Background: OpACIN was the first trial testing neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) versus the same combination given adjuvant. An unexpected high pathologic responses of 78% was observed in the neoadjuvant arm with a 2-year relapse-free survival (RFS) rate of 80%. The subsequent OpACIN-neo trial tested 3 different dosing schedules of neoadjuvant IPI + NIVO and identified 2 cycles IPI 1 mg/kg + NIVO 3 mg/kg q3w as most favorable schedule with a pathologic response rate of 77% and 20% grade 3-4 immune-related adverse events. Long-term data on the durability of the pathologic (path) responses upon neoadjuvant checkpoint inhibition are lacking so far. Therefore, we present here the updated RFS and overall survival (OS) data of both trials. Methods: In OpACIN 20 macroscopic stage III melanoma pts were randomized to receive either IPI 3 mg/kg + NIVO 1 mg/kg q3w 4 cycles adjuvant after lymph node dissection or split 2 cycles neoadjuvant and 2 adjuvant. In OpACIN-neo 86 macroscopic stage III melanoma pts were randomized to arm A (2x IPI 3 mg/kg + NIVO 1 mg/kg q3w, n=30), arm B (2x IPI 1 mg/kg + NIVO 3 mg/kg q3w, n=30), or arm C (2x IPI 3 mg/kg q3w followed by 2x NIVO 3 mg/kg q2w, n=26) followed by lymph node dissection in week 6. RFS and OS were estimated using Kaplan Meier method. All comparative efficacy endpoints are descriptive for OpACIN, since the trial was not powered for comparison of the arms. Results: After a median follow-up (FU) of 68.6 months for OpACIN (minimum FU of 59.8 months), median RFS and OS were not reached. Only 1/7 patients (pts) with a pathologic response on neoadjuvant therapy has relapsed. Estimated 5-year RFS and OS rates for the neoadjuvant arm were 70.0% (95%CI: 46.7-100.0) and 90.0% (95%CI: 73.2-100.0) versus 60.0% (95%CI 36.2-99.5) and 70.0% (95%CI: 46.7-100.0) for the adjuvant arm. After a median FU of 46.8 months for OpACIN-neo (minimum FU of 38.2 months), median RFS and OS were not reached. Of pts with path response on neoadjuvant therapy, 3/64 (4.7%) had an event (2 pts relapsed, 1 pt died due to toxicity), versus 14/21 (66.7%) without path response. This resulted in a 3-year RFS rate of 95.3% (95%CI: 90.3-100.0) for responding versus 36.8% (95%CI: 20.4-66.4) for non-responding pts (p<0.001). Of the pts who relapsed after response, 1 had major path response (<10% vital tumor) and 1 a partial response (10-15% vital tumor). Estimated 3-year RFS and OS rates are presented in the Table. Conclusions: Updated data from OpACIN and OpaCIN-neo trials confirm the durability of responses upon neoadjuvant combination checkpoint inhibition in high risk stage III melanoma. Pathologic response remains a reliable surrogate marker for RFS and OS. Clinical trial information: NCT02437279, NCT02977052.