Melanoma Treatment Before Surgery: How Neoadjuvant Immunotherapy Is Changing Stage III Melanoma Care

Last updated: July 7, 2026

Quick Answer

For patients with resectable stage III melanoma that's already spread to lymph nodes, giving immunotherapy before surgery, called neoadjuvant treatment, now beats the old "cut it out first" playbook. The phase III NADINA trial showed 12-month event-free survival of 83.7% with neoadjuvant nivolumab plus ipilimumab versus 57.2% with surgery followed by adjuvant nivolumab. Surgery still matters, but for a specific higher-risk group, the timing has flipped.

Key Takeaways

• Neoadjuvant means "before surgery." For select stage III melanoma patients, two doses of immunotherapy come first, then surgery.
• NADINA (2024) changed the standard. 12-month event-free survival was 83.7% vs 57.2% favoring the neoadjuvant approach.
• SWOG S1801 (2023) set the stage. 2-year event-free survival was 72% vs 49% with neoadjuvant-adjuvant pembrolizumab.
• Pathologic response drives next steps. In NADINA, 59% had a major pathologic response; those patients often skipped further adjuvant therapy.
• Not every melanoma qualifies. This applies to resectable stage III with clinically detectable nodal or in-transit disease, not stage 0, I, or most stage II.
• Toxicity is real. Grade 3+ adverse events hit 29.7% of the neoadjuvant dual-therapy arm vs 14.7% with adjuvant nivolumab alone.
• Canadian coverage is expanding. Canada's Drug Agency has recommended reimbursement for both pembrolizumab and nivolumab plus ipilimumab regimens with conditions.
• This requires a specialized team. Pathology response assessment, immune-toxicity management, and surgical coordination are non-negotiable.

What is neoadjuvant immunotherapy for melanoma?

Neoadjuvant immunotherapy means giving immune checkpoint inhibitors before the melanoma is surgically removed, while the tumor is still in place. The idea is simple: if immune cells are already circling the tumor, unleashing them while the tumor is still there gives the immune system more material to learn from, potentially producing a broader, more durable response than treating only after surgery.

In practice, patients with resectable stage III melanoma (visible or measurable lymph node or in-transit disease) get one to three cycles of a PD-1 inhibitor, sometimes combined with an anti-CTLA-4 drug, then proceed to surgery. Pathologists examine the resected tissue to see how much viable tumor is left. That result guides whether more therapy is needed afterward [8].

Decision rule: Neoadjuvant immunotherapy is considered when melanoma is stage III with macroscopic (clinically detectable) disease that's still resectable. It is not routine for thin primary melanomas or stage 0 melanoma in situ, which are handled with excision alone.

How does immunotherapy before surgery improve melanoma outcomes?

Giving immunotherapy before surgery appears to activate a stronger, more diverse anti-tumor immune response because the intact tumor supplies antigens that "train" T-cells more effectively than residual disease left after resection. The measurable payoff is longer event-free survival and higher rates of pathologic complete response.

Here's what the numbers look like:

TrialRegimenKey outcomeSWOG S1801 (2023)Pembrolizumab neoadjuvant + adjuvant vs adjuvant only2-yr EFS 72% vs 49%NADINA (2024)Nivolumab + ipilimumab neoadjuvant vs adjuvant nivolumab12-mo EFS 83.7% vs 57.2%NADINA follow-up (2025 ESMO)Same as above2-yr EFS 77.3% vs 55.7%

Beyond survival, pathologic response predicts long-term outcomes. In NADINA, patients with a major pathologic response had 12-month recurrence-free survival of 95.1%, compared with 57% in nonresponders. Any degree of pathologic response confers a survival advantage [5].

Neoadjuvant immunotherapy vs adjuvant for stage 3 melanoma

For resectable macroscopic stage III melanoma, neoadjuvant immunotherapy now outperforms the surgery-first, adjuvant-only approach on event-free survival. The advantage held up in both a phase II trial (SWOG S1801) and a phase III trial (NADINA).

Neoadjuvant approach (in NADINA):

• Two cycles of nivolumab + ipilimumab
• Then surgery
• Then response-adapted adjuvant therapy (or none, if major pathologic response)

Adjuvant approach (older standard):

• Surgery first
• Then up to a year of adjuvant nivolumab regardless of response

The neoadjuvant path also lets doctors see whether the drugs are working, because they can measure the tumor at surgery. Adjuvant-only treatment is essentially blind: you dose everyone and hope.

