Dr Omid Hamid on Choosing Targeted Therapy in Advanced Melanoma

Omid A. Hamid, MD, spoke with The American Journal of Managed Care® (AJMC®) about evaluating patients with advanced melanoma for targeted treatment options, including understanding toxicity risks, deciding who would be candidates for immune checkpoint inhibitors, what to do when immunotherapy cannot be tolerated, and more.

He is the chief of Translational Research and Immunotherapy, director, Melanoma Therapeutics, The Angeles Clinic and Research Institute.

AJMC®: Risk of toxicity is a major consideration for patients with resected stage III melanoma. How do you evaluate if the patient should receive adjuvant therapy?

Hamid: Yes, very interesting question. The adjuvant discussion is one that we've not had before and are fortunate to have now, not only in our stage III patients, but if you have looked at the KEYNOTE 716 data, you realize that the FDA has just approved it for high-risk stage II patients also. Ultimately, the concerns are similar to the concerns we have with other cancers where adjuvant therapy is an option, like breast cancer. There is a subset of patients who can recur, and we know that these drugs have benefit in recurrence-free survival for these patients, but we don't know which ones they are. Clearly, in my experience, I've had patients with high-risk melanoma who have not gone onto adjuvant therapy and have never recurred. So, the discussion for treatment, whether it's with a BRAF targeted therapy or an immunotherapy with checkpoint inhibition with [programmed cell death ligand 1 inhibitor] PD-1 inhibitors, is a long one, and it usually takes a couple of visits for me.

What you’re offering them is a benefit. You don’t know who’s going to get that benefit or not, and there’s toxicity. So, we have an extensive discussion about those toxicities. If they are BRAF mutated as half of cutaneous melanoma patients are, we talk about the BRAF inhibitors. Their toxicity is in the majority of times reversible. And what is it? There can be some cardiac toxicity with QT interval changes or changes in the ejection fraction of the heart. The BRAF inhibitors can cause rash, joint aches, fevers. Those can be managed. The BRAF inhibitors, along with the MEK inhibitors together, can cause bleeding or clotting, visual changes such as uveitis, which is reversible with the BRAF inhibitor, and fluid under the retina, which is reversible with the MEK inhibitor, but also there's a very small risk of a retinal vein occlusion, which is irreversible, so a change in vision. You can have interstitial lung disease with the MEK inhibitors. We go through each one of them and discuss how we would take care of them and the symptomatology.

Communication is very much key here. And for those people who think you can send someone away and bring them back every 6 weeks for therapy, it's difficult because some of these side effects are irreversible. When you talk with the immune therapies, they can have an effect on you long term. What that means is immune therapies can cause endocrine abnormalities where, in young patients, their thyroid would need to be replaced with thyroid medications, their adrenal glands, which they need for stressful situations, and there can be hormonal changes which may affect fertility. Again, the majority of immune-related events are manageable, but I’ve had patients who've had myasthenia gravis and patients who've had myocarditis, which brings us to the quandary of how we should be following these patients.

First of all, it's important to be able to understand the toxicities and how to identify them, not just as physicians, but as the nurses who see them, as our support staff who takes care of them, and to educate patients. For us, it’s an extensive discussion. For those patients who have a contraindication, we realize that we may need to hold the therapy for them.

AJMC®: Recent studies have examined the effects of immune checkpoint inhibitors like anti-CTLA-4, the anti-PD-1 antibodies in patients with advanced melanoma. Who would be considered strong candidates for immune checkpoint inhibitors?

Hamid: In advanced melanoma, I think you should begin with the thought that all patients are candidates for checkpoint inhibitors unless there's a contraindication. We have an embarrassment of riches where we've seen that these drugs, either alone or in combination, can affect the long-term survival of our patients. Just think about it. When I started my practice in the early 2000s, the median survival of someone with advanced melanoma was 6 to 8 months. And now we are on the precipice of a six-and-a-half-year median survival. We have unlocked the role of immunotherapy, not for every patient, but for a significant proportion of our patients. Not only does this help with overall survival, but also progression-free survival, which has a lot to do with the morbidity of this diagnosis. So, everyone is considered a strong candidate for immune checkpoint inhibitors.

