Background: At the first interim analysis of the randomized, open-label, phase 3 KEYNOTE-426 (NCT02853331) study, 1L pembro + axi showed statistically significant OS, PFS, and ORR over sun for advanced ccRCC. We report results with 5-y minimum follow-up. Methods: Adults with confirmed locally advanced or metastatic ccRCC with or without sarcomatoid features, no previous systemic therapy for metastatic ccRCC, KPS ≥70%, and ≥1 lesion measurable per RECIST v1.1 were randomly assigned 1:1 to receive pembro 200 mg IV Q3W for 35 doses (~2 y) + axi 5 mg PO BID or sun 50 mg PO QD on a 4-wk-on/2-wk-off schedule. Dual primary end points were OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Secondary end points included ORR and DOR per RECIST v1.1 by BICR, and safety. A post hoc analysis adjusting for the effect of subsequent therapy on OS using a 2-stage adjustment model was conducted. Results: Of 861 enrolled patients (pts), 432 were assigned to pembro + axi and 429 to sun. Median study follow-up was 67.2 mo (range, 60.0-75.0). Efficacy for the ITT population and IMDC risk subgroups are shown in table. For pembro + axi vs sun, the 60-mo OS rates were 41.9% vs 37.1%, and the 60-mo PFS rates were 18.3% vs 7.3%. Median DOR (range) was 23.6 mo (1.4+ to 68.6+) for pembro + axi and 15.3 mo (2.3-68.3) for sun. In pts who discontinued treatment, 237/381 pts (62.2%) in the pembro + axi arm and 300/406 pts (73.9%) in the sun arm received subsequent anticancer treatment. The HR for OS when adjusted for subsequent therapy was 0.67 (95% CI, 0.52-0.84). Clinical data on pts who completed 2 y of pembro will be presented. No new safety signals were observed. Conclusions: After 5 y of follow-up, pembro + axi had sustained OS, PFS, and ORR benefits over sun in advanced ccRCC. These results are the longest follow-up to date of an anti–PD-1/L1 inhibitor + VEGFR TKI in this pt population and continue to support the use of pembro + axi as a 1L standard of care for advanced ccRCC. Clinical trial information: NCT02853331.