Clinical trialPhase 3Melanoma (skin cancer)

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma

N Engl J Med · 2024423 patients

Blank CU, Lucas MW, Scolyer RA, van de Wiel BA, Menzies AM, Lopez-Yurda M, et al. N Engl J Med. 2024. 391:1696-1708

Study type: Clinical trial
Study name: NADINA
Phase: Phase 3
Design: Open-label randomised trial
Sample size: 423 patients
Source: N Engl J Med · 2024
Trial registration: NCT04949113

In plain words

When melanoma has reached the lymph nodes and the affected node can be felt or seen, the traditional approach was surgery first and then immunotherapy. In this study, giving just two courses of combined immunotherapy before surgery raised the chance of staying free of relapse at one year from about 57% to 84%. About 6 in 10 patients had a very good response and needed no further treatment after surgery.

Key results

83.7% vs 57.2%

12-month event-free survival

HR for progression, recurrence or death 0.32; 99.9% CI 0.15–0.66

8.00 months

Difference in restricted mean survival time

99.9% CI 4.94–11.05; P<0.001

59.0%

Major pathological response (neoadjuvant group)

Partial response 8.0%, no response 26.4%, progression 2.4%

95.1%

12-month relapse-free survival with major pathological response

76.1% with partial response and 57.0% with no response

Drugs in this study:Nivolumab (Opdivo)Ipilimumab (Yervoy)

Dose and schedule cards

Neoadjuvant nivolumab + ipilimumab (NADINA)

Resectable stage III melanoma with macroscopic (clinically detectable) lymph node metastases, ECOG 0–1, no prior immunotherapy or BRAF/MEK therapy; preferred approach in ESMO 2025On the page “Melanoma (skin cancer)” · Resectable melanoma: neoadjuvant and adjuvant

Resectable stage III melanoma with macroscopic (clinically detectable) lymph node metastases, ECOG 0–1, no prior immunotherapy or BRAF/MEK therapy; preferred approach in ESMO 2025

Drug	Dose	Route	Schedule
Neoadjuvant
Ipilimumab	80 mg (flat dose)	IV	Every 3 weeks, 2 cycles
Nivolumab	240 mg	IV	Every 3 weeks, 2 cycles
Adjuvant, only for a partial or no pathological response
Nivolumab	480 mg	IV	Every 4 weeks, 11 cycles

Cycle length: Neoadjuvant every 21 days × 2, then lymph node dissection; adjuvant every 28 days
Duration: Major pathological response: no adjuvant therapy; partial or no response: nivolumab for 11 cycles or, with a BRAF V600E/K mutation, dabrafenib + trametinib for 46 weeks

Regimen and doses from the trial registration and the publication. The ipilimumab dose in this regimen (80 mg flat) differs from that of the metastatic-disease regimen, and this use is not included in the FDA label.

On the page “Melanoma (skin cancer)” · Resectable melanoma: neoadjuvant and adjuvant

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Neoadjuvant ipilimumab + nivolumab

Two cycles of ipilimumab 80 mg plus nivolumab 240 mg every 3 weeks, then lymph node dissection (and resection of in-transit metastases if needed). Only patients with a partial pathological response or no response received adjuvant therapy: nivolumab 480 mg every 4 weeks for 11 cycles, or, with a BRAF V600E/K mutation, dabrafenib plus trametinib for 46 weeks.

2Surgery then adjuvant nivolumab

Lymph node dissection followed by 12 cycles of adjuvant nivolumab 480 mg every 4 weeks.

Source of the regimen details: Abstract of the paper and ClinicalTrials.gov NCT04949113 (description of arms and inclusion criteria)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 16 years or older with resectable stage III melanoma of cutaneous or unknown primary origin, with one or more biopsy-confirmed macroscopic (clinically detectable) lymph node metastases (palpable node, or enlarged node with a short axis of at least 15 mm per RECIST 1.1, or PET-positive node) and up to 3 resectable in-transit metastases; WHO performance status 0 or 1; no prior anti-CTLA-4/PD-1/PD-L1 immunotherapy or BRAF/MEK targeted therapy; LDH below 1.5 times the upper limit and adequate organ function (ClinicalTrials.gov).

Endpoints

Primary outcome: event-free survival (progression, recurrence or death). Other outcomes: pathological response, relapse-free survival by pathological response and safety.

Safety and side effects

Grade 3 or higher adverse events related to systemic treatment: 29.7% in the neoadjuvant group versus 14.7% in the adjuvant group.

Clinical significance and place in guidelines

Together with SWOG S1801, NADINA made the neoadjuvant approach the new standard for resectable macroscopic stage III melanoma. The ESMO 2025 guideline recommends, for previously untreated resectable stage III melanoma, neoadjuvant nivolumab–ipilimumab followed by adjuvant therapy guided by pathological response and BRAF status [I, A], and allows omission of adjuvant therapy in patients with a major pathological response [I, A]. Note: at the time that guideline was published, this use did not have formal EMA or FDA approval.

Limitations

Short follow-up (median 9.9 months) and open-label design; overall survival data are still immature; the control group did not use single-agent neoadjuvant therapy; severe adverse events were roughly twice as frequent in the neoadjuvant group.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.