NADINA: two doses of ipilimumab plus nivolumab before surgery beat a year of nivolumab after surgery in stage III melanoma
Giving just two cycles of combination immunotherapy before removing melanoma lymph nodes cut relapses by more than two-thirds compared with a year of standard immunotherapy after surgery, and most patients needed no further treatment.
Open-label phase 3 trial of 423 patients with resectable, macroscopic stage III melanoma randomised to two cycles of neoadjuvant ipilimumab (80 mg) plus nivolumab (240 mg) followed by lymph node dissection, with adjuvant therapy only for those without a major pathological response, or to upfront surgery followed by 12 cycles of adjuvant nivolumab. Primary endpoint was event-free survival.
12-month EFS was 83.7% vs 57.2% (HR 0.32). A major pathological response occurred in 59% of neoadjuvant patients, and 95% of those were event-free at 12 months without any adjuvant therapy. It established neoadjuvant immunotherapy as the standard for macroscopic stage III melanoma and showed that the pathological response can be used to stop treatment early in most patients.
- 12-month event-free survival 83.7% vs 57.2%; HR 0.32 (99.9% CI 0.15-0.66).
- Major pathological response (10% or less viable tumour) in 59.0% of neoadjuvant patients; 12-month recurrence-free survival 95.1% in those patients with no adjuvant therapy.
- Partial pathological responders (12-month RFS 76%) and non-responders (57%) fared progressively worse and received adjuvant nivolumab or BRAF/MEK therapy.
- Grade 3 or higher systemic treatment-related adverse events 29.7% vs 14.7%.
- Patients in the neoadjuvant arm received a median of two immunotherapy cycles instead of twelve.
Patients with melanoma that has spread to palpable lymph nodes should now be offered immunotherapy before rather than only after surgery: two cycles of low-dose ipilimumab with nivolumab, then surgery, with the pathology result deciding whether any more treatment is needed. Most patients respond well and are spared a year of adjuvant therapy. Serious side effects are more common than with nivolumab alone, mostly endocrine, and the approach requires close coordination between oncologists, surgeons and pathologists.
- Open-label; follow-up is short and overall survival is not yet reported.
- Higher rate of serious immune-related toxicity in the neoadjuvant arm, including permanent endocrinopathies.
- Requires expert pathological assessment of response to guide de-escalation, which not all centres can provide.
- Patients with in-transit-only disease or BRAF-mutated tumours preferring targeted therapy were handled differently, limiting generalisability.