Immunotherapy before surgery for resectable stage III melanoma, and why timing matters
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For decades, the order of treatment for melanoma that had spread to lymph nodes was fixed: surgery first, then — more recently — a year of medication afterward to lower the chance it came back. That afterward-only medication is called adjuvant therapy.
Neoadjuvant therapy flips part of that sequence. It gives a short course of immunotherapy before the operation, while the melanoma is still in the body. Over the past few years, two randomized trials have shown this is not just a rearrangement — it produces better outcomes than adjuvant treatment alone for the right patients. As a result, neoadjuvant immunotherapy is quickly becoming a preferred approach for macroscopic (clinically detected) stage III melanoma.
This article explains who it is for, why treating before surgery seems to work better, what the trials found, what a pathologic response means, and what the schedule looks like in practice. For how these drugs work and their side effects, see how immunotherapy treats advanced melanoma.
Neoadjuvant immunotherapy is used for resectable, macroscopic stage III melanoma — disease that can be felt or seen on a scan and that a surgeon judges removable. Typical situations include:
It is generally not used for melanoma found only under the microscope in a sentinel node (microscopic stage III), which is usually managed with adjuvant therapy after surgery, or for stage IV melanoma, which is treated primarily with systemic therapy. Whether disease is macroscopic and resectable is decided during the staging workup, ideally at a multidisciplinary tumor board.
Checkpoint inhibitors work by helping T cells recognize and attack melanoma. The leading explanation for why giving them before surgery works better is that the tumor itself is the teaching material:
Two randomized trials moved neoadjuvant immunotherapy from a promising idea to a standard option.
People with resectable stage IIIB–IV melanoma were assigned to receive pembrolizumab either entirely after surgery (about 18 doses) or split — three doses before surgery and the rest after. Splitting the treatment lengthened event-free survival: at two years, about 72% of the neoadjuvant group were alive and free of recurrence, versus about 49% of the adjuvant-only group. The total amount of drug and the surgery were essentially the same; only the timing of the first three doses changed.
People with macroscopic stage III melanoma received either two cycles of ipilimumab plus nivolumab before surgery, followed by treatment tailored to the pathology result, or surgery followed by a year of adjuvant nivolumab. The neoadjuvant approach substantially improved event-free survival — roughly 84% versus 57% free of an event at one year. People with a major pathologic response received little or no further drug therapy; those with less response went on to adjuvant treatment.
A pooled analysis from the International Neoadjuvant Melanoma Consortium, gathering results across earlier trials, reached the same conclusion: the depth of pathologic response after neoadjuvant treatment is a powerful predictor of whether the melanoma stays away.
After the pre-surgery drug course, the tumor and nodes are removed on schedule and a pathologist examines them closely for living melanoma cells. The findings are grouped:
This matters because response predicts the future. In pooled data, people with a pathologic complete or major response had roughly a 90% or higher chance of remaining recurrence-free at two years, compared with about half of those without one. Around 40% of people achieve a pathologic complete response with neoadjuvant immunotherapy, and the figure is higher with the ipilimumab-plus-nivolumab combination than with single-agent anti–PD-1.
A strong pathologic response can also reduce later treatment: in NADINA, people with a major response were spared a year of adjuvant drugs and simply followed with scans.
The details vary by center and regimen, but a common pattern is:
The side effects are those of the checkpoint inhibitors themselves — see managing immunotherapy side effects. A small number of people have a reaction severe enough to delay surgery, which is one reason these regimens are given at centers experienced with them.
Neoadjuvant immunotherapy — a short course of checkpoint inhibitors before surgery — has become one of the most important recent advances for stage III melanoma. Two randomized trials, S1801 and NADINA, showed it lengthens the time people stay free of recurrence compared with the older surgery-first approach, using the same drugs. The pathology result after surgery gives an early, personalized read on how well the treatment worked, and a strong response can mean less treatment afterward.
It applies to a specific group: melanoma that has spread to nodes or nearby skin, is large enough to see or feel, and can be removed. If that describes your situation, it is worth asking a melanoma specialist team whether starting with immunotherapy before surgery is the right plan for you.
Disclaimer: This article is for educational purposes only and not a substitute for professional medical advice. Always consult a qualified dermatologist or oncologist about your personal diagnosis and treatment plan.
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