Experience Shapes Use of Dual Immunotherapy in Advanced Melanoma

Michael B. Atkins, MD

Deputy Director, Georgetown Lombardi Comprehensive Cancer Center

The Scholl Professor & Vice Chair, Department of Medical Oncology

Georgetown University

Washington, DC

DISCUSSION QUESTION

• Have you had the opportunity to use nivolumab plus relatlimab (Opdualag) in patients with advanced melanoma?

ANKIT MANGLA, MD: It was pretty smooth immunotherapy for a dual checkpoint inhibition. There weren’t many adverse events [AEs]; maybe grade 1 skin rash. I’ve not used it very commonly, but I’ve probably had 3 or 4 patients on it and not [seen] more than that. It’s not the rough course we sometimes see with the ipilimumab [Yervoy] at 3 mg and nivolumab [Opdivo] at 1 mg. Fatigue is common…but apart from that, so far, we have not had a grade 3 or grade 4 event. But our experience is only with 3 to 4 patients; we have not used it that much.

MARK MARINELLA, MD: The last time I used it for stage IV melanoma in an older patient, I had to stop it because he got bad pemphigus.

MICHAEL B. ATKINS, MD: So you’ve seen some toxicities. For those of you haven’t used it, what are your perceptions?

TARAL PATEL, MD: This regimen does not help me because compared with single agent, it is a doublet, [and in most cases we already are] using doublet. If you want to compare whether this is better than ipilimumab/nivolumab, I will change my mind if we see it. The other problem is the way the company…combined [nivolumab and relatlimab] together. [Patients] never get a single agent, and there are toxicities including myocarditis.¹ It’s not as benign as we think. That’s why I’m not going to use it until I see it is better than ipilimumab plus nivolumab. We have plenty of experience with ipilimumab/nivolumab, so why change it unless it shows something better?

XUAN HUANG, MD: I would use it if I had an appropriate patient. I think [that would be those patients in whom] I previously would use monotherapy for based on performance status. I probably will consider doublet with relatlimab [for them].

DISCUSSION QUESTIONS

• For which patients do you recommend first-line immune checkpoint inhibitor (ICI) monotherapy?
• For which patients do you recommend a first-line dual ICI?

ATKINS: [Which are the] patients where you might give nivolumab/relatlimab instead of nivolumab/ipilimumab?

HUANG: In somebody with a good performance status I would still prefer to use nivolumab and ipilimumab. In somebody I think would have a hard time tolerating ipilimumab, I would probably try the relatlimab.

ARUN KUMAR, MD: If I had to use doublet, I would probably use ipilimumab/nivolumab. Otherwise, I would use a single agent.

ATKINS: So you would give a single agent rather than nivolumab/relatlimab to a patient who couldn’t tolerate, or you think might not tolerate, nivolumab/ipilimumab?

KUMAR: That’s what I’ve been doing, yes.

MANGLA: We have used nivolumab/relatlimab in patients where we had encountered autoimmune diseases, like patients who had psoriasis requiring immunosuppression or rheumatoid arthritis requiring mild immunosuppression, not with biologics, but maybe with hydroxychloroquine or methotrexate. Those are the patients [where] I feel very challenged to give an anti–CTLA-4, but I don’t want to give a monotherapy to the patient considering their tumor load. Those are the patients [in whom] I prefer to giving anti–LAG-3 and anti–PD-1.

ATKINS: To paraphrase that, those might be the population that you used to give monotherapy to. Now you would give nivolumab/relatlimab.

MANGLA: Yes, that’s correct.

DISCUSSION QUESTIONS

• Discuss your comfort level in managing immune-related AEs in the setting of metastatic melanoma. How has this changed over time? ​
• To what extent does ease/difficulty of managing potential toxicities factor into your recommendations, and how has this changed over time?

EVAN LANG, MD: There are certain immune-related AEs we feel comfortable managing, like hypothyroid issues and skin rashes. But I think there are some AEs that can be difficult to manage, for example, immune-related colitis, diarrhea, or pneumonitis, depending on the degree. If it’s severe, then it’s hard to manage, and they can go on for a long time after you stop medication. Sometimes that can be challenging. Some AEs can be easily managed, but some can be difficult and sometimes we have to discontinue the therapy.

ATKINS: Has your comfort with this changed over time?

LANG: I feel more comfortable because I’m not just treating melanoma. We use immunotherapies for all kinds of malignancies now, so I feel comfortable in managing those AEs.

ATKINS: How would you rate the various therapies [in terms of toxicity]?

PATEL: Single-agent nivolumab is in my opinion is 9 [out of 10], and the combination is about 7. I have no experience with relatlimab so I cannot comment on that.

ATKINS: So you’re using 10 as the has the maximum ease, so you’re pretty comfortable with managing nivolumab/ipilimumab?

PATEL: Yes, we’re using it for a lot of other [disease types] especially renal cell carcinoma, so we have extensive experience.

HUANG: It’s hard for me to answer this question because it depends on what the toxicities are. If it’s just hypothyroidism, I can easily supplement, or with hepatitis I can hold therapy. I had experience with a 84-year-old patient with ipilimumab/nivolumab…[who] ended up having a terrible colitis and was in the hospital for a long period of time for colitis. It took her months to recover. In that case, I managed the colitis, but the damage was already there. It took time for her to recover and eventually she decided not to go with the additional therapy, and she passed away. That was a lesson I learned. I have to carefully select a patient who could be a possible candidate.… Another case we [could] get is encephalopathy; that’s another disaster.

PATEL: Single-agent pembrolizumab can cause colitis and single-agent nivolumab can cause encephalitis. This is immunotherapy. We’re going to see the toxicity if we use it enough. I’m using low-dose ipilimumab, and they’re tolerating it much better than 3 mg.

ATKINS: We didn’t go into that but for when you [previously said you would use] nivolumab/ipilimumab for a patient, were you talking about nivolumab 3 mg and ipilimumab 1 mg—the kidney cancer dose, as opposed to the melanoma dose?

PATEL: That’s correct.

MANGLA: In my clinic, we mostly see melanomas. We are purists in that sense, so we go with ipilimumab 3 mg, nivolumab 1 mg. Toxicities are part of our practice. Our comfort level is pretty good even with ipilimumab 3 mg. In most other diseases we either are giving immunotherapy in combination with chemotherapy or using ipilimumab 1 mg. There are very few other disease indications that use ipilimumab 3 mg, nivolumab 1 mg. Ipilimumab 3 mg is not that commonly used outside of melanoma and not in association with chemotherapy, so I feel like chemotherapy [affects] these toxicities in some of these patients when they get along with immunotherapy because they get steroids along with it.

But we give anti–CTLA-4 and anti–PD-1 with no blanket of steroids or anything. We see a lot of toxicities and we are comfortable with them. As time has progressed, new drugs have come in, new biologics have come in, and tocilizumab [Actemra] has come in; all these things have helped our practice a lot. We are moving away from steroids [to] using biologics and these other stronger medicines to control [or] reduce the timeline of AEs. Colitis does not have to linger on for 4 to 6 weeks. Now it can be potentially resolved in 7 days if we if we bring in infliximab [Remicade] or biologics early.

_Reference:

_{1. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34. doi:10.1056/NEJMoa2109970}