Dual Immunotherapy Eliminates Postoperative Treatment in 60% of Stage 3 Melanoma Cases

NADINA showed that, in patients with advanced (stage III), resectable skin cancer (melanoma) , neoadjuvant (preoperative) treatment with the two immunotherapy drugs ipilimumab and nivolumab was more effective than adjuvant (postoperative) nivolumab alone.

Key Points:

• The preoperative combination of two immunotherapies (ipilimumab and nivolumab), followed by adjuvant treatment if there was no response, provided better "disease-free survival" than adjuvant nivolumab alone in stage III melanoma.
• Nearly 60% of patients in the experimental arm received only 2 cycles of neoadjuvant ipilimumab and nivolumab and did not need additional adjuvant treatment.
• Grade 3 or higher systemic treatment-related adverse events were more frequent in the neoadjuvant group: 29.7% versus 14.7% in the adjuvant group.

ASCO 2024 featured NADINA as one of its most notable studies. It was published on June 2 in NEJM at the same time as the congress.

Before This Study

Before this study, typical treatment for resectable stage III melanoma began with therapeutic lymph node dissection (removing affected lymph nodes), followed by adjuvant nivolumab or pembrolizumab for patients without a BRAF mutation, or dabrafenib/trametinib for those with a BRAF mutation.

Approximately 15-20% of patients have stage III melanoma at diagnosis. This proportion highlights the importance of early detection.

NADINA aimed to find a more effective and better-tolerated alternative to the current standard treatment for stage III melanoma.

Why NADINA Matters: A New Era in Melanoma

NADINA breaks new ground in 3 important ways:

1. It is the first phase 3 study comparing neoadjuvant immunotherapy with the current standard of adjuvant treatment in stage III melanoma.
2. It is the first study in melanoma to evaluate response-adapted adjuvant treatment instead of giving it to everyone.
3. It is the first phase 3 study in oncology to evaluate a neoadjuvant regimen consisting only of immunotherapy, without chemotherapy.

Details of the NADINA Study

Study Design:

• Participants: The study enrolled 423 patients with resectable, advanced (stage III) melanoma.
• Groups: Patients were randomized to two groups. The first received two courses of ipilimumab and nivolumab before surgery (the neoadjuvant group), while the second received 12 courses of nivolumab after surgery (the adjuvant group).
• Additional Treatment in the Neoadjuvant Group: Patients in the neoadjuvant group whose tumors did not show a partial or complete response received additional postoperative (adjuvant) treatment.
• Primary Outcome: The study's primary aim was to assess disease-free survival.

Findings:

• Disease-Free Survival: At a median follow-up of 9.9 months, the 12-month disease-free survival rate in the neoadjuvant group was 83.7% , compared with 57.2% in the adjuvant group (a difference of 26.5%). This indicates that neoadjuvant treatment significantly reduced the risk of recurrence, progression or death.
• Pathological Response: In the neoadjuvant group, 59% had substantial tumor regression on postoperative assessment (major pathological response), 8% had a partial response and 26.4% had no response.
• Recurrence-Free Survival: In the neoadjuvant group, 12-month recurrence-free survival was 95.1% among patients with substantial tumor regression, 76.1% among partial responders and 57% among nonresponders.
• Adverse Events: Grade 3 or higher adverse events were more common in the neoadjuvant group (29.7%) than in the adjuvant group (14.7%). However, these events did not lead to surgical complications.

Below are the disease-free survival data for NADINA's primary endpoint:

Commentary

Neoadjuvant treatment followed by response-based adjuvant therapy appears likely to replace adjuvant therapy in stage III melanoma.

NADINA should serve as a model for other neoadjuvant immunotherapy trials. It has shown that we should move toward response-based adjuvant therapy instead of giving both neoadjuvant and adjuvant treatment to every patient.

Future Studies

Future studies are planned to include groups receiving no perioperative (before-and-after-surgery) systemic treatment and groups receiving single-agent immunotherapy before surgery. These studies will help establish how different approaches affect long-term survival and provide benchmarks for evaluating new treatments.