A recent study shows that giving immunotherapy before surgery for stage III melanoma can help stop the spread of the disease and cut time spent in treatment. The immune checkpoint inhibitors nivolumab (Opdivo) and ipilimumab (Yervoy)  lowered the risk of death and of the disease growing by 27%. Immunotherapy uses the power of the body’s immune system to seek out and destroy cancer cells. When compared to current treatments for stage III melanoma, the drug combination led to a 68% reduction in the risk of the disease returning or growing and spreading.

This study was presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

“The results from the NADINA clinical trial show the benefits of giving immunotherapy before surgery for some patients with stage III melanoma where the involved lymph node can be felt,” said ASCO President Lynn Schuchter, director of the Tara Miller Melanoma Center at the University of Pennsylvania. “Notably, this treatment approach not only highlights the effectiveness of immunotherapy before surgery but also suggests that we can reduce the overall treatment burden for patients whose melanoma responds to treatment.”

Melanoma is the most dangerous form of skin cancer. Stage III melanoma is advanced cancer that has started to spread beyond the tumor. Sometimes it can be treated with surgery, but not always.

The current standard-of-care treatment for stage III melanoma is to remove the tumor and affected lymph nodes. Lymph nodes are the small, bean-shaped organs that are part of the body's immune system and help fight infection. Then medications, such as targeted therapy or immunotherapy, are given to lower the chances of the cancer coming back. Treatments given after the first treatment are called adjuvant therapies. Treatment given before surgery is called neoadjuvant therapy.

Better results for immunotherapy before surgery

The researchers randomly assigned 212 patients to receive neoadjuvant ipilimumab and nivolumab and then surgery. If there was not a strong response to treatment, they would receive adjuvant nivolumab for 1 year. Another 211 patients were randomly assigned to receive surgery and then adjuvant nivolumab.

To compare how well the two treatments worked, the researchers observed the time from when a patient is assigned to a treatment group until a disease-related event happens. The disease-related events were when the tumor becomes too big to be surgically removed, the tumor comes back after surgery, or a patient dies due to the melanoma or the treatment.

There were just 28 disease-related events among those who received neoadjuvant therapy (given before surgery). In contrast, there were 72 events among those who received adjuvant therapy (given after surgery).

The researchers estimated that at 1 year, about 4 of every 5 patients (83.7%) receiving neoadjuvant therapy would be event-free. In comparison, about 3 of every 5 patients (57.2%) receiving adjuvant therapy would be event-free. For nearly 3 of every 5 patients (58.0%) who received neoadjuvant therapy, the cancer had a strong response to the treatment. Those patients did not need to receive adjuvant therapy and had only 6 weeks of cancer treatment.

A new way to study cancer treatments

The NADINA clinical trial is the first phase 3 cancer study to use only immunotherapy drugs before surgery. In previous studies, immunotherapy has been combined with targeted therapy or chemotherapy to treat cancer before surgery. Nivolumab targets a protein called PD-1. Ipilimumab targets one called CTLA-4. This study confirms evidence from other clinical trials that nivolumab plus ipilimumab is an effective and safe treatment, according to ASCO expert Michael C. Lowe, MD, MA, disease team lead and co-chair of the Melanoma Working Group at Winship Cancer Institute of Emory University.

The NADINA study’s method of selecting treatment after surgery also offers benefits to people with melanoma. “Doctors were able to determine who got additional therapy based on how the cancer responded to treatment, which helps doctors personalize and individualize cancer therapy,” said ASCO expert Jyoti Patel, MD, FASCO, medical director of thoracic oncology and assistant director for clinical research at the Lurie Cancer Center of Northwestern University.

“Personalized treatment reduces the risks of overtreatment and unwanted side effects. It also helps patients avoid the burden of getting one more year of treatment. Also, if there were still cancer cells remaining after surgery, adjuvant therapy could be personalized to an appropriate oral medication,” said Dr. Patel.

This approach could also cut down on the time patients spend in hospitals. “NADINA should become a template for other neoadjuvant immunotherapy trials,” said lead study author Christian U. Blank, MD PhD, of the Netherlands Cancer Institute. “For melanoma, this approach can save a lot of time spent in hospital for about 60% of patients.”  

What is the NADINA study?

The NADINA study included 423 patients. About two-thirds of the patients were from Europe, with the rest mainly from Australia. About two-thirds of the patients were men. The average age of all participants was about 60 years.

The researchers compared neoadjuvant therapy using 6 weeks of ipilimumab and nivolumab before surgery to 1 year of nivolumab after surgery. After surgery in the neoadjuvant group, the doctors would check whether ipilimumab plus nivolumab destroyed 90% or more of the tumor cells in the surgically removed lymph nodes.

If neoadjuvant therapy led to a strong response from the cancer, then no treatment was given after surgery. If there was not a strong response, then patients would receive nivolumab after surgery. Or, if the tumor had a mutation in the BRAF gene, they would receive the targeted therapies dabrafenib (Tafinlar) and trametinib (Mekinist) instead. These are standard-of-care adjuvant treatments for melanoma.

The most common side effects in the neoadjuvant treatment group were infection, diarrhea, abnormal blood counts, rash, fever, and fatigue. Nearly 3 of every 10 patients (29.7%) in the neoadjuvant treatment group experienced serious side effects related to these treatments. In comparison, about 3 of every 20 patients (14.7%) in the adjuvant treatment group experienced serious side effects.

Talking through melanoma treatment with your cancer care team

If you have stage III melanoma, talking with your cancer care team can help you understand more about your recommended treatment plan and how it may benefit you. Consider asking your doctor these questions:

• Is surgery possible for my diagnosis?
• Do you think immunotherapy treatment before surgery would benefit me? Why or why not?
• Does my melanoma have a BRAF mutation?
• Does the melanoma involve the lymph nodes?
• Is treatment recommended after my surgery?
• How will I be monitored to watch for the cancer coming back?

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Dr. Patel is the Editor in Chief of ASCO’s Patient Information Editorial Board. Dr. Lowe is an expert on ASCO’s Cancer Communications Committee. Read more about our collaboration with ASCO.