Trade-off: neoadjuvant dual-checkpoint therapy causes more grade 3+ adverse events (29.7% vs 14.7%) [2]. For anyone weighing this decision, it's worth reviewing what a melanoma oncologist near you actually does during these consults.

What drugs are used for neoadjuvant melanoma treatment?

The two main regimens supported by randomized data are pembrolizumab (single-agent PD-1 blockade) and nivolumab plus ipilimumab (dual PD-1 and CTLA-4 blockade). Both are given intravenously every three weeks for a short pre-surgical course.

Common regimens:

• Pembrolizumab, 3 cycles before surgery, then up to 15 cycles after (Cancer Care Ontario regimen, based on SWOG S1801)
• Nivolumab + ipilimumab, 2 cycles before surgery (nivolumab 240 mg + ipilimumab 80 mg every 3 weeks), with adjuvant therapy tailored to pathologic response (based on NADINA)
• Relatlimab + nivolumab, a LAG-3 antibody combined with anti-PD-1, tested in a phase II trial showing pCR over 50% and pathological response over 90%, with no grade 3-4 immune-related events reported in the preoperative setting [1]
• T-VEC + pembrolizumab, an oncolytic virus combined with anti-PD-1, being tested in stage III patients with clinically apparent nodal disease [7]

BRAF/MEK inhibitors (dabrafenib + trametinib) can be used as adjuvant treatment after neoadjuvant immunotherapy in BRAF-mutant tumors that didn't achieve a major pathologic response.

How long does neoadjuvant immunotherapy take before surgery?

Most neoadjuvant courses run roughly 6 weeks before surgery, though the total treatment timeline extends longer depending on adjuvant therapy afterward.

Typical timelines:

• Nivolumab + ipilimumab (NADINA style): 2 cycles, 3 weeks apart → surgery about 6 weeks after the first infusion
• Pembrolizumab (SWOG S1801 style): 3 cycles, 3 weeks apart → surgery around 9 weeks after starting
• Recovery + adjuvant: if further therapy is needed, it typically runs several months to a year post-op

Add staging scans, biopsies, and multidisciplinary review, and most patients are looking at 2-3 weeks of workup before the first dose. Being organized about scheduling matters, especially if you're coordinating between an oncologist, surgeon, and pathologist.

Side effects of neoadjuvant immunotherapy for melanoma

The most common side effects are immune-related: skin rash, colitis (diarrhea), thyroid dysfunction, liver enzyme elevation, and pneumonitis. Serious grade 3+ events happen in roughly 12-30% of patients depending on the regimen, with dual-checkpoint therapy causing more toxicity than single-agent PD-1 blockade.

Frequency of grade 3+ treatment-related adverse events:

• Adjuvant nivolumab alone (NADINA control arm): 14.7%
• Neoadjuvant pembrolizumab (SWOG S1801): about 12%
• Neoadjuvant nivolumab + ipilimumab (NADINA): 29.7%

Common milder side effects:

• Fatigue
• Itchy rash
• Mild diarrhea
• Joint aches
• Hypothyroidism (often permanent, managed with thyroid hormone)

Serious complications to watch for:

• Severe colitis
• Hepatitis
• Pneumonitis
• Adrenal insufficiency
• Neurologic events

Any new symptom during immunotherapy needs prompt reporting. Immune-related adverse events can escalate fast, and early steroids usually resolve them. This is a big reason provincial guidelines (like BC Cancer's 2025 protocol) require treatment at centres with expertise in managing these reactions.

Does neoadjuvant immunotherapy actually work for stage 3 melanoma?

Yes, and the evidence is now among the strongest in modern melanoma oncology. Two randomized trials, real-world Australian data, and multiple community-cancer-centre reports all point in the same direction: patients live longer without recurrence when immunotherapy comes before surgery.

Evidence snapshot:

• SWOG S1801 (phase II): 2-year event-free survival 72% vs 49%
• NADINA (phase III): 12-month event-free survival 83.7% vs 57.2%; hazard ratio 0.32
• Australian real-world data: anti-PD-1 + anti-CTLA-4 superior to anti-PD-1 alone; patients with only in-transit metastases had similar outcomes to those with nodal disease [3]
• Community cancer centre analysis: 44 patients with resectable stage III melanoma, 84% event-free survival at median 16-month follow-up, 67% major pathologic response [4]

Pathologic response is doing double duty here: it's both a prognostic marker and a decision-making tool. Patients with a major pathologic response have 95%+ recurrence-free survival at 12 months and may safely skip more adjuvant therapy.

