When is Nivolumab/Relatlimab Therapy Viable in BRAF+ Melanoma?

Clinicians discuss the best treatment options for a 46-year-old woman diagnosed with BRAF+ melanoma.

As treatment options evolve in the melanoma space and new data emerge regarding the use of PD-1 inhibitors or immunotherapy, the next question is, which patient population best suits them?

During a Meeting of the Minds panel, experts in melanoma gathered to discuss recent updates, including those from the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, the most prevalent of which was from the phase 2/3 RELATIVITY-047 trial (NCT03470922).¹ This assessed the use of nivolumab (Opdivo) plus relatlimab-rmbw (Opdualag) vs nivolumab alone in previously untreated metastatic or unresectable advanced melanoma.

To make the discussion more interactive, the panel began with a patient case of a 46-year-old woman who had been diagnosed with BRAF-positive melanoma. After reading through the case, the clinicians relied on updates from important trials to determine a treatment plan.

The panel was led by Michael A. Postow, MD, chief of the Melanoma Service and co-director of the Melanoma Disease Management Program. He was joined by Evan Lipson, MD, associate professor of oncology at Johns Hopkins Medicine; Hussein A. Tawbi, MD, PhD, professor, deputy chair, and director of Personalized Cancer Therapy in the Department of Melanoma at The University of Texas MD Anderson Cancer Center; Megan Schollenberger, MSN, CRNP, senior nurse practitioner in the Melanoma and Cancer Immunology Programs at Johns Hopkins School of Medicine; Kathleen Madden, FNP, MSN, AOCNP, APHN, nurse practitioner in the Melanoma Program at NYU Langone Pearlmutter Cancer Center; and Theresa Rodgers, MPAS, PA-C, physician’s assistant in Melanoma Medical Oncology at MD Anderson Cancer Center.

Patient Details: Sarah, 46-year-old female with metastatic BRAF-positive melanoma

• Primary melanoma: Right shoulder, 3.8 mm Breslow thickness with ulceration
• BRAF mutation: V600E-positive
• Disease burden: Multiple pulmonary nodules (largest, 4.2 cm), hepatic lesions, and extensive lymphadenopathy
• Performance status: ECOG 1
• Lactate dehydrogenase: 245 U/L (normal range)
• Prior treatment: None for metastatic disease

Treatment History:

• Diagnosed with Stage IV melanoma 2 months ago after progressive dyspnea
• CT imaging revealed extensive metastatic disease
• Molecular testing confirmed BRAF V600E mutation
• Currently evaluating first-line treatment options

Current Status:

• Symptomatic from disease burden (fatigue, mild dyspnea)
• Motivated for treatment, concerns about returning to work as an elementary school teacher
• Strong family support system
• No contraindications to immunotherapy or targeted therapy

Postow: When we’re thinking about this type of situation, and we see this type of patient in our clinic, many of the important parts of the clinical ascertainment of where we are have to [defer] to what disease symptoms this patient might have. This patient had some mild dyspnea related to the lung metastases and some fatigue. This young patient, who’s 46 years old and is on medical leave from her job as a teacher, is motivated for treatment, has some concerns about returning to work, has an excellent family support system, but is otherwise a healthy 46-year-old with BRAF mutant melanoma.

There are many different frontline options that one can think about, including the nivolumab plus relatlimab combination, the nivolumab plus ipilimumab [Yervoy] combination, and even BRAF and MEK-directed targeted therapy. This is a classic case that we might all have in our clinical practice—of a young patient with BRAF metastatic disease with symptoms. Dr Tawbi, I’d love to hear from you first, if you could walk us through some of the considerations with the nivolumab and relatlimab combination, including some discussion of the 4-year updates from the RELATIVITY-047 data that were presented at ASCO this year. How would that affect your approach to thinking about treatment for this patient?

Tawbi: This is a patient that we see very regularly. For patients who are treatment naive, we have the opportunity, now, to give them long-term outcomes with combination checkpoint inhibitors. For a long time, we had the combination of PD-1 and CTLA-4 that was improving the response rates for our patients and giving us a long-term benefit, but came at the risk of a high incidence of grade 3/4 toxicities. We always had to decide between the combination vs single agent PD-1, knowing that single agent PD-1 is highly effective and also can give long-term benefit, and we always had to think about trading off the clinical outcomes against the higher toxicity of combination immunotherapy. With the advent of LAG-3 blockade, which is done at this point, with relatlimab and nivolumab in combination with anti-PD-1 nivolumab, we got into a space where we may be able to get benefit at a lower rate of toxicity.

RELATIVITY-047 was the phase 2/3 clinical trial that was designed to compare the combination of nivolumab and relatlimab at 480 mg of nivolumab in combination with 160 mg of relatlimab given every 4 weeks, in comparison to single-agent nivolumab, and that study had already been reported. Even after the first 13 months of follow-up, we had seen a truly significant difference in the progression-free survival [PFS], which almost doubled compared with the single-agent PD-1. It improved the response rates by about 10% and it had what looked like a potential impact on overall survival.

