Neoadjuvant Immunotherapy Combination Improves Outcomes in Patients With Melanoma

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Neoadjuvant immunotherapy given for stage III melanoma—followed by adjuvant therapy only if there is not a deep response to treatment—may produce better outcomes for patients than the current standard of care, which is adjuvant immunotherapy alone. These results from the NADINA trial were presented by Christian U. Blank, MD, PhD, and colleagues at the 2024 ASCO Annual Meeting (Abstract LBA2).

Christian U. Blank, MD, PhD

Christian U. Blank, MD, PhD

About the NADINA Study

The current standard-of-care treatment for resectable stage III melanoma is to remove the tumor and affected lymph nodes and then give systemic medications, such as targeted therapy or immunotherapy, adjuvantly. Recent evidence from phase I and II clinical trials has suggested that adding neoadjuvant immunotherapy before surgery may help improve patient outcomes.

One phase II trial, SWOG 1801, showed a significant improvement in outcomes for patients that receive a single immunotherapeutic before and after surgery. SWOG 1801 was the first study that led to the widespread use of neoadjuvant therapy in resectable stage III melanoma.

In the phase III NADINA trial, researchers studied whether treatment with ipilimumab and nivolumab before lymph nodes were surgically removed was more effective than treatment with nivolumab after the removal of lymph nodes. If this strategy did not induce a major pathologic response, patients would receive adjuvant therapy with nivolumab or, if the tumor contained a mutation in the BRAF gene, they would receive the targeted therapies dabrafenib plus trametinib.  

The study included a total of 423 patients: 212 received neoadjuvant therapy and 211 received adjuvant therapy. About two-thirds of the patients were men, and the average age of all participants was about 60 years. The patients were followed for a median of 9.9 months.

Key Findings

The researchers found that there were significantly fewer disease-related events among those who received neoadjuvant therapy than those who received adjuvant therapy alone (28 events vs 72 events, respectively). Those who received neoadjuvant therapy had a 27% absolute reduction in the risk of the disease returning in the first 12 months.

The researchers estimated that at 12 months, 83.7% of those receiving neoadjuvant therapy would be event-free compared to 57.2% of those who received adjuvant therapy alone. About three of every five patients who received neoadjuvant therapy did not need any additional adjuvant therapy because they had a major pathologic response and therefore had only 6 weeks of treatment. 

The benefits of neoadjuvant therapy continued to be seen when patients were evaluated based on whether the cancer had a BRAF mutation. In those with a BRAF mutation, the researchers estimated that 83.5% of patients who received neoadjuvant therapy were event-free at 12 months compared to 52.2% who received adjuvant therapy; for those without a BRAF mutation, the estimated 12-month event-free survival was 83.9% for neoadjuvant therapy and 62.4% for adjuvant therapy. 

The most common side effects (grade ≥ 3) in the neoadjuvant therapy arm were infection, diarrhea, abnormal blood counts, rash, fever, and fatigue. Serious treatment-related side effects arose in 29.7% of patients who were in the neoadjuvant arm and 14.7% of patients who were in the adjuvant arm. 

“NADINA should become a template for other neoadjuvant immunotherapy trials, leaving out the sandwich approach of neoadjuvant plus adjuvant therapy for all patients by incorporating a response-driven adjuvant therapy part. For melanoma, this approach can save a lot of time spent in hospital for about 60% of patients and thus also saves a lot of resources,” said lead study author Dr. Blank, of the Department of Medical Oncology at the Netherlands Cancer Institute, Amsterdam.

Next Steps

The researchers will look to further investigate how neoadjuvant immunotherapy may be personalized in melanoma. They also will study whether the surgical removal of lymph nodes can be skipped for patients who have a major pathologic response after receiving neoadjuvant immunotherapy. The ongoing follow-up for the NADINA trial will include collecting quality-of-life data and patient-reported outcomes through an app, and will also include a report on distant metastasis–free survival and overall survival in the future.

ASCO Perspective

“This randomized phase III clinical trial confirms data from several early clinical trials that treatment with immunotherapy for melanoma prior to surgery improves outcomes compared to patients receiving immunotherapy only after surgery. Importantly, in this study, patients received two immunotherapies, nivolumab and ipilimumab, confirming previous smaller studies that this combination is sufficiently tolerated, allows patients to undergo the planned potentially curative surgery, and leads to excellent responses,” commented Michael C. Lowe, MD, MA, of Emory University School of Medicine.

Disclosure: This study was sponsored by the Netherlands Cancer Institute, with co-sponsorship for Australia by the Melanoma Institute Australia and funded by Bristol Myers Squibb and National Health and Medical Research Council Australia. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.