Bottom line: for resectable stage III melanoma with macroscopic disease, giving immunotherapy first is now supported by phase III evidence, guideline recommendations from ASCO, NCCN, and ESMO, and real-world confirmation.

Who is a good candidate for neoadjuvant melanoma immunotherapy?

The typical candidate has stage III cutaneous melanoma with at least one clinically detectable lymph node metastasis or resectable in-transit metastases, is fit for both immunotherapy and surgery, and is being managed by a multidisciplinary team. Not every stage III patient qualifies, and stages 0, I, and most stage II patients don't fit at all.

Generally eligible:

• Resectable macroscopic stage III cutaneous melanoma
• One or more clinically detected nodal metastases, or resectable in-transit metastases
• Good performance status
• Access to a treatment centre with immune-toxicity expertise and melanoma-experienced pathology

Generally not eligible:

• Stage 0 (in situ) or stage I melanoma, surgery alone is standard; see the stage 1 melanoma overview
• Most stage II melanoma with no nodal disease
• Mucosal or uveal (ocular) melanoma
• Distant metastatic (stage IV) disease that isn't resectable, though face stage 4 melanoma situations have their own pathways
• Active autoimmune disease requiring systemic immunosuppression
• Poor performance status or major comorbidities

Common mistake: patients read about NADINA and assume every melanoma diagnosis warrants immunotherapy first. It doesn't. If you've been diagnosed with an early melanoma such as stage 0 melanoma, surgical excision remains the correct primary treatment.

Cost of neoadjuvant immunotherapy treatment

In Canada, publicly funded coverage for neoadjuvant immunotherapy in resectable stage III melanoma has expanded significantly. Canada's Drug Agency has recommended reimbursement, with conditions, for both pembrolizumab (2024) and nivolumab plus ipilimumab (2025) in eligible patients. Actual out-of-pocket cost varies by province.

What patients typically pay in Canada:

• Provincial coverage generally applies for eligible stage III patients meeting the reimbursement criteria
• Some patients may have gaps for adjuvant portions, ancillary drugs, or private-plan coordination
• Pathology, imaging, and hospital care are covered under provincial health plans

In the United States: list prices for these regimens run into the hundreds of thousands of dollars per treatment course, though most patients pay much less through insurance and manufacturer assistance programs.

Minor surgery clinics don't administer neoadjuvant immunotherapy, but they play a role in the diagnostic pathway (biopsy, primary excision, staging referral). If you're pricing out surgical steps, the minor surgery pricing page covers what a private surgical consult and excision typically involve.

What happens if neoadjuvant immunotherapy doesn't shrink the tumor?

If the tumor doesn't respond, the patient still proceeds to surgery, and the treatment plan afterward changes. Nonresponse is a signal that a different systemic approach is needed post-op, and it also signals higher recurrence risk.

Response categories after neoadjuvant therapy:

ResponseDefinition12-mo recurrence-free survival (NADINA)Pathologic complete response (pCR)0% viable tumor~95% (grouped with MPR)Major pathologic response (MPR)≤10% viable tumor95.1%Partial response11-50% viable tumor76.1%Nonresponse>50% viable tumor57.0%

What happens when there's no response:

• Surgery still occurs (the tumor is usually still resectable)
• Adjuvant therapy is added, not skipped, often switching drug class, e.g., BRAF/MEK inhibitors for BRAF-mutant disease
• Closer surveillance imaging afterward
• Clinical trial enrollment may be discussed

Nonresponse is uncommon but not rare. About 20-25% of NADINA patients did not achieve a major pathologic response, so treatment teams plan for this scenario upfront.

Neoadjuvant immunotherapy melanoma clinical trials

Active trials are refining who benefits most, testing new drug combinations, and exploring whether surgery can be de-escalated after excellent response. Interested patients should ask their oncologist about ongoing studies.

