New Treatment Strategies for Patients with Advanced Melanoma

During a presentation at the National Comprehensive Cancer Network 2022 Annual Conference, Genevieve Boland, MD, PhD, FACS, Section Head, Melanoma/Sarcoma Surgery; Surgical Director, Termeer Center for Targeted Therapies; and Director, Therapeutic Intralesional Program, Massachusetts General Hospital, Boston, discussed how targeted treatments and immunotherapies are improving the treatment landscape for melanoma.

She noted that the combination of relatlimab plus nivolumab (Opdualag) represents a new standard of care that should replace treatment with an anti–PD-1 agent alone for patients with advanced melanoma.

In the RELATIVITY-047 clinical trial of patients with untreated stage III or IV melanoma, treatment with relatlimab, a novel antibody that blocks LAG-3, plus nivolumab led to an improvement in median progression-free survival compared with nivolumab (Opdivo) alone (10.12 vs 4.63 months, respectively; P = .0055), with progression-free survival that favored the combination across key prespecified subgroups. The toxicity profile was also manageable when compared with that seen with anti–PD-1 monotherapy. As a result of these findings, in March 2022, the FDA approved relatlimab plus nivolumab for the treatment of adult and pediatric patients aged ≥12 years who have unresectable or metastatic melanoma.

Dr Boland cautioned, however, that some patients may not be ideal candidates for this combination, including rapid progressors with high levels of lactate dehydrogenase, those with liver and bone metastases, those with bulky disease who may fare better with the combination of ipilimumab (Yervoy) plus nivolumab, patients with disease progression on adjuvant anti–PD-1 therapy, and those with severe autoimmune disease.

Dr Boland went on to discuss ongoing investigations into the optimal sequencing of treatments for patients with melanoma. She noted that nivolumab plus ipilimumab followed by dabrafenib (Tafinlar) plus trametinib (Mekinist) is associated with prolonged overall survival at 2 years (and likely beyond), and more durable responses, compared with the converse. In patients with BRAF mutation–positive melanoma, nivolumab plus ipilimumab followed by BRAF/MEK inhibitor therapy (if necessary) should be the preferred treatment sequence.

Systemic Therapies

The goal of systemic adjuvant treatment is to reduce the risk for relapse and mortality by targeting residual micrometastatic disease. Dr Boland noted that recent therapies (eg, BRAF inhibitors, MEK inhibitors, PD-1 inhibitors, CTLA-4 inhibitors) have translated into a marked survival advantage in patients with metastatic melanoma, with 1-year survival now at >50%.

Dr Boland went on to say that there is growing interest in the use of neoadjuvant therapy in melanoma, although there are currently no FDA-approved neoadjuvant regimens. In the OpACIN-neo study, neoadjuvant treatment with ipilimumab 1 mg/kg plus nivolumab 3 mg/kg resulted in a pathologic response rate of 77% in patients with stage III melanoma, with grade 3/4 toxicity in only 20% of patients. Furthermore, after a median follow-up of 24.6 months, only 1 of 64 (2%) patients with a pathologic response had relapsed.

Results of PRADO, an extension cohort of the OpACIN-neo trial, confirmed that patients with stage III melanoma respond well to this neoadjuvant regimen, allowing some to omit therapeutic lymph node dissection.

Stage IV Melanoma

In the setting of stage IV melanoma, “treatment with ipilimumab plus nivolumab is associated with unprecedented responses, up to a 50% response rate, but certainly comes at a price, which is increased toxicity,” Dr Boland said. Nivolumab followed by ipilimumab seems to perform better than ipilimumab followed by nivolumab but is also more toxic.

“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,” she said. Recently reported data also show that salvage ipilimumab plus nivolumab is more effective than ipilimumab alone, which suggests that second-line dual immune checkpoint blockade can be effective.

BRAF/MEK inhibitor combination regimens are associated with improved outcomes compared with BRAF inhibitor monotherapy in stage IV melanoma, Dr Boland said. Median survival in patients treated with these combined therapies is currently >2 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.” She also noted that the tolerability of combined BRAF/MEK inhibitor therapy is excellent compared with single-agent therapy.

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