Neoadjuvant immunotherapy given for stage III melanoma, followed by adjuvant therapy only if there is not a deep response to treatment, promises better outcomes for patients than the current standard of care, which is adjuvant immunotherapy alone. 

The research was presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place May 31-June 4 in Chicago, Illinois.

“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 Christian U. Blank, MD PhD, Medical Oncology at the Netherlands Cancer Institute, Amsterdam.

The current standard-of-care treatment for stage III melanoma that can be treated by surgery is to remove the tumor and affected lymph nodes and then give systemic medications, such as targeted therapy or immunotherapy, to lower the chances of the cancer coming back (also known as adjuvant therapies). 

Recent evidence from phase 1 and phase 2 clinical trials has suggested that adding immunotherapy before surgery (neoadjuvant therapy) may help improve patient outcomes. 

One phase 2 trial, SWOG 1801, showed a significant improvement in outcomes for patients that receive a single immunotherapy drug before and after surgery, which was the first study that led to the widespread use of neoadjvuant therapy in resectable stage 3 melanoma.

In the phase 3 NADINA trial, researchers studied whether treatment with the immunotherapies ipilimumab and nivolumab before lymph nodes were surgically removed was more effective than treatment with nivolumab after the removal of lymph nodes. 

If this treatment did not destroy 90% or more of the tumour cells in the surgically removed lymph nodes (called a major pathological response), patients would receive adjuvant therapy with nivolumab or, if the tumour 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 participants receiving neoadjuvant therapy and 211 participants receiving 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 (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. 

About 3 of every 5 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 the participants were evaluated based on whether the cancer had a BRAF mutation.

In those with a BRAF mutation, the researchers estimated that 83.5% of people 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 or higher) in the neoadjuvant arm were infection, diarrhoea, abnormal blood counts, rash, fever, and fatigue. 

Serious side effects related to these medications arose in 29.7% of patients who were in the neoadjuvant arm and 14.7% of patients who were in the adjuvant arm. 

“This randomised phase 3 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.” – Michael C. Lowe, MD, MA, Emory University School of Medicine, Atlanta, Georgia

Next Steps

The researchers look to further investigate how neoadjuvant immunotherapy may be personalised in melanoma. 

They also will study whether 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 report on distant metastasis-free survival and overall survival in the future.

This study was sponsored by the Netherlands Cancer Institute (NKI), with co-sponsorship for Australia by the Melanoma Institute Australia (MIA) and funded by Bristol Myers-Squibb (BMS) and National Health and Medical Research Council Australia (NHMRC).

Source: ASCO