Ipilimumab (CTLA-4) + nivolumab–relatlimab (PD-1/LAG-3) drives 69% MPR (63% pCR) in resectable stage III melanoma—at the cost of 26% G3 and 1 G5 myocarditis

Neoadjuvant INR combines low-dose ipilimumab (CTLA-4 blockade) with fixed-dose nivolumab–relatlimab (PD-1/LAG-3 blockade) to deepen pathologic responses while keeping treatment short. In this Phase II trial in high-risk resectable AJCC8 stage IIIB–D melanoma (NCT06295159), patients received ipilimumab 1mg/kg once plus nivolumab–relatlimab 480/160mg q4w for 2 doses, then surgery; 20 patients enrolled (Aug 2024–Jan 2026), with 16 resected and evaluable for pathology (median time to surgery 73 days). Among resected patients, pCR was 10/16 (63%) and MPR (pCR+near-pCR) was 11/16 (69%); by contrast, the most-used neoadjuvant benchmark regimen (ipi 1mg/kg + nivo 3mg/kg x2 in OpACIN-neo) delivered a ~77% pathologic response rate with ~20% G3–4 irAEs, and Phase III NADINA established neoadjuvant ipi/nivo as superior to adjuvant PD-1 with 1-year EFS 83.7% vs 57.2% (though cross-trial comparisons are imperfect). Safety: among 19 treated, 26% had grade 3 AEs (colitis, encephalitis, headache, hyperglycemia, rash) and there was 1 grade 5 myocarditis; median follow-up was 9.8 months, and no post-surgery recurrences were reported to date (immature EFS/OS).