Recently, the FDA approved the combination of relatlimab plus nivolumab for patients with unresectable or metastatic melanoma. However, many challenges remain in the selection of patients who will benefit from these agents and in determining alternative options for those who are ineligible for the combination. In this interview in honor of Melanoma Awareness Month, Dr. Benjamin Izar discusses the risk-benefit balance of immunotherapy selection and offers advice for clinicians in how to choose the optimal treatment for their patients with melanoma.

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today in honor of Melanoma Awareness Month, I'm joined by Dr. Benjamin Izar, who is here to discuss the recent approval of relatlimab plus nivolumab for unresectable or metastatic melanoma. Thank you so much for joining us.

Benjamin Izar, MD: Thanks for having me. I'm a medical oncologist at Columbia University Irving Cancer Center, and I'm specialized in the treatment of patients with melanoma. This includes patients with cutaneous melanomas and patients with the more rare subtype of mucosal melanoma. I have a particular interest in understanding the molecular underpinnings of immunotherapy response and resistance. I run a research lab that is a molecular and computational biology lab to address some of these questions.

Oncology Data Advisor: Great, thank you. So by way of background, what are some of the most challenging aspects of treating patients with unresectable or metastatic melanoma?

Dr. Izar: Upfront, I think that one of the most difficult populations that we deal with are patients who present with or who develop metastasis of the brain. The brain is a very tricky organ in that it sits in a very confined space in the skull and there's no room for expansion. Once there's disease in the brain, which is very common in patients with metastatic melanoma, that requires clinical action. These patients tend to have worse clinical issues; they develop seizures, headaches, trouble with their vision, paralysis of their limbs. Unfortunately, most drugs that work really well in patients without brain metastases (mets) work less well in these patients. This includes almost everything that we currently have in our arsenal, including immunotherapy.

This is based on my experience in the real world—in clinical trials, the data may look a bit more promising because these patients are highly selected. But in reality, most patients wouldn't qualify for those studies and therefore are less likely to respond to most of the drugs we have. The second problem with this population of patients, those with active brain metastasis, is the fact that they are excluded from the vast majority of clinical trials and therefore may not have the potential benefit from novel therapeutic developments.

The second emerging problem that we are seeing more and more now is related to recent therapeutic developments. This is the fact that we give immunotherapies more and more in the adjuvant setting—meaning that patients with limited disease get their tumor resected and then they go on to receive, say, a year of immunotherapy, either nivolumab or pembrolizumab. The problem that we are encountering now is that many of these patients that have disease recurrence while on that therapy usually recur with very limited disease, so it's only one or two metastatic sites. It's really unclear what to do with them because, theoretically, one could treat them with aggressive combination immunotherapy. The issue with the latter is such combinations can be very toxic.

On the flip side, the less invasive approach in this case would be surgical resection of those one or two lesions, sometimes multiple resection, which is a very reasonable approach; but it only controls that one disease site, not potential other microscopic disease. The problem is that many of those patients, once they have a first recurrence, tend to have another recurrence. Thus, systemic therapy may provide benefit, yet it has been proven to us that the single-agent programmed cell death protein (PD-1) therapy or immunotherapy was not sufficient to control their disease. Therefore, it is unclear whether potentially repeated surgeries or potentially toxic therapies are the right answer for these patients, but I believe we will see more novel therapies and trials in this space to address these questions.

Oncology Data Advisor: Thank you. So in light of this recent approval of relatlimab plus nivolumab, how does this impact the treatment landscape for these patients?

Dr. Izar: That's a very, very good question, and I'm sure that if you ask two people, you might get three different opinions. This combination was tested in patients with metastatic melanoma who do not have brain mets, so this is an important group of patients who were excluded from that study. The study was positive in the sense that it improved progression-free survival compared with patients who were receiving monotherapy with nivolumab. As we have learned with other immunotherapies, we really need to learn what the long-term outcomes will be for these patients and whether this combination will, in fact, prolong survival of patients with longer follow-up data. Interestingly, this study is that it was initially designed to understand whether patients who have expression of lymphocyte activation gene 3 (LAG-3), which is the target of relatlimab, will have a better response—so is the presence of this target important and a priority? One would think that the answer would be yes, but in the trial, presence of the biomarker was not associated response.

If we think about the spectrum of patients with metastatic melanoma, even within patients with metastatic disease, one can stratify different risk categories. On the one end of the extreme, the worst-risk patients are patients with multiple concurrent metastatic sites. These patients have more than three organs involved by the metastatic melanoma, and they may also have another negative prognostic marker—a high level of lactate dehydrogenase (LDH), which is marker of disease burden of melanoma in some patients. Furthermore, I would put in that category any patient who presents with more than a single brain met that is large in size. Further along this spectrum are patients with bulky involvement of the liver another poor predictor for response to immunotherapies. If we go along that spectrum, we will find on the other end "lower-risk" patients who have just a single site of metastasis— for example, a single lung metastasis.

Patients who have high-risk disease should really be treated with the most aggressive combination—if they can tolerate it and there's no contraindication—with a combination of ipilimumab (ipi) and nivolumab (nivo), and they should be treated with the full dose. There's also data on so-called flipped dosing, where a lower dose of ipi is given and a higher dose of nivolumab is given to spare toxicity, but this is again not tested in patients with brain metastasis. Then for patients with slightly lower risk, one can consider giving the flip dose if there's a concern for significant risk of toxicity.

