Guiding Treatment Decisions in Newly Diagnosed Metastatic Melanoma

Anna C. Pavlick, DO

Despite the approvals of targeted agents and immunotherapy in the treatment paradigm of metastatic melanoma, clinical trials remain the gold standard for patients with newly diagnosed disease, according to Anna C. Pavlick, DO.

However, if trials are unavailable or patients are ineligible to enroll, the decision of single-agent versus combination immunotherapy must be made, as well as the optimal dosing schedule. If a patient has BRAF-mutated disease, Pavlick adds, then it becomes a question of which approach should be used first, immunotherapy or targeted therapy.

“Just because the patient has a target, doesn't mean that you should reflexively give them targeted therapies,” said Pavlick, a professor in the Department of Medicine as well as the Ronald O. Perelman Department of Dermatology at NYU Langone Health Perlmutter Cancer Center. “You need to look at their disease progression, the amount of disease they have, their other comorbidities, and other factors that will indicate how aggressive their disease is.”

If the patient appears to have aggressive disease, targeted therapy might be an ideal treatment choice, as it tends to take longer for immunotherapy to become effective, explained Pavlick. Conversely, a patient with indolent disease should most likely receive immunotherapy.

In an interview during the 2020 OncLive^® State of the Science Summit™ on Advanced Melanoma, Pavlick, who is also the director of High Reliability Organization Initiatives and co-director of the Melanoma Program at NYU Langone Health Perlmutter Cancer Center, discussed key trials that have shed light on how to best treat patients with newly diagnosed, metastatic melanoma.

OncLive: What are some questions that you have when treating patients with metastatic melanoma?

Pavlick: Do we give [these patients] immunotherapy? Do we give them targeted therapy? How do we look at genetics? What are some of the key trials that help us in our decision? How can we properly treat a patient with metastatic disease?

How are you currently approaching treatment in practice?

[My treatment decisions] really depend upon whether patients have a genetic mutation or not. Fifty percent of patients who have metastatic melanoma will harbor a BRAF mutation, and we have targeted agents against these [mutations]. Patients who have a BRAF mutation can then either receive targeted therapy or immunotherapy. Patients who do not have a mutation are offered immunotherapy.

The biggest question is really in the patients with BRAF-mutant disease: What comes first? Do we give them immunotherapy? Do we give them targeted therapy? Immunotherapy will take some time to work, so if we have a patient who's really not doing well, and we know they have a BRAF mutation, we’re probably going to turn to [targeted] drugs first. If we have someone with more indolent disease, who looks and feels well, we’re most likely going to give them immunotherapy.

Encorafenib (Braftovi) and binimetinib (Mektovi) is a notable targeted combination in the space. Could you speak to the COLUMBUS trial and the updated results that read out?

The COLUMBUS trial was just published within the past year, and it [explored the] next generation of BRAF and MEK inhibitors. We started with vemurafenib (Zelboraf) and cobimetinib (Cotellic), probably back in 2011. Then, the next generation was trametinib (Mekinist) and dabrafenib (Tafinlar), in 2013. Now, we have encorafenib and binimetinib.

The COLUMBUS trial looked at this combination of drugs compared with vemurafenib alone, and clearly, the combination was superior. We also looked at encorafenib and binimetinib compared with encorafenib alone, and again, the combination was superior. Why do we need another generation of BRAF/MEK drugs? Because we hope that as our targets become more specific and we hit them better, the durability of response will last longer, and patients may have a longer survival.

Will we be able to stop targeted therapy in these patients at some point? We still don't know. Sometimes, because of toxicity, you're forced to stop treatment and the patient’s cancer never comes back. Other times, when you're forced to stop, the cancer does return. That [question] is really still being explored.

We don't know what to do with [regard to] that yet, but the safety profiles of these new medicines are also very different than those of the prior BRAF/MEK inhibitors. Patients may tolerate these [agents] a little bit better. The data [from that trial] suggest that it may be a more superior combination [in that regard, compared with older-generation inhibitors]. The combination offers doctors the ability to pick and choose what drugs they want [to use]. If patients don't tolerate one combination of BRAF/MEK inhibitors, they know they also have another combination to look into.

What is the role of immunotherapy in this space as it compares with other cancers? Could you discuss the importance of the CheckMate-067 trial?

