Neoadjuvant Immunotherapy in Stage III Melanoma: Improved Outcomes with Response-Driven Approach

Recent advancements in the treatment of stage III melanoma highlight the benefits of neoadjuvant immunotherapy, as demonstrated by the phase III NADINA trial. This study compared the efficacy of administering ipilimumab (Yervoy) and nivolumab (Opdivo)  before lymph node removal to the traditional approach of giving nivolumab after surgery.

The results, presented at the 2024 ASCO Annual Meeting, indicate that this strategy yields superior event-free survival (EFS) and could potentially replace the current standard of care.

NADINA trial

The NADINA trial involved 423 patients with resectable, macroscopic stage III melanoma. Participants were randomized to receive either neoadjuvant therapy with ipilimumab and nivolumab followed by surgery or adjuvant nivolumab post-surgery (212 patients were enrolled for the neoadjuvant arm and 211 for the standard-of-care adjuvant group).

Most patients were male (65%) and ages were mixed between those over and under the age of 60. Most patients were enrolled in Europe (66%) and the T stage was balanced across T1 (14%), T2 (18.9%), T3 (21.3%), and T4 (23.2%). All patients had at least 1 PET-positive lymph node at diagnosis, with 19.6% having 2 to 3 nodes and 3.5% with more than 3 positive nodes. There were 11.3% of patients with metastases in transit.

If the neoadjuvant therapy did not result in a major pathologic response (MPR), patients received additional adjuvant therapy. The study’s interim analysis, with a median follow-up of 9.9 months, revealed significant improvements in EFS for the neoadjuvant group, including:

• EFS Rates: The 12-month EFS rate was 83.7% for patients receiving neoadjuvant therapy compared to 57.2% for those receiving adjuvant therapy alone. This represents a 26.5% absolute reduction in disease-related events.
• Response Rates: Nearly 60% of patients in the neoadjuvant arm achieved an MPR, allowing them to skip additional adjuvant therapy. Those with an MPR had a 12-month EFS rate of 95.1%.
• BRAF Mutation Subgroup: Patients with BRAF mutations also benefited from neoadjuvant therapy, with an EFS rate of 83.5% at 12 months versus 52.2% for the adjuvant group. For those without BRAF mutations, the rates were 83.9% versus 62.4%, respectively.

Adverse events and safety profile

While the neoadjuvant approach showed promising efficacy, it also resulted in a higher incidence of grade ≥ 3 systemic treatment-related adverse events compared to the adjuvant approach (29.7% vs. 14.7%).

Common side effects included infection, diarrhea, abnormal blood counts, rash, fever, and fatigue. Despite this, the surgery-related grade ≥ 3 adverse events were similar between the two groups (14.1% vs. 14.4%).

Clinical implications and future directions

The NADINA trial establishes three important benchmarks for melanoma treatment:

• It is the first phase III trial to compare neoadjuvant immunotherapy with adjuvant therapy in stage III melanoma.
• It adapts the administration of adjuvant therapy based on the response to neoadjuvant treatment.
• It evaluates a neoadjuvant regimen consisting solely of immunotherapy without additional chemotherapy.

This approach can significantly reduce hospital time and resource use for approximately 60% of patients. The findings suggest that neoadjuvant therapy, with response-driven adjuvant therapy, may become the new standard of care for resectable, macroscopic stage III melanoma.

These findings could save resources and improve patient quality of life by tailoring treatment based on individual responses.

Next steps in research

Ongoing follow-up of the NADINA trial will focus on collecting quality-of-life data and patient-reported outcomes, as well as assessing distant metastasis-free survival and overall survival. Researchers will also explore whether the surgical removal of lymph nodes can be skipped for patients who achieve a major pathologic response after neoadjuvant immunotherapy.

In summary, the phase III NADINA trial demonstrates that neoadjuvant immunotherapy with ipilimumab and nivolumab significantly improves outcomes for patients with stage III melanoma. This response-driven approach offers a promising alternative to the current standard of care, potentially setting a new benchmark for melanoma treatment.