A multicenter, randomized phase Ib trial to evaluate neoadjuvant immunotherapy combination of nivolumab alone or plus ipilimumab with the IL-2 superkine MDNA11 alone or with tocilizumab in patients with high-risk, surgically resectable melanoma: The NEO-CYT trial.

Abstract

TPS9612 Background: Neoadjuvant immunotherapy, administered upfront of surgery in patients with resectable stage III melanoma, has shown superior efficacy in recent trials compared to post-surgical adjuvant treatment, due to enhanced anti-tumor immunity when the tumor microenvironment is intact. A pre-operative regimen of 2 cycles of ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy (as per NADINA trial) results in substantially improved event-free survival. However, even with this regimen 41% of patients did not achieve a Major Pathologic Response (MPR), with 8% having a partial pathological response and 26.4% showing pathological non-response. Previous analyses have shown a ‘cold’ CD4-IL-2 signature being associated with no-response, which could be overcome by the addition of IL-2. MDNA11 is a long-acting engineered interleukin (IL)-2 albumin fusion protein, with enhanced affinity for IL-2 receptor β (IL-2Rβ/CD122) and no binding to IL-2Rα (CD25). This design enhances the stimulation of IL-2Rβ-expressing CD8+ T cells and NK cells whilst diminishing the activation of Tregs constitutively expressing the heterotrimeric receptor containing IL-2Rα. Thus, we hypothesize that MDNA11 combination with nivolumab +/- ipilimumab may further enhance clinical outcomes of neoadjuvant standard therapy. Methods: This is a phase Ib, prospective, open-label, randomised study where a 6- week neoadjuvant phase is followed by a 7-week surgery/post-surgery phase and a 49-week adjuvant phase as per clinical practice. The study population will include adult patients of either sex aged ≥ 18 years with surgically resectable stage IIIB/C/D cutaneous melanoma. Twenty patients will be enrolled in each arm for a total of up to 80 patients. The ARM A is the control one with Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles as for NADINA trial; the ARM B includes Nivolumab 240 mg every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM C includes Ipilimumab 80 mg plus Nivolumab 240 mg administered every 3 weeks for 2 cycles plus MDNA11 at 30 μg/kg on week 0 followed by MDNA11 at 60 μg/kg on week 2 and week 4; the ARM D adds tocilizumab 4 mg/Kg on week 0 at the same schedule of the ARM C. The study’s primary endpoint is the Major Pathologic Response (MPR) rate at surgery, defined as ≤10% viable tumor in the treated tumor bed. Co-primary endpoints include the incidence, severity, and duration of treatment-related adverse events, particularly immune-related, as per CTCAE v5.0. Health-related quality of life will be analyzed using longitudinal models. Exploratory analyses will investigate biomarker associations with outcomes to generate hypotheses. Clinical trial information: 2024-519010-31-00.