LBA8010 Background: The phase 3 CheckMate 816 study established neoadjuvant NIVO + chemo as a standard of care for eligible pts with resectable NSCLC. Here, we report the 4-year survival update from this study, representing the longest follow-up among all global phase 3 studies evaluating neoadjuvant or perioperative immunotherapy-based treatments. Methods: Adults with stage IB (≥ 4 cm)–IIIA (per AJCC v7) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK alterations were randomized 1:1 to receive NIVO 360 mg + chemo Q3W or chemo alone Q3W for 3 cycles, followed by surgery. Event-free survival (EFS) and pathologic complete response (pCR; both per blinded independent review) were primary endpoints and were both statistically significant. Overall survival (OS) was a key secondary endpoint. Exploratory analyses included efficacy by pCR status and extent of resection. Results: At the 23 Feb 2024 database lock (median follow-up, 57.6 mo), NIVO + chemo continued to improve EFS vs chemo (median, 43.8 mo vs 18.4 mo; HR [95% CI], 0.66 [0.49–0.90]); 4-year EFS rates were 49% vs 38%. EFS favored NIVO + chemo vs chemo regardless of whether pts had lobectomy or pneumonectomy (Table), with 56%–57% vs 40%–43% of pts without disease recurrence at 4 years. NIVO + chemo also continued to show OS improvement vs chemo (HR [98.36% CI], 0.71 [0.47–1.07]; P = 0.0451; median OS was not reached [NR] in both arms, and the significance boundary was not met at this interim analysis). An OS improvement of 13% was sustained over time for NIVO + chemo vs chemo; 4-year OS rates were 71% vs 58%. Pts in the NIVO + chemo arm who had pCR continued to have improved OS vs those who did not (HR [95% CI], 0.08 [0.02–0.34]); 4-year OS rates, 95% vs 63%); a similar trend was seen in the chemo arm, although few pts had pCR with chemo (n = 4). No new safety signals were observed at this update. Additional survival analyses in pt subgroups and by ctDNA levels will be presented. Conclusions: In this 4-year analysis from CheckMate 816, neoadjuvant NIVO + chemo sustained EFS and OS separation vs chemo over time and demonstrated the long-term survival benefit of having pCR in pts with resectable NSCLC. These data provide the first understanding of the long-term benefits of neoadjuvant immunotherapy when added to chemo, reinforcing neoadjuvant NIVO + chemo as a standard of care, and providing a benchmark to assess the benefits of all perioperative immunotherapy-based treatments. Clinical trial information: NCT02998528 . [Table: see text]