Neoadjuvant nivolumab plus ipilimumab as a novel standard of care in resectable stage III melanoma

In the randomised phase III NADINA trial, two cycles of nivolumab plus ipilimumab prior to therapeutic lymph node dissection (TLND) and response-driven adjuvant therapy significantly decreased the risk of disease progression, recurrence, or death as compared with TLND and adjuvant nivolumab alone for patients with resectable, macroscopic stage III melanoma. Together with SWOG S1801, NADINA defines neoadjuvant immunotherapy as the new standard of care for macroscopic stage III melanoma.

Background

To date, the standard of care (SOC) for resectable, macroscopic stage III melanoma is therapeutic lymph node dissection (TLND) followed by adjuvant therapy with nivolumab, pembrolizumab or, in BRAF-mutated melanoma, dabrafenib plus trametinib. The recent phase II SWOG S1801 trial showed superior event-free survival (EFS) of neoadjuvant plus adjuvant pembrolizumab as compared to adjuvant pembrolizumab. Additional phase II trials demonstrated safety and high efficacy of neoadjuvant ipilimumab plus nivolumab, providing the rationale for testing neoadjuvant nivolumab plus ipilimumab against SOC in a phase III trial.

Study design

NADINA is an international phase III study in which patients ≥16 years with resectable, macroscopic, nodal stage III melanoma, naïve to immune checkpoint inhibitors and BRAF/MEK inhibitors, were randomised (1:1) to (a) two cycles of neoadjuvant treatment with ipilimumab and nivolumab (q3w), followed by therapeutic lymph node dissection and in case of not achieving a major pathologic response (MPR) 46 weeks of adjuvant dabrafenib/trametinib or 11 cycles of adjuvant nivolumab; or (b) therapeutic lymph node dissection followed by 12 cycles of adjuvant nivolumab (q4w). The primary outcome measure was EFS, analysed in the intention-to-treat population. Secondary outcomes included overall survival, pathological response and recurrence-free survival (RFS), adverse events, surgical complications and health-related quality of life.

Results

A total of 423 patients were randomised to the neoadjuvant group (N= 212) or the adjuvant group (N= 211). After a median follow-up of 9.9 months, the 12-month EFS was 83.7% in the neoadjuvant group and 57.2% in the adjuvant group (HR[99.9%CI]: 0.32[0.15-0.66], p< 0.0001). Interestingly, the EFS benefit for nivolumab plus ipilimumab was observed in all key subgroups. In the subgroup of BRAF-mutated melanoma, estimated one-year EFS rates were 83.5% and 52.1%, and in BRAF-wildtype 83.9% and 62.4% for neoadjuvant versus adjuvant treatment respectively. Of the patients in the neoadjuvant group, 59.0% had a pathologically complete or near-complete response, 8.0% had a pathological partial response and 26.4% a pathological non-response. In 2.4% of patients in the neoadjuvant group, disease progression had occurred before surgery and in 4.2% of patients surgery had not yet been performed or was omitted. In the neoadjuvant group, the 12-month RFS rates according to pathological response were 95.1% for patients with a major pathological response, 76.1% for those with a pathological partial response and 57.0% for  those with a pathological non-response. Grade 3 or higher systemic treatment-related adverse events occurred in 29.7% of patients in the neoadjuvant group and in 14.7% of patients in the adjuvant group. One patient in the adjuvant arm died due to treatment-related toxicity (pneumonitis).

Conclusions

The NADINA study is the first phase III trial that evaluates neoadjuvant immunotherapy against SOC in melanoma, and is also the first phase III trial in oncology evaluating a neoadjuvant regimen consisting of immunotherapy alone. The study demonstrated that neoadjuvant treatment with ipilimumab and nivolumab resulted in a highly statistically significant EFS benefit as compared to standard of care adjuvant PD-1 blockade. Nearly 60% of patients in the neoadjuvant arm needed only six weeks of treatment. No new safety signals were observed.

Reference

Blank CU, et al. Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: the phase 3 NADINA trial. Presented at ASCO 2024; Abstract LBA2.