Notable ongoing studies:

• Dana-Farber phase II randomized study, comparing neoadjuvant nivolumab + ipilimumab followed by adjuvant nivolumab or observation, versus adjuvant nivolumab alone, in treatment-naive resectable clinically detectable stage III melanoma [6]
• T-VEC + pembrolizumab (NCT03842943), single-arm phase II combining oncolytic virus therapy with anti-PD-1 before complete lymph node dissection in stage III melanoma [7]
• OMIT trial, investigating whether therapeutic lymph node dissection can be safely omitted for patients with major pathologic response after neoadjuvant ipilimumab/nivolumab
• Biomarker sub-studies, evaluating tumor mutational burden, IFN-γ signature, and PD-L1 expression as predictors of response

Trial participation offers access to newer regimens (like LAG-3 combinations) and to trial-level monitoring, but eligibility criteria are strict. A referral discussion at a comprehensive cancer centre is the fastest way to know what's open.

How to prepare for surgery after neoadjuvant immunotherapy

Preparation involves timing surgery within the recommended window (usually 1-3 weeks after the last dose), managing any residual immune-related side effects, and confirming imaging is up to date. The pre-op checklist is more detailed than for standard melanoma excision because immunotherapy affects wound healing and inflammation.

Practical prep steps:

1. Restaging imaging, usually a PET-CT or CT scan close to surgery to confirm the disease is still resectable
2. Blood work, checking for immune-related organ toxicity (liver, thyroid, adrenal)
3. Steroid check, if you're on steroids for an immune-related adverse event, the surgical team needs to know
4. Medication review, some drugs get paused; blood thinners in particular
5. Wound-care planning, immunotherapy can cause skin reactions that complicate incisions
6. Recovery logistics, arrange help for the first week post-op, especially after lymph node dissections

Your surgical oncology team will coordinate this. If you're also managing a scar from a previous procedure and noticing changes, that's worth flagging separately, the guide on when to see a specialist about a changing scar is a useful reference.

Can you skip surgery if neoadjuvant immunotherapy works well?

Not yet as a standard, but this is an active research question. Right now, surgery remains part of the plan even when neoadjuvant immunotherapy produces a pathologic complete response, because there's no reliable way to confirm complete tumor eradication without pathology from a resected specimen.

Current standard: proceed with surgery after neoadjuvant therapy, regardless of imaging response, because pathologic assessment guides adjuvant treatment and confirms whether the disease is truly gone.

What's being tested: trials like OMIT are examining whether lymph node dissection can be safely omitted in patients with major pathologic response on a biopsied index node. Early signals are promising, but this is not routine care in 2026.

Common mistake: patients see a dramatic response on scans and assume they're done. Imaging can look clean while microscopic residual disease persists, which is why surgery still matters even after excellent immunotherapy response. The NCI PDQ continues to include surgery in stage III treatment pathways, alongside neoadjuvant and adjuvant systemic options [8].

How Melanoma Treatment Before Surgery Fits into Overall Melanoma Care

Melanoma treatment before surgery isn't a replacement for excision in most patients, it's a refinement for a specific higher-risk subset. Early-stage disease still gets excised first, and surgical clinics remain the entry point for suspicious lesions.

The care continuum:

1. Suspicious lesion, dermatology or minor surgery assessment, then biopsy. If you're trying to figure out whether a spot is worrisome, checking your skin for melanoma at home and comparing moles vs melanoma are good starting points.
2. Diagnosis + staging, pathology, imaging, sentinel node biopsy where indicated
3. Stage-based planning:
   • Stage 0/I: wide local excision alone
   • Stage II: wide excision, sentinel node biopsy, adjuvant therapy considered
   • Stage III resectable macroscopic: neoadjuvant immunotherapy pathway (this article)
   • Stage IV: systemic therapy first, surgery selective
4. Follow-up, surveillance imaging, skin checks, and long-term care planning. Life after melanoma covers what that looks like practically.

Minor surgery centres like TMSC play a real role in the front end: diagnostic biopsies, primary excisions for early-stage disease, and prompt referral into oncology for advanced cases. The best skin cancer clinic pathway outlines how that referral coordination works.

Frequently Asked Questions

Is neoadjuvant immunotherapy chemotherapy?
No. Immune checkpoint inhibitors work by unblocking the immune system, not by killing cells directly the way chemotherapy does. Side effects and monitoring differ from chemotherapy.

How many patients respond to neoadjuvant immunotherapy?
In NADINA, 59% achieved a major pathologic response (≤10% viable tumor) and 47.2% had a complete pathologic response. Real-world community centre data show similar numbers, with 67% major pathologic response in one 44-patient series [4].

