NeoIRENIE: A phase 2 randomized trial of intensified neoadjuvant therapy for melanoma patients with multi-omic biomarker or clinically predicted poor response to standard immune checkpoint inhibitor (ICI) therapy.

TPS9610 Background: Neoadjuvant immunotherapy (NAT) with immune checkpoint inhibitors (ICI) has emerged as superior treatment for stage III melanoma, demonstrating improved outcomes compared to adjuvant therapy. The SWOG-1801 trial showed 23% EFS benefit at 2 years for NAT versus adjuvant PEMBRO (72% vs 49%, P=0.004), while the NADINA trial confirmed superiority of NAT IPI/NIVO over adjuvant NIVO (2-year RFS 83.7% vs 57.2%, HR 0.32). Pathological response, particularly major pathological response (MPR; ≤10% viable tumor), strongly correlates with improved outcomes, with the International Neoadjuvant Melanoma Consortium pooled analysis (N=610 ICI patients) demonstrating 3-year RFS of 93% for MPR patients versus 41% for those with no pathological response. However, standard NAT with IPI (1mg/kg) and NIVO (3mg/kg) achieves MPR in only ~60% of patients. Multi-omic biomarkers can predict poor response to anti-PD-1 therapy, identifying patients who may benefit from intensified ICI therapy. The NeoIRENIE trial evaluates whether intensified ICI regimens improve pathological response in poor prognosis patients identified by biomarker prediction, treatment failure, or mucosal histology. Methods: Phase 2, non-comparative, multicenter, randomized trial with 3 cohorts (N=493, Table 1). All pts undergo therapeutic lymph node dissection/completion surgery at week 6 with path response evaluation per INMC criteria. Cohorts 1a, 2 and 3 pts without MPR receive adjuvant NIVO 480mg Q4W for 11 doses. CT, MRI brain and FDG PET/CT performed at baseline, pre-surgery and during 10-year follow-up. Tumor, blood and stool samples collected at baseline, wk 3, surgery and recurrence. Primary endpoint: path response rate in each INMC response category. Secondary endpoints: event-free survival, RECIST response rate, metabolic response rate, overall survival, safety/tolerability, surgical outcomes and quality of life. Exploratory endpoints: biomarker analyses and validation of multi-omic predictive model. Clinical trial information: NCT06999980 . Cohort N Resectable Melanoma Patient Population *Arms(Randomization) 1a 168 Stage IIIB/C/D cutaneous; biomarker-predicted poor responders; treatment-naïve A-D(1:1:1:1) 1b 154 Stage IIIB/C/D cutaneous; biomarker-predicted high responders; treatment-naïve E-F(1:1) 2 111 Stage IIIB/C/D cutaneous; recurrence within 6 months of adjuvant or NAT ICI therapy A-C(1:1:1) 3 60 Any stage mucosal melanoma; treatment-naïve A-B(1:1) * Arms: A=IPI 3mg/kg + NIVO 1mg/kg Q3W x2. B=NIVO 480mg + RELA 160mg + IPI 1mg/kg Q4W x2. C=NIVO 480mg + RELA 160mg Q4W x2. D=IPI 1mg/kg + NIVO 3mg/kg Q3W x2. E=IPI 1mg/kg + NIVO 3mg/kg Q3W x2. F=PEMBRO 200mg Q3W x2.