On the other end of the spectrum, patients in the low-risk group can do really well with single agent PD-1 and will have pretty low rates of serious toxicities. So we're slicing the pie quite a bit when it comes to where we will fit the relatlimab (rela) combo in this. I suspect that patients who are perhaps older, who might have contraindications for getting the most aggressive therapy of ipi and nivo, and who might be on the higher-risk side might be patients who I could see getting the combo. On the other end of the spectrum, I think it's really a conversation to have. I do think that more patients who could probably get away with single agent PD-1 will want to have this conversation about perhaps thinking about the combo. In particular on the lower-risk end, this is a conversation that will happen with patients when I can see that there is a good reason to give them combo in some instances, or when patients might prefer a slightly more aggressive approach with combination. I can also see that the rela combo could be used in that cohort that I mentioned in the introduction: the patients who progress in the adjuvant setting on a single agent PD-1. They have low-volume disease, and maybe you don't want to do serial surgical resections, but you also don't want to go all in with ipi/nivo. For patients in that context, that would be a reasonable cohort to consider the new rela combo.

So I think it will have a role across the spectrum of melanoma, but I think there will be much more nuanced conversations about risk-benefit balances for these patients. The other thing that should be mentioned is that the study, fortunately, included some rare subtypes of melanoma such as mucosal melanoma and acral melanoma. Generally speaking, although the data is not very good, these tend to have a lower response to immunotherapies and having additional options is helpful.

Oncology Data Advisor: Thank you. That was an awesome overview of all the considerations. So looking ahead, is there any additional research in targeting LAG-3, and how do you think this will continue to impact the field in the future?

Dr. Izar: I think there are two questions that we as a community will have to ask about this combination. They both relate to the points that I raised earlier. First, is this combination effective in patients with brain mets? This cohort is difficult to study in a clinical trial. The way they've been studied in the past is by limiting it to patients who are asymptomatic, who have a small number of brain mets (three or less), and who have lesions that are relatively small. In terms of the study design, one can imagine that the new combination has to be compared with existing therapies (such as ipi/nivo), but that would be a very high bar and would likely require a large number of patients. One possible avenue would be a triple combination (such as ipi/nivo/rela) compared with dual combinations. A key consideration there is, of course, the potential added toxicity from giving more drug.

One study that I would also like to see is in that second population that I mentioned, where we might be able to prevent patients from going through serial surgeries, avoiding the toxicities of ipi/nivo, would be asking whether in this context—in the post–PD-1 or the on PD-1 failure in the adjuvant setting—whether the combination could rescue some of those patients either in combination with surgery or without surgery altogether. These are areas where I hope there will be some activity with respect to prospective trials.

Oncology Data Advisor: Great, thank you. In light of all these considerations and these future directions, do you have any words of advice for members of the care team who are managing these patients?

Dr. Izar: The care of these patients has become more and more complex, and this is out of an abundance of options, which is positive. There are a couple of strong pieces of advice that I feel very comfortable giving. Perhaps the most important one is that patients with brain mets should get ipi/nivo unless there is an absolute contraindication, because these patients, if not treated properly, have a very high chance of dying from those brain mets. Once the brain is involved, that takes precedence over other organs that we can handle in other ways. Ideally, these patients should be treated by a multidisciplinary team of neurosurgeons, neuro-oncologists, radiation oncologists, and medical oncologists. At Columbia University Medical Center (CUMC), we have a weekly brain metastasis conference with those members, discussing the best course of action for each individual patient. This includes, of course, patients with brain metastasis from other cancers and also primary brain tumors.

Another strong recommendation that I would give out is giving ipi/nivo upfront. I would also consider that in patients with high disease burden who have involvement of the brain or the liver and who have a high LDH, which usually involves people with multiple concurrent metastatic sites, if the patient does not have a BRAF mutation. Sometimes in that context, when there's very rapidly evolving disease that is difficult to control with the pharmacodynamics of immunotherapy, in this instance, one can consider instead doing a BRAF/MEK inhibition.

Apart from this, giving immunotherapy upfront for almost every patient over targeted therapy, given the recent data that has emerged from the recent DREAMseq study. This study tested what was the best first-line therapy for patients with BRAF-mutated melanoma: BRAF/MEK inhibition versus immunotherapy first, and then switching to the other regimen if there was disease progression. What emerges from this study is that patients getting immunotherapy first fare better long term; importantly, patients with initial immunotherapy who progressed had the same rate of benefit from subsequent BRAF/MEK inhibition, while patients who progressed through upfront BRAF/MEK inhibition had a lower response to subsequent immunotherapy compared with the upfront Immunotherapy response rates.

Ultimately, our role is to educate patients about all of these options based on their unique disease and individual risks for toxicities.

Oncology Data Advisor: This is all really important, valuable advice. Thank you so much for sharing it with us.

For More Information

Tawbi HA, Schadendorf D, Lipson EJ, et al (2022). Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med, 384:2394-2405. DOI:10.1056/NEJMoa2109970

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.