Dr Lipson presented the original data that led to the FDA approval of this combination.² It’s a combination that we tried to use in the first line regularly. The important aspects were that nivolumab and relatlimab offered that additional benefit, that superiority over single agent PD-1, with about a 10% increase in the rate of grade 3/4 toxicity. It’s still a bit of a trade-off, but the benefit is quite significant compared with how much toxicity you have to pay. The other component was that we had the ipilimumab/nivolumab combination for a very long time. In fact, when we had reported the original data, there were already 5- and 7-year data from the phase 3 CheckMate 067 [NCT01844505] trial, so we knew that ipilimumab/nivolumab can give you long-term benefit.³ Nivolumab/relatlimab was still a [young] combination, and we’re still trying to understand its impact in the long term. This idea of being able to see whether the benefit that we saw after only 13 months of follow-up was maintained for a longer period of time is quite critical. Now that we have a 4-year median follow-up of exactly 45 months, one can look back and see whether the PFS remains that much better, whether the overall survival remains better, and whether the melanoma-specific survival is better.

In the publication for which Dr Lipson was the first author, we just showed that the 4-year data are very consistent. The PFS benefit remains solid, with about a 22% decrease in the risk of progression or death with an HR of .78. We still see an impact, translating into overall survival, as the HR is .77, and the confidence intervals around that do not cross 1, indicating that this may be a true benefit. We’ve become interested in melanoma-specific survival because our patients are an older population, and they can die of other causes, and that’s where you also see an impressive impact with nivolumab and relatlimab, with an HR of .72; the confidence interval does not cross 1, indicating that the benefit persists. The toxicity at 4 years does not look any worse than it was before.

Postow: This is great news for nivolumab and relatlimab, and it’s great to see those HRs remaining so favorable for PFS with longer follow-up. What would be your approach for patients with BRAF-mutant melanoma?

Tawbi: The phase 3 DREAMseq trial [NCT02224781], which took a long time to accrue and give us results, showed a clear difference in favor of starting with immunotherapy first. We had suspected, as melanoma oncologists, that that would be the answer because immunotherapy has been, historically, the one able to give us the long-term benefit. While we don’t have a direct comparison of starting with dabrafenib [Tafinlar]/trametinib [Mekinst] vs nivolumab/relatlimab, the clear message from DREAMseq is that checkpoint blockade gives you a better long-term outcome. When I’m deciding for my patients, the very simple decision is definitely immunotherapy first, and then I decide between the 2 combinations based on the discussions that we’re going to have even later. With ipilimumab/nivolumab, you have a higher response rate, it seems. That comes at the cost of a higher rate of grade 3/4 toxicity. Now, with nivolumab/relatlimab, we also have an improvement in PFS and objective response with lower toxicity.

We do not resort to single-agent PD-1 in a patient like this anymore because we have randomized evidence that combinations are better than single agents. That is not an option for this [patient], especially at 46 [years old]. We have to maximize our chances of survival, and I would not consider single-agent PD-1.

Postow: Dr Lipson, could you talk us through this indirect treatment comparison between nivolumab/relatlimab and ipilimumab/nivolumab? We don’t have a head-to-head randomized trial here, but there are a lot of efforts that try to look across these 2 different combination regimens when it’s time to think about frontline immune therapy.

Lipson: We don't have a direct head-to-head. That is what brought us to look at this indirect treatment comparison, and it’s what spurred a lot of the real-world comparison data that were presented at ASCO earlier this year. We took the 2 large studies, we took the RELATIVITY-047 study that Dr Tawbi just referred to, and we looked at all of [the patients] factors as they enrolled into the trial. We looked at the CheckMate 067 study, and we tried to compare the combination arms in each of those trials with each other, and we compared the nivolumab monotherapy arms in each of those trials with each other. What we saw was that when you use those weighted numbers and put the curves next to each other, for the most part, the curves were right on top of one another for the combination arms from each trial.

There are some caveats here, lots of them. The first is that when we were testing ipilimumab/nivolumab back in the day, there was no relatlimab/nivolumab, which means that if a patient progressed after ipilimumab/nivolumab, they did not have another combination therapy to fall back on, which is not true for the patients who participated in the RELATIVITY-047 trial. If they progressed on relatlimab/nivolumab, they did have a second combination to fall back on. If you look at the [weighted] melanoma-specific survival curves, what you’ll see is that the relatlimab/nivolumab curve is slightly above the ipilimumab/nivolumab curve. A lot of us suspect that that’s because, in the modern day, we now have 2 combinations to use, where back in the day, when we were testing at ipilimumab/nivolumab, we only had one. There were some caveats, just based on the time around which the trials were being conducted.