It is that small subset where there is a contraindication: those patients who have had a transplant, those patients who have autoimmune disease, those patients who have a contraindication to an immunotherapy, who've had a diagnosis like lupus or myasthenia gravis in the past. What we have tried to do in very well-controlled trials is understand the risks to those patients. While most trials exclude those patients, the experience that's been presented from us and other institutes show that you can give this therapy to a small subset of patients. We don't have biomarkers on who really needs it and who doesn't. We can't say that because your PD-L1 is one way or another or because your tumor expresses this protein, you are going to do well, and the others don't.

So, we are giving it to the majority of our patients. If you have a contraindication, again, we have a long discussion about the morbidity and mortality of your diagnosis versus the risks of this treatment. Hopefully, there are other options for these patients: clinical trials, targeted agents. At times, we have to rely on the data we have with these patients. Who are these patients, those who have had toxicity already on these inhibitors? We know that the incidence of recrudescence is about 50%. Those who have an autoimmune disease, we know again about 50% of them have an exacerbation of their autoimmunity, those patients on transplant, that is beyond the scope of a small article or even one visit, an extended visits and extended discussions. Only through clarity of discussion and evaluation of risks do we move forward.

AJMC®: What are some treatment options for patients with advanced melanoma who cannot tolerate the immunotherapy option?

Hamid: Great question. What are some of the other options? Obviously, we've made great forays into targeted therapies for patients who have BRAF mutations. We don't ever underestimate the role of molecular of other mutations. Those patients get full next-generation sequencing over their tumors as other mutations like ERRB4 and RAS mutations and ALK mutations exist. There are other trials for patients who have genetic mutations that lead them to an ability to be treated with other drugs.

So BRCA mutations, ATM mutations, check 2 mutations are those that lent to a high mutational load and possibly benefits from [poly (ADP-ribose) polymerase] PARP inhibitor clinical trials. Now there is a subset of patients who have BRAF fusions or non-standard mutations and there are targets for those. NRAS mutations are about 20% of melanomas. We have been accruing to trials that block that pathway, so RAS inhibitors. What I mean to say is that that's not something a patient should really know, but their oncologists should request the next-generation sequencing and then seek the opinion of someone who has that expertise.

AJMC®: And what are the treatment options for patients with advanced melanoma with the BRAF mutation and how would the BRAF wild type affect treatment options?

Hamid: One of the first things that you should do for a patient who has metastatic melanoma is evaluate whether they hold that BRAF mutation, whether it's in the metastatic setting or the adjuvant setting, because that opens another set of options for them. The options are the FDA-approved combinations that are there for BRAF mutated agents, whether it's vemurafenib and cobimetinib, or dabrafenib and trametinib, or encorafenib and binimetinib. Those combinations have shown to have survival advantage for our patients and can deal with symptomatic rapidly growing disease. By virtue of having that BRAF mutation, you are then eligible for other treatments, other trials that target that mutation and that pathway.

Clearly, at this point, we have an understanding that dual checkpoint inhibition should be, for those patients who can tolerate it, the first-line therapy for BRAF mutant patients. That’s from the DREAMseq Trial, Michael Atkins and others. It was presented through [Eastern Cooperative Oncology Group] ECOG, but you do understand that despite the fact that you have immunotherapeutic combinations, you can utilize these targeted agents and these other set of clinical trials. For patients that are wild type then again, the treatments that begin with immune checkpoint inhibitors either with combination LAG-3 PD-1 combination, combination anti-CTLA-4 NTP1, or clinical trials. More treatment options are available for those patients. Those are the newer agents that we have by specific antibodies. We have adoptive T-cell therapies that are coming forward. We have other checkpoint inhibitors; we have local oncolytic and injectables. We have not run out of options, if you're BRAF wild type.

What I say to every patient and every physician is that when you have this idea that you have run out of options, you need to review the data and perhaps reach out for a consultation with a physician like myself, who has the expertise in the clinical trials. Understand that if you're a melanoma patient, there is comfort in knowing that a lot of these trials were begun in melanoma, showed benefit, and have gone on to show benefit in other solid tumors. There is a robust pipeline of options.