Does neoadjuvant immunotherapy cure melanoma?
It significantly improves the odds of remaining disease-free, but "cure" language is used cautiously in oncology. Patients with major pathologic response have around 95% recurrence-free survival at 12 months, but long-term follow-up is still accumulating.

What's the difference between pembrolizumab and nivolumab + ipilimumab?
Pembrolizumab is single-agent anti-PD-1; nivolumab + ipilimumab combines anti-PD-1 with anti-CTLA-4. The combination has higher response rates but more toxicity. There's no head-to-head trial yet comparing them as neoadjuvant regimens.

Can I get neoadjuvant immunotherapy at any hospital?
No. It requires a centre with expertise in immune-related adverse event management and pathology capable of assessing treatment response. Most Canadian regional cancer centres qualify.

Will I lose my hair?
Hair loss is not typical with immune checkpoint inhibitors. Some patients experience mild hair thinning or color change (vitiligo-like depigmentation), but full alopecia is uncommon.

How long is recovery after surgery following neoadjuvant therapy?
Similar to standard lymph node dissection or wide excision, usually 2-6 weeks depending on the procedure, though wound healing may be slightly slower if you had significant immune-related inflammation.

Is neoadjuvant therapy covered in Canada?
For eligible stage III melanoma patients, yes. Canada's Drug Agency has recommended reimbursement (with conditions) for both pembrolizumab and nivolumab plus ipilimumab regimens. Provincial implementation varies.

Does this apply to amelanotic melanoma?
The trials enrolled cutaneous melanoma broadly. Amelanotic melanoma qualifies if it's cutaneous, resectable, and stage III with macroscopic disease, but mucosal and uveal (ocular) melanomas were excluded from NADINA.

Can neoadjuvant therapy be repeated if melanoma comes back?
Retreatment strategies exist but are individualized. Recurrence after neoadjuvant plus surgery usually triggers a new systemic plan, sometimes involving different drug classes or clinical trial enrollment.

Conclusion and Next Steps

Melanoma treatment before surgery has moved from experimental to guideline-recommended for a defined patient group: resectable stage III melanoma with clinically detectable nodal or in-transit disease. Phase III evidence from NADINA, combined with phase II data from SWOG S1801 and consistent real-world confirmation, makes this one of the clearest practice shifts in modern oncology.

What to do next:

1. Confirm your stage. Neoadjuvant immunotherapy only applies to stage III macroscopic disease. Earlier stages are still handled surgically.
2. Get to a multidisciplinary team. Ask your primary care doctor or surgeon for referral to a comprehensive cancer centre with melanoma expertise.
3. Ask specific questions. Which regimen fits your stage and BRAF status? What's the timing? What monitoring is in place for immune-related side effects?
4. Handle the front end promptly. Suspicious lesions still need biopsy and excision. If you need surgical evaluation for a mole, cyst, or suspicious spot in the GTA, TMSC operates clinics in Oakville, Mississauga, Vaughan, and North York.
5. Stay engaged post-treatment. Skin surveillance, imaging, and follow-up matter as much as the treatment itself.

Surgery still has a central role in melanoma care. What's changed is the sequencing for a specific group of patients, and for those patients, giving immunotherapy first is now the evidence-based choice.

References

[1] Neoadjuvant Immunotherapy Strategies In Stage III Melanoma - https://www.nature.com/nature-index/topics/l4/neoadjuvant-immunotherapy-strategies-in-stage-iii-melanoma

[2] Neoadjuvant immunotherapy monotherapy and combination comparisons - https://www.sciencedirect.com/science/article/pii/S1040842826003604

[3] Real-world neoadjuvant immunotherapy for stage III melanoma in Australia - https://www.sciencedirect.com/science/article/pii/S0959804926006465

[4] Community cancer center experience with neoadjuvant immunotherapy - https://ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e21561

[5] Pathological response as prognostic marker in neoadjuvant melanoma therapy - https://ascopubs.org/doi/10.1200/EDBK_390614

[6] Dana-Farber phase II neoadjuvant nivolumab + ipilimumab trial - https://www.dana-farber.org/clinical-trials/20-534

[7] T-VEC + pembrolizumab neoadjuvant trial (NCT03842943) - https://clinicaltrials.gov/study/NCT03842943

[8] NCI PDQ Melanoma Treatment - https://www.cancer.gov/types/skin/hp/melanoma-treatment-pdq

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