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Blank CU, et al. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. The New England journal of medicine. 2024;391:1696-1708. PMID 38828984

One-paragraph summary

NADINA randomised 423 patients with resectable macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery, or to surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or non-response received adjuvant treatment, so the trial compares two whole pathways rather than two drugs. At a median follow-up of 9.9 months, estimated 12-month event-free survival was 83.7% (99.9% CI 73.8–94.8) in the neoadjuvant group and 57.2% (45.1–72.7) in the adjuvant group; the difference in restricted mean survival time was 8.00 months (99.9% CI 4.94–11.05, P < .001) with a hazard ratio for progression, recurrence or death of 0.32 (99.9% CI 0.15–0.66). In the neoadjuvant group 59.0% had a major pathological response, 8.0% a partial response, 26.4% a non-response and 2.4% progression; in 4.2% surgery had not yet been performed or was omitted. Estimated 12-month recurrence-free survival among major pathological responders was 95.1% (NCT04949113).

Key findings

  • 12-month event-free survival 83.7% vs 57.2%; HR 0.32 (99.9% CI 0.15–0.66), P < .001.
  • Restricted mean survival time difference 8.00 months (4.94–11.05).
  • Major pathological response in 59.0%; among those, 12-month recurrence-free survival 95.1%.
  • Major pathological responders received no adjuvant therapy at all, so the neoadjuvant arm delivered two cycles against the adjuvant arm's twelve.
  • The pathological-response distribution is itself an outcome: 59.0% major, 8.0% partial, 26.4% non-response, 2.4% progression.

Limitations

  • Median follow-up at publication was 9.9 months; the 95.1% recurrence-free survival among responders rests on that.
  • The primary endpoint is event-free survival, not overall survival, and no trial in the current phase 3 landscape compares modern neoadjuvant against modern adjuvant therapy with overall survival as primary (see clinical trials landscape).
  • Event-free survival definitions in neoadjuvant trials contain components that can only occur in one arm's timeline, which is the structural basis of the time-bias critique levelled at the companion trial SWOG S1801 (Olivier 2024, PMID 38621314). NADINA's phase 3 design answers the chance-finding objection but not the endpoint-construction one.
  • The comparison confounds sequencing with treatment duration and with de-escalation; it cannot separate them.
  • NeoCombi's five-year data are a caution about pathological response as a surrogate in a different modality: 60% of patients recurred despite high pathological response rates to targeted therapy (Menzies 2024, PMID 38754780).

Why it matters

NADINA is the first phase 3 trial to test neoadjuvant immunotherapy against the adjuvant standard in melanoma, and its effect size is large enough that the 2024 European guideline already recommends the approach (Garbe 2025, PMID 39709737). More importantly, it operationalises something adjuvant therapy structurally cannot offer: a pathological read-out within weeks that permits de-escalation of both surgery and systemic therapy. The PRADO cohort had shown the concept was feasible (Reijers 2022, PMID 35661157); NADINA showed it works at phase 3 scale. The open question it leaves is whether the advantage is a survival advantage or a rearrangement of when treatment is given.

Cited by wiki pages

  • neoadjuvant therapy
  • adjuvant therapy
  • surgical management and margins
  • overview
  • guidelines
  • clinical trials landscape