Truong Factors Age and High-Grade Toxicity Risk Into IO Selection in Melanoma

EVENT REGION Illinois, Minnesota, Nebraska, Wisconsin

PARTICIPANT LIST Sakeer Hussain, MD | David A. Potter, MD, PhD | Yan Ji, MD | Bety Ciobanu, MD | Rabih Fahed, MD | Nirav Patel, MD

Thach-Giao Truong, MD

MODERATOR

Medical Director, Melanoma Program

Cleveland Clinic

Cleveland, OH

HUSSAIN: He’s 78, and he has pul-monary and hepatic metastasis, so I would see whether he would be able to tolerate a dual immune checkpoint inhibitor such as ipilimumab [Yervoy] plus nivolumab [Opdivo], but if I can’t, I would probably go with nivolumab/ relatlimab [Opdualag]. Otherwise, I’ll choose a single agent.

POTTER: The elevated LDH and extensive visceral metastases [influence the choice].

JI: I [chose] nivolumab/relatlimab. I think the response rate is similar to ipilimumab/nivolumab, and the grade 3 toxicity is much less. With ipilimumab/ nivolumab, we expect 60% grade 3 toxicity.¹ It’s only about 20% [with nivolumab/relatlimab], and that would be my choice.² The only time I think I may consider doing ipilimumab/nivolumab is for those patients with brain metastasis.

TRUONG: Yes, this patient had a lot of disease, but they didn’t have a lot of symptoms, and so given the comparable response rates and better toxicity profile, that’s how you made your choice. All those choices in the poll are the category 1 choices from the NCCN guidelines.³ They included pembrolizumab [Keytruda] plus low-dose ipilimumab, and that’s category 2B because it’s not a formal FDA approval. Those were data that were shared in a larger phase 2 setting, and there wasn’t a formal phase 3 trial that evaluated that combination.

Monotherapy is still listed as a category 1, even though the combinations are stated as preferred. I would interpret that to say that that’s just the way the registration reads. They all have phase 3 data supporting their use. The patient selection for each of these then becomes more nuanced.

Are there patients for whom you are still recommending first-line monotherapy?

CIOBANU: Currently, I have a patient on a single-agent pembrolizumab who is aged 98 with some age-appropriate comorbidities, dementia that presented with isolated large occipital adenopathy, which, on biopsy, was proven to be a melanoma. Otherwise, he did not have any other sites of disease, so he was not a candidate for surgery. Given his age and comorbidities and a very minimal burden of disease, I decided to go with pembrolizumab. After a few months, he developed another adenopathy…and we continued the treatment, and eventually that disappeared, and the original one also almost disappeared [after more than] a year in treatment.

TRUONG: I would agree. That is one of the reasons it’s still category 1. There are patients for whom, if you want to avoid toxicity, the single agent has the lowest toxicity, and the absolute response rate without intertrial comparison is about 40% on those trials, so that is not unreasonable.

HUSSAIN: The last patient I saw had stage IV metastatic melanoma and was relapsed after 20 or 22 years with bone-only metastasis. [However,] she lives 70 miles away from where I practice, is more than 80 years old, and transportation is an issue, so I give her only a single agent because of the toxicity and [how she does not have] access to the office all the time.

FAHED: I do not use a single agent. I think RELATIVITY-047 [NCT03470922] has shown that dual therapy is becoming the standard of care. [It has a] similar toxicity profile and more efficacy. I’m happy with the nivolumab/relatlimab schedule of every 4 weeks, and I rarely ever use a single-agent IO [immunotherapy].

PATEL: For me, single agent is for if the patient has a lot of comorbidities and for older patients. With a single agent, I lean more toward pembrolizumab than nivolumab. I think the adverse event profile [or] the length of experience [makes me] more comfortable using pembrolizumab.

TRUONG: Does anyone think of the interval as part of your decision there?

PATEL: If somebody is not able to come [to the office] more frequently and requests a longer duration, then I [have used] 6-week dosing of pembrolizumab at 400 mg instead of 200 mg, and it has worked well so far.

DISCUSSION QUESTIONS

• Discuss your comfort level in managing immune-related adverse events in the setting of metastatic melanoma.
• To what extent does the ease or difficulty of managing potential toxicities factor into your recommendations?

TRUONG: There is efficacy that is balanced against toxicity. We’re most concerned about the grade 3 [or higher] toxicity rate because it can potentially be longer-term IO toxicities such as diabetes. Even with nivolumab/relatlimab, there is myocarditis, though the rate is low. We worry about these long-term toxicities and the acute hospital admissions from colitis or pneumonitis. CheckMate 067 [NCT01844505], the ipilimumab/ nivolumab regimen with high-dose ipilimumab, has the highest rate, which is a 55% rate of grade 3/4 toxicities,¹ whereas single-agent therapy is 10% [for pembrolizumab]⁴ and 16% [for nivolumab]¹ depending on the trial [Table 1⁵]. RELATIVITY-047 is a bit higher than single agent [21%], not necessarily higher compared with nivolumab, but potentially [higher] compared with pembrolizumab.²

TRUONG: We all know that there are toxicities. How is your comfort level in terms of managing immune-related adverse events? Many of you see other cancers. At this point, melanoma isn’t the only histology that uses immunotherapy. How do you feel about the issue of IO toxicity risk impacting your choice at this point?

