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Neoadjuvant Ipilimumab Plus Nivolumab Results in Longer EFS Than Adjuvant Nivolumab in Resectable, Macroscopic Stage III Melanoma

Findings from NADINA study
10 Jun 2024

NADINA, a phase III, investigator-initiated study compared neoadjuvant with adjuvant immunotherapy in patients with resectable, macroscopic stage III melanoma. Two cycles of neoadjuvant ipilimumab plus nivolumab followed by a therapeutic lymph-node dissection and response-driven adjuvant treatment resulted in longer event-free survival (EFS) as compared with the current standard care of up-front therapeutic lymph-node dissection followed by 12 cycles of adjuvant nivolumab.

The results in the neoadjuvant group, an estimated EFS at 12 months of 83.7% and a major pathological response (MPR) in 59.0% of the patients, are in line with the efficacy found in the preceding phase II studies that evaluated neoadjuvant ipilimumab plus nivolumab. The study findings are presented at ASCO 2024 Annual Meeting along with simultaneous publication by Dr. Christian U. Blank of the Department of Medical Oncology and Division of Molecular Oncology and Immunology, Netherlands Cancer Institute in Amsterdam, Netherlands and colleagues on 2 June 2024 in The New England Journal of Medicine.

The authors wrote in the background that standard management of resectable, macroscopic stage III melanoma is currently surgery, which can be followed by adjuvant systemic therapy. PD1 inhibitors nivolumab and pembrolizumab have been shown to prolong recurrence-free survival (RFS) as compared with either the CTLA4 inhibitor ipilimumab or placebo. Among patients with melanoma with a BRAF V600E or V600K mutation, BRAF targeted therapy with dabrafenib plus trametinib has shown a benefit as compared with placebo.

Despite adjuvant systemic treatment, a substantial proportion of patients have disease recurrence within the first few years after surgery. In addition, none of the approved adjuvant immunotherapies have shown a significant overall survival (OS) benefit despite long-term follow-up, a finding that emphasises the need for new treatment approaches. Based on preclinical and phase I data, neoadjuvant administration of immune checkpoint inhibitors is hypothesised to yield efficacy superior to that of adjuvant administration. Recent phase II data provided the rationale for testing neoadjuvant regimen against the current standard care of adjuvant anti–PD1 in the randomised phase III study.

In the phase III NADINA study, the investigators randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or non-response received adjuvant treatment. The primary endpoint was EFS.
A total of 423 patients underwent randomisation. At a median follow-up of 9.9 months, the estimated 12-month EFS was 83.7% (99.9% confidence interval [CI] 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI 4.94 to 11.05; p < 0.001; hazard ratio for progression, recurrence, or death 0.32; 99.9% CI, 0.15 to 0.66). 

In the neoadjuvant group, 59.0% of patients had MPR, 8.0% had a partial response, 26.4% had a non-response (>50% residual viable tumour), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month RFS was 95.1% in patients in the neoadjuvant group who had MPR, 76.1% among those with a partial response, and 57.0% among those with a non-response.

Adverse events of any cause of grade 3 or higher were reported in 47.2% of the patients in the neoadjuvant group and in 34.1% in the adjuvant group. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% of the patients in the adjuvant group.

According to the authors, advantage in EFS comes with higher toxicity, which emphasises the need to identify subgroups of patients who may benefit from one or the other scheme; the efficacy of these treatments in specific subgroups of patients should be investigated in head-to-head comparison trials. Alternative neoadjuvant regimens with anti–PD1 backbones, including the combination with anti–LAG3, which has shown promising results in a phase II study, could be considered for comparison with neoadjuvant ipilimumab plus nivolumab.

NADINA is the first phase III study in oncology evaluating a neoadjuvant regimen consisting of immunotherapy alone. Despite the evident superiority of neoadjuvant treatment over adjuvant treatment, this first, preplanned interim analysis of the study reflects a relatively short follow-up. Follow-up is ongoing for the assessment of long-term EFS and distant metastasis–free survival, health-related quality-of-life, and ultimately OS.

The study was supported by Bristol Myers Squibb, a grant in Australia from the National Health and Medical Research Council (NHMRC), investigator grants from the NHMRC and funding from Nicholas and Helen Moore and Melanoma Institute Australia.


Blank CU, Lucas MW, Scolyer RA, et al. Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. NEJM; Published online 2 June 2024. DOI: 10.1056/NEJMoa2402604

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