[I have been a] melanoma doctor for 20 years, [and I can tell you] we certainly know that chemotherapy is not the drug of choice for this type of cancer. We have been very fortunate to be able to harness a patient's immune system to attack the disease. Immunotherapy really is among the premier therapies that we have been able to exploit over the past 10 years to [improve] patient survival.

Whether [a patient receives] a BRAF inhibitor or does not, immunotherapy is clearly a choice because we know that even patients who have a BRAF mutation can respond just as well to [this approach] as those who do not have the mutation. As such, this [strategy] has really become the cornerstone of melanoma therapy. We're looking to build on [the success that we have seen] to make responses even better so that we can cure more patients. I never thought I would say the words "cure" and "melanoma" in the same sentence, but many of us are getting very confident that we are now curing patients.

CheckMate-067 was a randomized, phase III trial comparing ipilimumab (Yervoy) plus nivolumab (Opdivo) with ipilimumab alone and nivolumab alone. Ipilimumab was the first immunotherapy to receive approval in 2011; it's a CTLA-4 inhibitor. The drug has a lot of toxicity, but it was all we had for several years. Then, the PD-1 inhibitors came along and clearly supplanted anti—CTLA-4 therapy. [PD-1 agents] are more effective and they have less toxicity.

The CheckMate-067 trial essentially asks the question, "If we take 2 drugs that we know are effective and put them together, are their effects synergistic?" And the answer is, "Yes." We were very pleasantly surprised to move that survival needle in melanoma up to about 50%. If you think about it, only about 15 years ago, our survival [rate] was about 5% for patients with stage IV disease. Now, we're somewhere between a 50% and 60% survival rate, which is really exciting. It was this trial that gave immunotherapy a strong foothold as the cornerstone of how to move forward and [improve outcomes in] our patients.

You mentioned that one of the questions with immunotherapy is determining the appropriate dosing for these agents. What did the CheckMate-511 trial show? How might those insights be applied to practice?

CheckMate-511 essentially [looked at] the building blocks of the combination of ipilimumab and nivolumab. When [giving the combination] at a standard dose, you give a higher dose of ipilimumab at 3 mg/kg and nivolumab at 1 mg/kg. If you treat patients with that combination, you get a very high response rate—about 50% or a little bit higher. However, you also incur a 50% toxicity rate, which is pretty significant because we're not just talking about grade 1/2 toxicities. We're talking grade 3/4 toxicities, so patients can get pretty sick.

What the CheckMate-511 trial did was look at what we call a “flip dose” of ipilimumab/nivolumab. Rather than giving standard-dose ipilimumab, we gave nivolumab at 3 mg/kg and low-dose ipilimumab at 1 mg/kg. The results were comparable with [those of standard-dose] nivolumab /ipilimumab. Again, [we saw] about a 50% response rate, but the toxicity was dramatically better. [These data are] still very early, but they are intriguing. We'll have to see if responses remain durable. [Regardless], it's very exciting information for the simple reason that if this shows that the durability and the responses are exactly the same, whereas the toxicity is so much better, there's just no question as to what the preferred mode of therapy would be: It would be “flip dose.”

What is your take-home message regarding metastatic melanoma treatment?

Clinical trials are still the first choice when it comes to treating a patient with melanoma because [a] 50% [survival rate] does not equate to an 100% cure. When we can take 100% of our patients and tell them that we can [eliminate] their disease, then we won't have to do clinical trials anymore. Most of the trials that are out there take the staples [of treatment], which is either immunotherapy or combination targeted therapies, and build on them. Some trials even take targeted therapies and add immunotherapy to [those agents].

I'm still a staunch believer that clinical trials are the gold standard for how to treat patients with metastatic melanoma. However, if patients are not eligible for a trial, or no trials are available for those patients, then you clearly have the decision of single-agent immunotherapy with a PD-1 inhibitor, or combination immunotherapy. Do you give the combination at standard dose? Do you give the combination at “flip dose?” If the patient has very aggressive disease and harbors a BRAF mutation, do you start out with targeted therapy? What do we do with those targets? Do we add immunotherapy? So many questions need to be answered, which is why clinical trials are so important. If you can get your patient onto a study, we can get these answers that much faster and make a difference for more patients with this disease.