May 6, 2022/Cancer/Innovations

The Changing Treatment Landscape for Patients with Metastatic Melanoma

Immune therapy and targeted therapies have led to durable responses and potential cures


After decades of limited options for managing metastatic melanoma, advances are now occurring at a fast pace.


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“It’s an exciting time to be a melanoma doctor because there are so many new treatments that have developed over the past 10 years,” says Lucy Boyce Kennedy, MD, a medical oncologist in the Taussig Cancer Institute at Cleveland Clinic. “Before 2010, no randomized controlled trial had ever shown that any drug prolonged survival in people with metastatic melanoma. Fortunately, things have changed.”

The treatment landscape shifted with the development of immune checkpoint inhibitors (ICIs) and targeted therapies.

“It’s a good time to take a step back and evaluate where we are now and where the field is going,” says Dr. Kennedy, whose commentary on improving outcomes for patients with metastatic melanoma was recently published in JCO® Oncology Practice.

The role of ICIs and targeted therapies

Immune checkpoint inhibitors that target cytotoxic T lymphocyte antigen-4 and programmed death receptor-1 (PD-1) have ushered in a new era for cancer immunotherapy, explains Dr. Kennedy. One promising use of ICIs is the treatment regimen of ipilimumab plus nivolumab.

“The combination has been shown to lead to durable responses – including remission – even in people with stage 4 melanoma,” says Dr. Kennedy. A median overall survival of 72 months was reported in 2021 in patients who received ipilimumab plus nivolumab for metastatic melanoma.


New options continue to hit the market. In March 2022, the FDA approved a combination of the antibody relatlimab and nivolumab for metastatic melanoma. In addition to a burgeoning market for ICIs, examination of molecular drivers of melanoma has led to the development of targeted therapies, including BRAF/MEK inhibitors.

“Those classes of drugs — which include encorafenib plus binimetinib, dabrafenib plus trametinib, and vemurafenib plus cobimetinib — have completely transformed the way we manage patients whose melanoma has a BRAF V600 mutation,” explains Dr. Kennedy.

Choosing frontline treatments

With so many systemic therapies available, medical oncologists may grapple with decision-making when it comes to selecting the optimal frontline therapy. Dr. Kennedy points to 2021 results of the DREAMseq Trial for guidance. The DREAMseq study compared the efficacy and toxicity of the treatment sequence of nivolumab/ipilimumab followed by dabrafenib/trametinib to the converse sequence for patients with BRAF V600-mutated melanoma.

“The study showed that patients who are treated with immune therapy first have improved overall survival compared to people who start with targeted therapy and then progress to immune therapy later,” says Dr. Kennedy.

Areas of ongoing research

While new therapies offer hope, areas of unmet need remain as researchers seek to refine treatment options and optimize patient selection. Dr. Kennedy notes four such areas:

  • Selecting among immune therapy combinations. “How do we choose between the different immune therapy options now that we have the tried-and-true regimen of ipilimumab plus nivolumab combination and the new combination of nivolumab plus relatlimab? Those combinations have not been compared,” she says.
  • Identifying biomarkers. “No prospectively validated biomarkers exist to predict for response, resistance or toxicity,” says Dr. Kennedy. “So it becomes an individualized discussion when I meet patients with stage 4 melanoma for the first time. I explain treatment options and what we know about response rates, long-term survival and toxicity so we can share in the decision-making.”
  • Overcoming resistance to immune therapy. “Although many patients will respond to immune therapy, it doesn’t work for everyone, unfortunately,” she says. “Work needs to be done to identify the reasons that immune therapy doesn’t work for some patients and find different ways to manipulate the immune system or target other signaling pathways to help overcome that resistance.”
  • Optimizing management of patients with brain metastases. Data indicates that immune therapy can lead to durable responses even in patients with brain metastases. However, those trials primarily included patients with small and asymptomatic brain metastases, says Dr. Kennedy. “People who have larger brain metastases or a lot of symptoms can be very difficult to treat, so optimizing the management of those cases is another unmet need,” she adds.

Staying abreast of practice-changing advances

The fast pace of advancements also creates challenges for medical oncologists who care for patients with various cancer diagnoses.

“Oncology is changing so quickly; all of the various fields are moving in parallel or different directions,” says Dr. Kennedy. “The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology are updated as new trial data appears, but it is very difficult to keep abreast of breaking developments when things change so quickly.”

She encourages oncologists to seek advice from Cleveland Clinic and clinical research institutions that are investigating novel immune therapies and offer alternative approaches for patients in whom other treatments have been exhausted.

“Outcomes for patients with metastatic melanoma are much better than they were 10 or 15 years ago, and it’s immensely exciting to see these new developments on the horizon with the potential to cure,” says Dr. Kennedy.

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