Advanced melanoma: fewer relapses if immunotherapy is given before surgery

Advanced melanomas: recurrences which remain frequent

The current standard treatment for stage III melanoma that can be treated with surgery involves removing the tumor and affected lymph nodes, then administering systemic medications, such as targeted therapy or immunotherapy, to reduce the chance of recurrence cancer (also called adjuvant therapies).

A significant proportion of patients with resectable stage III melanoma experience recurrence after standard treatment, namely therapeutic lymph node dissection with adjuvant therapy.^1-4.

Small studies have suggested that using immunotherapies earlier, before surgery (neoadjuvant situation) could improve patient outcomes^5-7. But until now, there have been no phase 3 clinical trials using neoadjuvant immunotherapy.

Immunotherapy before or after surgery?

Presented at the 2024 ASCO Congress, the NADINA phase 3 trial⁸ aims to evaluate whether treatment with the immunotherapies ipilimumab and nivolumab⁹ before surgical lymph node removal was more effective than nivolumab treatment after lymph node removal.

If this treatment did not kill 90% or more of the tumor cells in the surgically removed lymph nodes (called a major pathological response), patients received adjuvant treatment (after surgery) with nivolumab or, if the tumor contained a particular mutation in the BRAF gene, they received the targeted therapies dabrafenib plus trametinib.

27% fewer recurrences if immunotherapy is given before

The study included a total of 423 patients; 212 participants receiving neoadjuvant treatment and 211 participants receiving adjuvant treatment. Patients were followed for a median duration of 9.9 months. And the results are clear in terms of reducing the risk of recurrence:

• Fewer recurrences in those who received neoadjuvant therapy than in those who received adjuvant therapy (28 events versus 72 events, respectively). Those who received neoadjuvant treatment had a 27% absolute reduction in risk of recurrence during the first 12 months.
• At 12 months, 83.7% of people receiving neoadjuvant treatment would no longer experience events, compared to 57.2% of those who received adjuvant treatment. Approximately 3 out of 5 patients who received neoadjuvant therapy did not require any additional adjuvant therapy because they had a major pathological response and therefore only had 6 weeks of treatment.
• In people with a BRAF mutation, researchers estimated that 83.5% of people who received neoadjuvant therapy had no recurrence at 12 months, compared with 52.2% who received adjuvant therapy.
• For people without BRAF mutations, the estimated 12-month recurrence-free survival was 83.9% for neoadjuvant therapy and 62.4% for adjuvant therapy.

This combination of immunotherapies, however, leads to more frequent and more serious side effects: serious side effects linked to these drugs occurred in 29.7% of patients in the neoadjuvant group and 14.7% of patients in the adjuvant group, even if the quality of life of the two groups seems identical according to complementary results¹⁰ also presented at ASCO 2024.

Towards a new standard of treatment for melanoma

“This randomized phase 3 clinical trial confirms data from several early clinical trials that immunotherapy treatment of melanoma before 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 great answers” specifies Professor Michael C. Lowe of the Emory University School of Medicine (Atlanta) and principal author of the study.

Researchers are continuing their work to study how neoadjuvant immunotherapy can be personalized in melanoma. Data on quality of life, metastasis-free survival and overall survival will also need to complete this work, as the current follow-up of barely one year does not allow this information to be available.

We know that melanoma is the first cancer to benefit from immunotherapies and to see its prognosis changed by these compounds. Today, it is logically on this formidable cancer that the use of immunotherapies before surgery is evaluated, but we can think that these very encouraging results (even if we await the data on overall survival) could lead to exploring this same strategy. in other cancers.