Christian Blank: We have pioneered neoadjuvant checkpoint inhibition in recent years. In melanoma, the efficacy of neoadjuvant checkpoint inhibition versus the current standard of adjuvant therapy needs to be confirmed in a phase 3 trial before neoadjuvant therapy can be considered a standard option for this patient population.

The NADINA trial is an international, open-label, two-arm, randomized phase 3 trial that includes 420 patients in Australia, Europe and the USA with stage III cutaneous or unknown primary melanoma. The current standard for resectable stage III melanoma is adjuvant anti-PD-1 therapy, which improves recurrence-free survival, but a considerable proportion of patients have a relapse in the years after therapeutic lymph-node dissection, and no overall survival benefit has been found so far.

The NADINA trial aims to compare the efficacy of neoadjuvant ipilimumab plus nivolumab with that of adjuvant nivolumab in macroscopic stage III melanoma. Patients diagnosed with recurrent or de novo stage III melanoma, including up to three in-transit metastases, will be randomly assigned to receive neoadjuvant treatment or adjuvant treatment.

Patients in the experimental arm will receive two cycles of 80 mg of ipilimumab plus 240 mg of nivolumab and will undergo therapeutic lymph-node dissection at week 6. In the case of pathological partial response or no response, surgery will be followed by adjuvant nivolumab (11 cycles) or adjuvant dabrafenib plus trametinib (for 46 weeks).

Patients in the standard control arm will undergo upfront therapeutic lymph-node dissection, followed by 12 cycles of 480 mg of nivolumab. The primary endpoint will be the event-free survival, defined as the time from randomization until progression to unresectable stage III or stage IV melanoma, recurrent melanoma, a new primary melanoma or death due to melanoma or treatment. We hope to see an overall survival benefit, which could become practice changing for stage III melanoma treatment.

Christian Blank is a professor of medical oncology at Leiden University, a staff member at the Netherlands Cancer Institute and a professor at the University of Regensburg, Regensburg, Germany.