United States.
Is there anything I didn’t ask you that you would want to make sure that viewers know about either DREAMSeq or about advanced melanoma?
PECORA: Yes, there is another important finding that just got published. Another very significant finding and that is one of the side effects of immunotherapy is your immune system overreacts. We give prednisone for that. People were concerned that if you give prednisone, you might shut off the immune effect. It turns out you don’t. In fact, if you have some side effects by enlarging, you do better than if you have no side effects. There was another very important finding however, and that is that if the prednisone isn’t working, you must go to a stronger immune suppressant therapy and there’s a variety of them. When you do that, you shut off the T cells and you do much worse. The goal is to avoid secondary immune suppression. The learning point from this is that doctors should not hesitate to start prednisone early and often when needed. This is because if you start early, it’s highly likely you won’t need to go for secondary medication. It’s only if you let the autoimmunity take hold and cook for a week without intervening with prednisone. By the time you intervene with prednisone, it’s not strong enough and you must add a second medication. Physicians who take care of melanoma patients should not hesitate giving prednisone early and often as needed, but if possible, avoid the secondary immune suppressive medications.
And for the next steps in this research, is this it, or is there something you and your colleagues want to build upon from what you found from this trial?
PECORA: Yes. In melanoma, if you add metastatic melanoma, almost 100 percent of people died. Now with immunotherapy and targeted therapy, we’re carrying about half. There are still half of the people that haven’t come back or don’t go away. We’re trying to understand what’s different about those people and what we’re going to do differently. We have a whole new generation of immunotherapies. We have a whole new generation of targeted therapies and now we’re starting to combine immunotherapies with targeted therapies upfront. Our hope is by following those paths, we will help the rest of the patients that we’re not helping today.
END OF INTERVIEW
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