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New Standards of Care for Melanoma

JHOP - June 2022 Vol 12, No 3 - NCCN Highlights, Melanoma

Genevieve Boland, MD, PhD, Section Head, Melanoma/Sarcoma Surgery, Massachusetts General Hospital Cancer Center, Boston, discussed emerging standards in the treatment of melanoma during the 2022 NCCN conference.

Relatlimab plus nivolumab represents a new standard of care that should replace monotherapy with a PD-1 inhibitor in the treatment of advanced melanoma, Dr Boland said. Relatlimab, a novel antibody that blocks LAG-3, plus the PD-1 inhibitor nivolumab showed an improvement in median progression-free survival (PFS) versus nivolumab alone (10.12 months vs 4.63 months, respectively; P = .0055) in the RELATIVITY-047 study of patients with untreated stage III or IV melanoma, with PFS that favored the combination across the key prespecified subgroups. The safety profile of this combination was also more manageable than with the PD-1 inhibitor alone.

Based on these data, the combination of relatlimab plus nivolumab was approved by the FDA in March 2022 for the treatment of unresectable or metastatic melanoma in patients aged ≥12 years.

Although relatlimab plus nivolumab can be considered the new standard treatment for advanced melanoma, some patients may not be ideal candidates for this combination, including patients with rapidly progressing disease and high levels of lactate dehydrogenase, those with liver and bone metastases, and patients with bulky disease, who may fare better on the combination of ipilimumab plus nivolumab; patients whose disease progresses after receiving adjuvant anti–PD-1 therapy; and those with severe autoimmune disease.

The optimal sequencing of therapies is also under investigation. Nivolumab plus ipilimumab followed by dabrafenib plus trametinib is associated with increased overall survival at 2 years and likely beyond, and with more durable responses compared with the converse, Dr Boland said.

In patients with melanoma and BRAF mutation, nivolumab plus ipilimumab, followed by a BRAF and MEK inhibitor therapy if necessary, should be the preferred treatment sequence.

Systemic Neoadjuvant Treatment for Resectable Melanoma

The goal of systemic neoadjuvant treatment is to reduce the risk for disease relapse and mortality by targeting residual micrometastatic disease. Recent therapies (ie, BRAF inhibitors, MEK inhibitors, PD-1 inhibitors, and CTLA-4 inhibitors) have translated into a marked survival advantage in metastatic melanoma, with the 1-year survival rate now more than 50%, said Dr Boland.

“The main concern with neoadjuvant therapy is the concern of disease progression during therapy. We could miss our window in terms of treating a patient [with excision]…and they become unresectable,” she said. In other cancers, however, the role of neoadjuvant therapy is well-established.

Neoadjuvant immunotherapy as monotherapy provided no clear benefit in patients with high-risk resectable melanoma, with 17% of patients having disease progression after receiving nivolumab monotherapy and their cancer becoming unresectable, and nearly 75% of patients having grade 3 or 4 adverse events in a study by Amaria and colleagues.1 This study also showed that neoadjuvant ipilimumab plus nivolumab expanded the T-cell recognition of tumors in patients with macroscopic stage III melanoma.

The OpACIN-neo study identified neoadjuvant ipilimumab 1 mg/kg plus nivolumab 3 mg/kg as the optimal treatment regimen for stage III resectable melanoma, with a pathologic response rate of 77% and grade 3 or 4 adverse events in only 20%. After a median follow-up of 24.6 months, only 1 (2%) of the 64 patients with a pathologic response had relapsed disease.2

In a substudy of the OpACIN-neo study, the pathologic response in the index node represented the entire lymph node basin. This finding “may allow us to be a lot more refined and nuanced in the way we make decisions” in managing the patient afterwards, Dr Boland said.

The PRADO study confirmed the high pathologic response rate and safety observed with ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg), while allowing the omission of therapeutic lymph-node dissection in 60% of the patients.

Treatment for Stage IV Disease

In patients with stage IV melanoma, the combination of “ipilimumab plus nivolumab is associated with unprecedented responses, up to a 50% response rate, but it certainly comes at a price, which is increased toxicity,” Dr Boland said. Nivolumab followed by ipilimumab may have better results than ipilimumab followed nivolumab, but the former combination is more toxic than the latter.

“In terms of where we stand now, for first-line treatment of stage IV melanoma, ipilimumab plus nivolumab is generally preferred, but for less-fit patients, one can think about anti–PD-1 monotherapy with nivolumab or pembrolizumab,” Dr Boland said. Newly reported data also show that salvage treatment with ipilimumab plus nivolumab is more effective than ipilimumab alone, which suggests that second-line dual immune checkpoint blockade can be effective.

BRAF plus MEK inhibition is associated with improved outcomes compared with a single-agent BRAF inhibitor in stage IV melanoma, Dr Boland said. There are now 3 regimens of a BRAF plus a MEK inhibitor that have demonstrated improved outcomes compared with a single-agent BRAF inhibitor.

The median survival with the combined BRAF plus MEK inhibitors is now more than 2 years; up to 33% of patients remain progression-free for more than 3 years, and others for more than 5 years.

“The next step is figuring out who these people are,” said Dr Boland. “In the studies, they often were patients with a lower burden of disease, so we’re curious how this will fare in the adjuvant setting; maybe these are patients in whom targeted therapy may have a more profound effect on their ultimate outcomes.”

In addition, the tolerability of the combination of the BRAF plus MEK inhibitors is excellent compared with single-agent therapy.


  1. Amaria RN, Reddy SM, Tawbi HA, et al. Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma. Nat Med. 2018;24:1649-1654. Errata in: Nat Med. 2018;24:1941; Nat Med. 2018;24:1942.
  2. Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optional combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-new). Lancet Oncol. 2019;20:948-960.
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