Neoadjuvant nivolumab alone versus nivolumab plus ipilimumab for resectable stage III melanoma

SWE-NEO: Swedish NeoAdjuvant Trial Comparing Anti-PD-1 Monotherapy to Combined Anti-CTLA-4/Anti-PD-1 Blockade in Resectable Stage III Melanoma

This trial will try two pre-surgery immunotherapy approaches—nivolumab alone or nivolumab plus ipilimumab—in adults with resectable stage III melanoma to see which gives better tumor response and longer benefit.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 128 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Karolinska University Hospital (Academic / other)
• Drugs / interventions: immunotherapy, prednisone
• Locations: 3 sites (Gothenburg and 2 other locations)
• Trial ID: NCT06794775 on ClinicalTrials.gov

What this trial studies

This is a phase III, randomized, open-label multicenter trial in patients with resectable stage III melanoma who are randomized to receive either two courses of nivolumab monotherapy or two courses of combined nivolumab plus ipilimumab prior to planned surgical resection. After surgery, patients without a major pathological response receive adjuvant PD‑1 inhibitor therapy or BRAF+MEK inhibitors for BRAF V600E-mutant tumors, while those with a major pathological response do not receive routine adjuvant therapy. Active clinical follow-up is conducted for three years after surgery with survival follow-up up to ten years. Sequential blood and tumor samples are collected for biomarker analyses to correlate molecular features with treatment response.

Who should consider this trial

Good fit: Adults (≥18 years) with histologically confirmed resectable stage III cutaneous, acral, or unknown primary melanoma, WHO performance status 0–1, and who can undergo complete surgical resection are ideal candidates.

Not a fit: Patients with unresectable disease, significant comorbidities that prevent safe use of immunotherapy or surgery, or those unlikely to tolerate higher rates of immune-related toxicity may not receive benefit from the combined regimen.

Why it matters

Potential benefit: If successful, the trial could show whether adding ipilimumab before surgery increases tumor clearance and improves long-term outcomes for resectable stage III melanoma patients.

How similar studies have performed: Prior randomized neoadjuvant trials (SWOG S1801 and NADINA) showed advantages for neoadjuvant approaches versus adjuvant-only therapy, but a direct head-to-head comparison of PD‑1 alone versus PD‑1/CTLA‑4 combination in this setting is novel.

Eligibility criteria

Inclusion Criteria:

1. Participants must be at least 18 years of age.
2. Can provide a signed informed consent as described in the protocol, including compliance with the requirements and restrictions listed in the ICF and in this protocol.
3. World Health Organization (WHO) Performance Status 0 or 1.
4. Patients must have

   1. Histologically or cytologically confirmed Stage III melanoma. In the case of in-transit metastases (with or without lymph node metastases)' ≤3 resectable in-transit metastases are allowed.
   2. Patients with cutaneous, acral, or unknown primary melanomas are eligible for enrollment.
   3. Resectable tumors are defined as having no significant vascular, neural or bony involvement. Only patients where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable.
5. Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
6. Female patients of childbearing potential must be willing to use a highly effective method of contraception, for the course of the study through 150 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Highly effective methods of contraception include one or more of the following:

   1. male partner who is sterile (vasectomised) prior to the female study subject's entry into the study and is the sole sexual partner for the female subject;
   2. hormonal (oral, intravaginal, transdermal, implantable or injectable)
   3. an intrauterine hormone-releasing system (IUS)
   4. an intrauterine device (IUD) with a documented failure rate of \< 1%.
7. Male patients of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 150 days after the last dose of study therapy. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. A unique female sexual partner must postmenopausal, permanently sterilized (e.g. hysterectomy or tubal ligation), or use a highly effective method of contraception.
8. No other malignancies, except if treated with curative intent and with a cancer-related life expectancy of more than 5 years.
9. No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1.
10. No prior targeted therapy targeting BRAF and/or MEK.

Exclusion Criteria:

1. Unresectable melanoma
2. Uveal/ocular or mucosal melanoma
3. Any serious or uncontrolled medical conditions that, in the investigator's opinion, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results .
4. Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
5. Women who are pregnant or breastfeeding.
6. Any condition that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial.

Where this trial is running

Gothenburg and 2 other locations

• Sahlgrenska University Hospital — Gothenburg, Sweden (Recruiting)
• Skane University Hospital — Lund, Sweden (Recruiting)
• Karolinska University Hospital — Stockholm, Sweden (Recruiting)

Study contacts

• Study coordinator: Hildur Helgadottir, MD, PhD

Conditions Malignant Melanoma Stage III; Immune checkpoint inhibitors; Nivolumab; Ipilimumab; Neoadjuvant; anti-PD-1; anti-CTLA-4