American Melanoma Institute · 5 min read
Why giving immunotherapy before surgery helps in stage III melanoma you can feel or see on scans, and what the S1801 and NADINA trials showed.
For years the order was fixed. The surgeon removed the melanoma and the involved lymph nodes, and drug treatment came afterward. For stage III melanoma that can be felt as a lump or seen on a scan, 2 trials have now shown that reversing the order works better. Treatment given before surgery is called neoadjuvant therapy.
Checkpoint inhibitors work through T cells, the immune cells that recognize and destroy cancer, by releasing a brake on them. A T cell has to meet its target before it can learn to attack it.
While the tumor is still in place, it holds a large supply of melanoma proteins and a population of T cells already gathered around it. Giving the drug at that moment appears to wake up a larger and more varied set of T cells, which then travel through the body and hunt for melanoma cells that have spread. Once the tumor is out, much of that teaching material is gone. This idea came from laboratory work and small studies, and the trials below put it to the test.
SWOG S1801 (Patel and colleagues, New England Journal of Medicine, 2023) enrolled 313 patients with stage IIIB to stage IV melanoma that could be felt or measured on scans and could be removed by surgery. Half had surgery followed by 18 doses of pembrolizumab. The other half received 3 doses of pembrolizumab first, then surgery, then 15 more doses.
Both groups received the same drug and the same total number of doses. Only the timing differed. At 2 years, 72% of the group treated before surgery were free of what the trial called events (melanoma growing, returning, or a complication that blocked planned treatment), compared with 49% of the group treated only afterward. Serious treatment-related side effects were similar: 12% and 14%.
NADINA (Blank and colleagues, New England Journal of Medicine, 2024) was a phase 3 trial of 423 patients with stage III melanoma in lymph nodes large enough to feel or see on imaging. The neoadjuvant group received 2 cycles of ipilimumab plus nivolumab and then had surgery. The comparison group had surgery first, followed by 12 cycles of nivolumab.
At 12 months, an estimated 84% of the neoadjuvant group were event-free, compared with 57% of the surgery-first group. The combination brought more side effects. Serious treatment-related side effects occurred in about 30% of the neoadjuvant group and 15% of the comparison group.
Neoadjuvant treatment gives doctors something surgery-first never could: a direct look at how the melanoma responded. After the operation, the pathologist examines the removed lymph nodes under the microscope and estimates how much living tumor remains. This is called the pathologic response.
In NADINA, 59% of patients in the neoadjuvant group had a major pathologic response, meaning little or no living melanoma was left in the specimen. Another 8% had a partial response, and 26% had no response, defined as more than half of the tumor still alive. A scan before surgery can mislead here. A lymph node may look unchanged in size and still contain mostly scar tissue and immune cells.
The response predicted what came next. At 12 months, 95% of patients with a major response were free of recurrence, compared with 76% of those with a partial response and 57% of those with no response. NADINA also used the result to guide treatment. Patients with a major response stopped there and received no more drug therapy, while those with a partial response or no response went on to further treatment after surgery.
A poor response is useful information as well. It tells the oncologist early that a different drug approach may be needed, and patients whose melanoma carries a BRAF mutation have targeted therapy as another option.
Both trials enrolled people whose melanoma could be felt on examination or seen on imaging before surgery. Most stage III melanoma is found another way, as microscopic deposits in a sentinel lymph node. Those patients have already had the involved node removed, and the trial results do not apply to them. Treatment after surgery remains their standard option.
Delay is the main worry people raise, since the operation is pushed back by several weeks. In NADINA, melanoma progressed during that window in about 2% of the neoadjuvant group. The care team repeats scans before surgery to check.
The National Cancer Institute lists pembrolizumab before surgery among the treatment options for stage III melanoma that can be removed. The NCCN patient guidelines name pembrolizumab alone, or nivolumab plus ipilimumab, as preferred neoadjuvant choices. This approach works best at a center where the surgeon, the medical oncologist, and the pathologist plan the sequence together.
Several questions remain open. The single-drug and 2-drug approaches have not been compared head to head, so the choice weighs a possibly stronger response against a higher rate of side effects. Follow-up in both trials is still short, and more data is needed on long-term survival. Researchers are also studying whether people with an excellent response can safely have a smaller operation.
