2024 Top Story in Oncology: Neoadjuvant Nivolumab and Ipilimumab for Resectable Stage III Melanoma

The NADINA trial¹ was a highly anticipated investigator-initiated phase III trial that has not only redefined the standard of care for macroscopic stage III melanoma but also begs us to reconsider our treatment paradigms in other solid tumors.

The study randomized 423 patients to the old approach of surgery (therapeutic lymph node dissection [TLND]) followed by a year of adjuvant systemic therapy or to two doses of low-dose ipilimumab (80 mg) and full-dose nivolumab (240 mg) every 3 weeks followed by TLND.

Patients who achieved a major pathologic response (MPR; MPR = pathologic complete response [pCR] and near-pCR) did not receive any further adjuvant systemic treatment. Patients with a non-MPR either continued with nivolumab or switched to dabrafenib and trametinib if they harbored a BRAF mutation.

The MPR rate was 59%, meaning that nearly two-thirds of patients did not need to receive subsequent therapy after two neoadjuvant doses of the combination. This approach resulted in a massive improvement in the 12-month event-free survival rate of 26.5% in the neoadjuvant group versus the adjuvant group (83.7% vs 57.2%; HR, 0.32; P < .001).

These results open the window of opportunity to safely de-escalate surgery, as has been previously done in other cancers, such as breast-conserving surgery from the age of mastectomy. TLND is a potentially morbid surgery, with chronic lymphedema, which is known to significantly impact the quality of life, being a frequent occurrence (~25%–35%).

Moreover, immunotherapy seems mechanistically to work best prior to the removal of the tumor — potentially, also prior to any immunosuppressive procedures, such as chemotherapy or radiotherapy. At the moment, there is a dogma that, first, the standard-of-care approach must have been delivered before adding in a novel therapy. This might not yield the best results when using immunotherapy, and we are at risk of discarding therapies that might have had a benefit if they were simply delivered in a different order. In melanoma, the situation was relatively straightforward, as there was no established neoadjuvant therapy; however, for other solid tumors, this will require courage from investigators to have well-designed investigator-initiated trials that attempt to break these dogmas.

Despite this academic-sponsored study being well-conducted, of very high quality, and preceded by great work in phase I/II trials that formed a strong basis for this successful trial, an academic sponsor cannot submit the dossier to the regulators for approval. The FDA and EMA must oblige the pharmaceutical company to do their utmost to attempt to register this approach with the regulators to have the largest impact possible for all patients with melanoma around the world.

In the end, the NADINA trial is an amazing achievement driven by passionate academics that will have a lasting impact on the treatment of solid tumors.