CIOBANU: We’ve been using all these agents in other malignancies. I am relatively comfortable with immunotherapy. The ipilimumab/nivolumab combination in melanoma always gives me a little bit of trepidation, just because of the high doses of ipilimumab compared with the other malignancies, where we use a lower dose of ipilimumab. I understand that it’s probably the most efficacious regimen out of them, and we now have 10-year overall survival data for this combination.⁶ Whenever possible, for a younger patient with a more robust performance status, it will be the way to go, but a lot of our patients are older patients and have comorbidities and social issues. I think the combination of nivolumab/relatlimab is an option to rely on in other patients because, in the patients for whom we use ipilimumab/nivolumab, sometimes all you can get is 1 or 2 doses of ipilimumab. They have severe toxicities, and you have to discontinue the ipilimumab and continue with nivolumab alone. I don’t think there are too many patients who tolerate more than 4 doses of ipilimumab, if that.

TRUONG: Yes, I think only about half of the patients finished all 4 doses [in the] CheckMate 067 data. There is a higher grade 3 toxicity rate that’s pertinent for older patients. You could also argue that for younger patients, getting diabetes when you’re in your 20s or 30s is almost more devastating than in some of the patients who are older and who already have it. In a different context, with younger patients, the risk of fertility concerns is not well defined, [there are] quality of life issues if you get hypothyroidism or hypophysitis, and there is an impact on sexual function that is significant as well. It’s a significant consideration; nivolumab/relatlimab is offering a significant decrease in grade 3 toxicity.

[In terms of] tolerability and ease of toxicity mitigation/management, monotherapy is the easiest. For ipilimumab/ nivolumab in melanoma, the majority of people use the ipilimumab 3 mg/kg dose. The 1 mg/kg dose, which is also used in lung cancer or genitourinary cancers, is another option. Dr Ji mentioned that if she’s going to go for the higher-toxicity regimen, it’s usually because there is concern about the disease [with] brain metastases. In those settings, the 1 mg/kg ipilimumab/nivolumab dose wasn’t studied.⁷ The weighing of higher efficacy vs toxicity plays a role.

DISCUSSION QUESTIONS

• What efficacy and safety data stand out from the RELATIVITY-047 trial?
• How do you balance efficacy, safety, patient preferences, goals of therapy, and quality of life when recommending a first-line regimen?

TRUONG: What do you feel stands out to you when you look at the RELATIVITY-047 trial compared with CheckMate 067 and KEYNOTE-006 [NCT01866319]?

CIOBANU: [The choice is] between ipilimumab/nivolumab and nivolumab/relatlimab; most of us will feel more comfortable with nivolumab/relatlimab. In light of this regimen being quite tolerated and with a lower risk of grade 3 toxicity, only 21%, a little bit over the single agent, which is more in the 12% to 15% [range, we should] think about patient characteristics that will make you choose monotherapy instead of nivolumab/ relatlimab [Table 2⁸]. Compared with ipilimumab/nivolumab, the advantage is that we have 10-year overall survival data because this is the longest trial that we know, and we are still following these patients out.⁵ But otherwise, it’s equally effective and better tolerated. We’ll just have to see the duration and how this is going to compare with ipilimumab/nivolumab in the long term.

HUSSAIN: The data are compelling. The tolerability is a big thing when you compare it with ipilimumab/nivolumab unless the patient is very young and has brain metastasis or something, in which [case] you probably want to use ipilimumab/nivolumab.

POTTER: For the vast majority of patients, I would go with nivolumab/relatlimab. The question that comes up in my mind has to do with what you do with the young, fit patient in their 20s or 30s with elevated LDH and acral primary who is symptomatic and has M1c disease with liver metastases. Those are the patients for whom the decision-making is the most difficult.

TRUONG: Dr Ji, you were leaning toward nivolumab/relatlimab before, but you mentioned brain metastases. What are your reasons when you choose ipilimumab/nivolumab?

JI: I think now there are some brain metastasis data from nivolumab/relatlimab as well. But if you look at the intracranial activity, I still feel like ipilimumab/nivolumab gave the stronger data. I have a patient who had either multiple brain metastases or solitary brain metastasis…[with] no other site of disease, [and] we just kept the IO ongoing, and there has been no progression for the past year or 2. There is some very good evidence to support that use.

Are we going to see the same trend with nivolumab/ relatlimab? I think potentially we could. For me, I think it is a balance of efficacy and then toxicity. Both can cause severe toxicity. You never know when their AE [adverse event] is going to kick in. I’ve had some patients who had myasthenia gravis, and they [can only tell me] they feel tired and weak. When you suspect those unusual AEs—I have a patient with a pericardial effusion, a patient with septic meningitis—there are a lot of [unusual] AEs, and you just have to be cautious that when they have some unusual symptoms, [you] initiate the workup.

_{DISCLOSURE: None of the participants had known relevant disclosures.}

_REFERENCES

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