Physicians Discuss Frontline Immunotherapies for Metastatic Melanoma


During a Targeted Oncology™ Case-Based Roundtable™ event, Evan J. Lipson, MD, and participants discussed factors influencing their choice of immunotherapy for a patient with BRAF-negative metastatic melanoma.

Lipson headshot

Evan J. Lipson, MD

Associate Professor of Oncology

Johns Hopkins Medicine

Baltimore, MD


A 73-year-old man with a history of stage III melanoma underwent surgical resection 12 years ago; his lymph node dissection (LND) was positive for nodal involvement. The patient declined complete LND and adjuvant systemic therapy. He remained active since his surgery and maintained regular follow-up appointments.

On routine follow-up, the patient presented with moderate asthenia that limited his daily activities. His ECOG performance status was 1, and his physical examination was unremarkable. Notable laboratory findings included lactate dehydrogenase (LDH) level of 380 U/L (reference range, 110-240 U/L). A full-body CT scan revealed pulmonary and hepatic nodules but no evidence of brain metastases. He underwent core-needle biopsy of the largest hepatic lesion in segment IVb without any complications. Pathology revealed metastatic melanoma.

What first-line therapy are you most likely to recommend for this patient with metastatic melanoma with no BRAF-activating mutation?

Nivolumab plus ipilimumab
Nivolumab plus relatlimab-rmbw
Pembrolizumab plus low-dose ipilimumab


  • What factors guide your choice of frontline therapy for this patient?

EVAN J. LIPSON, MD It looks like we have a pretty even split between nivolumab [Opdivo] plus ipilimumab [Yervoy] and pembrolizumab [Keytruda]. Dr Haake, tell me what guides your decision making here. What guides how you might make a choice for this patient frontline with visceral disease, no brain metastases?

SCOTT HAAKE, MD: I’m optimistic in this setting. I’m trying to get a deep, durable response. Based on what I’ve heard so far, I think he could tolerate multiple agents and so I’m leaning towards the data that I think are going to give me the deepest, most durable response possible.

LIPSON: So you’re thinking: he has visceral disease, an elevated LDH, and you might only have 1 opportunity to treat him because the disease could get bad quickly; already his performance status has declined, let’s give him dual therapy and be aggressive up front.

HAAKE: I think so, yes.

JIGAR SHAH, MD: I chose the ipilimumab/nivolumab because I’m trying to get as deep of a response as possible. And with that much of liver metastases, I may not have chance down the line, so I wanted to hit it hard up front.

VICTOR GIAN, MD: The nivolumab/relatlimab [Opdualag] is certainly great. But, just to clarify, isn’t the nivolumab/ipilimumab primarily better in patients with brain metastases? Single agent is the way I went [in this case].

LIPSON: That’s a great question. The data would suggest that in a patient with brain metastases, nivolumab/ipilimumab is our treatment of choice and it outperforms anti–PD-1 monotherapy.1 We don’t know the activity of nivolumab/relatlimab in patients with brain metastases. That trial is ongoing, but we don’t have a readout yet, so it could well be that we have activity, we just don’t know it.

LESTER PORTER, MD: I [would] change my choice to nivolumab with relatlimab.

LIPSON: What about this case made you say that?

PORTER: He does not have a brain metastasis… [but] he does have visceral involvement. He’s not that symptomatic, but I think the visceral involvement makes me want to give more than single [agent], and the relatlimab seems to add fewer adverse events.1,2 There may be a little higher response rate, so that’s why I was thinking toward that first line.1,3

LIPSON: Dr Gian, what made you vote for pembrolizumab?

GIAN: Primarily because the toxicity rate of double immunotherapy is fairly high in a relatively asymptomatic patient and he doesn’t have [brain metastases].1 That was the primary reason here.

LIPSON: I agree with you. There is a balance here between the likelihood of a bad toxicity versus giving somebody the extra boost of having 2 drugs on board versus 1. Nivolumab/relatlimab is perhaps somewhere in the middle on both of those. Toxicity is not quite what it is with nivolumab/ipilimumab but it’s higher than it is with PD-1 monotherapy.1-3 But, as we discussed a moment ago, we don’t yet know what the activity of nivolumab/relatlimab is in patients with brain metastases. In this patient in particular, we don’t have that issue because we didn’t see any brain metastases. So here we might split the uprights and use nivolumab/relatlimab because we’re trying to give him the benefit of an increased progression-free survival but also not turn up the heat quite so bad for fear of bad toxicity.


1. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. J Clin Oncol. 2022;40(2):127-137. doi:10.1200/JCO.21.02229

2. 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

3. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-2532. doi:10.1056/NEJMoa1503093

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