AJMC®: Well, like you just said, there’s a robust pipeline of options. How do you yourself sequence treatment options for patients with advanced melanoma?

Hamid: What we work hard to do is to understand the patient, their disease process. What that means is looking at their sequencing, understanding of what the pace of the growth of their disease is, and where the disease is located. Patients with melanoma have a high incidence of brain metastases, and therefore, we look forward to combinations that have shown benefit there. Patients who have low volume disease can be part of other trials. Those that have accessible tumors can be part of adoptive T cell therapies or also part of treatments with oncolytic therapies, which have shown benefit. What we always do is work in our initial consultations sequence. That does not mean you've shown up, here's your first option, and let's move on. We say, here's your first option; Here's what is standard now and what is available in our programs for you should this option not work for you. Understand that the current options lend to long-term survival and the significant proportion of those patients don't need any treatment beyond their first line of treatment.

AJMC®: You had mentioned that there has been a lot of progress with survival rates. So, although great progress has been made in patients with advanced melanoma have greater survival rates today than historically, what trials would you like to see conducted for patients with unresectable advanced melanoma?

Hamid: I'm going to turn that around and say we are conducting phenomenal significant paradigm-shifting trials right now in melanoma. What we've realized is adoptive T cell therapy has brought another treatment for our patients who don't respond to checkpoint inhibitors. What we're now doing is working to improve those T cells in many different ways: changing the T cell, changing what we give to activate the T cells. What I wanted to see last year at this time and is ongoing now are combinations with checkpoints and other T cell therapies. What I’ve wanted to see is the utilization of these therapies for patients with brain metastases that have been historically left out of these clinical trials. And now we do have those trials.

What I’d like to see more of is the ability to get patients onto these paradigm-shifting trials, these trials that have informed therapy for a host of our patients. When I get nostalgic and I think about when I started, the trials were few and far between. They took a long time to accrue, and they took a long time to get to the end-user, to our physicians and patients making decisions. That's not true in melanoma.

Now that survival has increased, that we have true collaborations between our pharmaceutical partners and our patients and our colleagues, you can get onto a trial and that trial can complete within a year or two, and that data can be available to patients during their journey. It does not take many, many years. So, these trials are being done. I find these combinatorial trials are interesting, utilizing them for patients with brain metastasis and moving them not only into those patients with the highest risk of disease, but also into the adjuvant setting. The recent approval of relatlimab nivolumab for advanced unresectable melanoma in 2022 has allowed us to utilize that combination in a clinical trial in the adjuvant setting. We are bringing that benefit into a greater proportion of our patients and earlier in their care journey.

AJMC®: Could you please provide any closing thoughts on disease management considerations for melanoma or actionable mutations for melanoma that you find noteworthy to share with your colleagues?

Hamid: Sure. I would say to you the following: we're continually making strides in our care of patients with advanced and unresectable melanoma. What we're now doing is working hard to understand how to best treat those subsets of melanoma that you hear less and less about—mucosal melanomas and acral melanomas. They have a lower response rate to checkpoint inhibitors, and we're looking at our data and finding better options. Ocular melanoma, which is completely different than the other melanomas. Ocular melanoma, for a long time, because of the fact that it didn't have a high mutational burden, was not responsive to immunotherapy. What we know now is that there is a drug that works for our patients with ocular melanoma. It’s called tebentafusp. It's a bispecific antibody, and it was just approved by the FDA. Those breakthroughs came through clinical trials, and what is very much interesting is now we're taking that drug tebentafusp and utilizing it for cutaneous melanoma. We're using that platform of bispecific immune targeted antibodies and utilizing other bispecifics for a multitude of solid tumors that has come through clinical trials. We have made breakthroughs in the management, in the adjuvant setting—that's early disease—and breakthroughs in the management of patients where we had never had breakthroughs: brain metastasis and the most advanced patients with leptomeningeal disease.

Over the last decade and a half, we have changed survival for our patients. Our patients have become advocates for their own health and their own benefit. In May of 2022, we're in the best position we have ever been with partners who believe in the clinical trial pathway in sequencing of tumors and utilizing molecular and immuno-therapeutics for the benefit of our patients.