When you look at the curves on top of one another, it does give you some reassurance that both combinations are in the same ballpark. Regarding efficacy, we did something similar for toxicity, and the ipilimumab/nivolumab [therapy] seemed more toxic when we did the indirect treatment comparison than the relatlimab/nivolumab [therapy]. Relatlimab/nivolumab’s strength is that it is a dual therapy with just a slight increase in toxicity over nivolumab monotherapy.

Postow: Theresa, I’m curious what your impressions are when you’re thinking about first-line treatment options for patients like this 46-year-old patient who has symptoms related to metastatic melanoma but wants to be able to be with family and keep working as much as possible. How do you talk to patients about this treatment choice, with long-term outcomes, response rates, PFS end points, and overall survival, when they’re making the treatment decision?

Rodgers: When our patients come in, especially for a first-time visit, the first thing that they’re asking us is, “Can you get rid of this melanoma? Is there a potential for a cure? Is there a potential for survival? What are my rates of survival? What’s going to give me the best chance?” They also consider the adverse effects and toxicity, and their lifestyle. We go over all of that with our patients. When it comes to long-term survival vs those immediate response rates, we can dive into the different types of treatment and the ways they work. With the immediate response rates, we can talk about how, in the past, chemotherapy could work quickly, but that doesn’t mean it’s going to last a long time. You may see [the cancer] shrink, but then see progression relatively quickly. We also see that, with targeted therapy as well, sometimes it does work very fast, but then the tumors can outsmart that targeted therapy and progress or have some resistance to that treatment.

With immunotherapy, we talk about how it doesn’t attack those cancer cells directly like chemotherapy does, but that it’s working on your T cells to attack the tumor, and that by having the T cells work to kill the cancer, then that is where you get those long-term outcomes. I always say, “We’re training your immune system to attack your melanoma.”

Postow: Kathy, when you have patients like this 46 year old with a high disease burden and symptomatic disease, and you start one of these regimens like relatlimab/nivolumab or ipilimumab/nivolumab, how do you follow along, see how she’s doing, and try to feel out if we are getting a treatment response like Theresa was talking about, or if we are unfortunately having some disease progression?

Madden: I like to use analogies that people can relate to. I like to have these conversations with patients and their support [system] of people who were involved with their care. Usually, when setting up an expectation for response patterns, I will share with patients several different types of response patterns that could emerge. Things could start melting away. You could be feeling better relatively quickly. Things could get worse before they get better. Or things could get worse at any point in time. The main take home is to advise the team if there are any changes, especially if they’re more symptomatic, that are disruptive to performance status and everyday activities, and also questioning the patients when we’re with them in clinic and when we’re on the phone, [maintaining] continuity with that questioning so they’re having a mental checklist that goes through [their mind] when they’re having an experience. I’ll ask them [about their] energy level? What is it from 0 to 10? That way, they can benchmark these types of things for themselves, so they know to reach out if there is something that’s being impacted.

Postow: We’re getting more tools all the time to see how things are going. As you said, sometimes that close relationship with the patient, and just seeing how they’re doing and what they’re telling you, is more important than any information on the scan.

Megan, could you tell us about how you act as the quarterback for all these specialists, or how you handle things when you have a complex toxicity that [requires] a lot of hands on deck? How do you pilot a patient through that type of experience in your practice?

Schollenberger: I’ve had a lot of experience over the past decade coordinating with specialists for immunotherapy toxicities, and I have tried to develop a relationship. I know our rheumatologist, our endocrinologist, and our gastroenterologist. I email back and forth with them. I use them as resources, all while quarterbacking the patient’s care, as you said, so when I have a patient with colitis, I use my gastroenterologist as a resource, but I remain involved in the patient’s care. I’m often the one who orders the steroids. I am the provider who is ordering the biologics like infliximab [Remicade] and vedolizumab [Entyvio], under the guidance of our gastroenterologist. I’m still owning their adverse effects and managing their care, but I have made sure to develop relationships with all our specialists.

References

1. Schadendorf D, Tawbi HA, Lipson EJ, et al. Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: an updated indirect treatment comparison (ITC) with 4-year follow-up data. J Clin Oncol. 2025;43(suppl 16):9554. doi:10.1200/JCO.2025.43.16_suppl.9554
2. FDA approves Opdualag for unresectable or metastatic melanoma. News release. FDA. March 18, 2022. Accessed September 11, 2025. https://tinyurl.com/sdtudr5p
3. Bristol Myers Squibb presents landmark 10-year follow-up data from CheckMate -067 which showed continued durable long-term survival benefit with Opdivo® plus Yervoy® in advanced melanoma. News release. Bristol Myers Squibb. September 15, 2024. Accessed September 11, 2025. https://tinyurl.com/5cjxhmmk