NADINA Trial: Immunotherapy Before Melanoma Surgery

For stage III melanoma that has reached the lymph nodes but can still be removed, the usual order has been fixed for years. Operate first. Then give immunotherapy for about a year to lower the risk of return. The NADINA trial flipped that order. It gave a short burst of immunotherapy first, then operated — and let the tumor's response decide what came next. The results were published in the New England Journal of Medicine in 2024. This is one of the clearest wins yet for treating before surgery.

What the trial tested

NADINA was an open-label phase 3 trial. It enrolled 423 people with resectable, macroscopic stage III melanoma. That means disease in the lymph nodes large enough to see or feel, but still operable. They were randomly assigned to one of two paths.

• Neoadjuvant group (212 people): two cycles of ipilimumab plus nivolumab, given every 3 weeks before surgery, then lymph node dissection. Both drugs are immune checkpoint inhibitors, medicines that release the brakes on immune cells so they can attack the cancer.
• Adjuvant group (211 people): surgery first, then 12 cycles of nivolumab alone, every 4 weeks.

The clever part came after surgery in the neoadjuvant group. Pathologists examined the removed tissue. People with a major pathologic response — 10% or less of the tumor still alive — received no further treatment. People with more remaining tumor went on to adjuvant treatment. That meant either more nivolumab or, for some, the targeted combination dabrafenib plus trametinib for 46 weeks.

What the trial showed

The primary endpoint was event-free survival (EFS). An event meant one of three things. The cancer became unresectable before surgery. It came back after treatment. Or the person died from the melanoma or its treatment.

At 12 months, 83.7% of the neoadjuvant group were event free, versus 57.2% of the adjuvant group. The estimated risk of progression, recurrence, or death was 68% lower (hazard ratio 0.32).

The response data explain why. After just two cycles, 59.0% of the neoadjuvant group had a major pathologic response. Another 8.0% had a partial response, 26.4% had a nonresponse, and in 2.4% the cancer progressed. Response predicted outcome. At 12 months, recurrence-free survival was 95.1% after a major response, 76.1% after a partial response, and 57.0% after a nonresponse.

For the majority who responded well, that meant two infusion cycles and surgery. Then no further treatment, instead of a year of therapy.

What the trial did not show

The follow-up in the published report was short: a median of 9.9 months. Longer follow-up will show whether the early advantage holds and whether people in the neoadjuvant group actually live longer. Overall survival results were not part of this report, so EFS gains are not yet proof of longer life.

The trial was also open label, meaning everyone knew their assignment. And the comparison was adjuvant nivolumab alone, one of several standard options in this setting.

Side effects

Two drugs are harder than one. In NCI's PDQ summary of the trial, 47.2% of the neoadjuvant group had at least one grade 3 or 4 adverse event. In the adjuvant-only group, 34.1% did. Counting only severe events related to the drug treatment, the NEJM report gives 29.7% versus 14.7%. One person in the adjuvant group died of treatment-caused lung inflammation (pneumonitis); no treatment-related deaths occurred in the neoadjuvant group.

Immune-related side effects from checkpoint inhibitors can sometimes be serious or lasting. The tradeoff — more early toxicity, less total treatment for responders — is exactly the kind of thing to weigh with a care team.

What to raise with the team

• Is my melanoma macroscopic stage III and still resectable — the situation this trial actually covered?
• Would you recommend immunotherapy before my surgery, and with one drug or two?
• If I have a major pathologic response, would I stop treatment afterward, as in the trial?
• Has my tumor been tested for a BRAF mutation, since that affects the backup options?
• Which immune side effects should I report immediately, and who do I call?

What this does not mean

• It does not apply to melanoma that is stage I, II, or IV, or to stage III disease found only under the microscope.
• It does not mean surgery is optional. Everyone in the trial was headed to surgery; the question was what comes before and after.
• Event-free survival is not the same as living longer. Follow-up so far is short, and the survival question stays open.
• It does not mean this sequence fits everyone. Two-drug immunotherapy carries a real chance of severe, sometimes lasting, side effects.

Sources

• NCI: Melanoma Treatment (PDQ) - Health Professional Version
• PubMed: Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma, N Engl J Med 2024
• NCI: Melanoma Treatment (PDQ) - Patient Version