Background: Early results of the OpACIN-neo study testing 3 different dosing schedules of neoadjuvant IPI + NIVO demonstrated that 2 cycles IPI 1mg/kg + NIVO 3mg/kg (IPI1NIVO3, arm B) was the most favorable schedule with 20% grade 3-4 immunotherapy-related adverse events (irAEs) and a pathologic response rate (pRR) of 77%. After a median follow-up (FU) of 8.3 months, none of the 64 patients (pts) with a pathologic (path) response ( < 50% viable tumor cells) versus 9/21 (43%) without a path response had relapsed. Here, we present the updated 2-year RFS, EFS and long-term toxicity data. Methods: In the phase 2 multi-center OpACIN-neo trial, 86 stage III melanoma pts with resectable and RECIST 1.1 measurable lymph node metastasis were randomized between 3 different dosing schedules of neoadjuvant IPI + NIVO: arm A: 2x IPI3+NIVO1 Q3W (n = 30), arm B: 2x IPI1+NIVO3 Q3W (n = 30), and arm C: 2x IPI3 Q3W followed by 2x NIVO3 Q2W (n = 26). Lymph node dissection was scheduled at week 6. Primary endpoints were toxicity, radiologic RR and pRR; RFS and EFS were secondary endpoints. Results: After a median FU of 24.6 months, the median RFS and EFS was not reached in any of the 3 arms. In total, 2 pts progressed before surgery, 12 pts relapsed (11 pts without path response and 1 pt with pCR) and 5 pts died (4 due to melanoma and one pt due to toxicity). Estimated 24-months RFS was 84% (95% CI 76-92%) for the total population, 97% (95% CI 93-100%) for pts with a path response and 36% (95% CI 17-74%) for pts without a path response. Estimated 24-months EFS for the total population was 82% (95% CI 74-91%). RFS and EFS did not differ between the arms. Of the 81 pts alive, 55 (68%) have ongoing irAEs; only 2 (3%) pts have ≥ grade 3 irAEs. Most frequent ongoing irAEs were vitiligo (35%), fatigue (14%), sicca syndrome (11%), rash (10%), arthralgia (7%) and endocrine toxicities (20%). 17 pts need hormone replacement therapy: 11 (14%) thyroid hormone and 7 (9%) hydrocortisone. No difference between treatment arms was observed. Ongoing surgery-related AEs were observed in 31 (38%) pts of which lymphedema was seen most frequently (17 pts; 21%). Conclusions: Extended follow-up data shows that 2 cycles of neoadjuvant IPI + NIVO without adjuvant therapy induces durable RFS. While almost no ongoing high-grade irAEs were observed, the majority of pts have low-grade ongoing toxicities. These outcomes strongly support the need to test 2 cycles of neoadjuvant IPI1+NIVO3 versus adjuvant anti-PD-1 in a randomized phase 3 trial. Clinical trial information: NCT02977052