Background: The randomized, double-blind, phase 3 KEYNOTE-564 study (NCT03142334) met its primary end point of disease-free survival with adjuvant pembrolizumab versus placebo after nephrectomy in patients with localized RCC who are at increased risk for recurrence. Extended follow-up (30-month median follow-up) continued to support the benefit of adjuvant pembrolizumab. We describe additional efficacy analyses of time to first subsequent drug treatment or any-cause death (TFST) and time from randomization to progression on next line of therapy or any-cause death (PFS2). Methods: Patients with histologically confirmed clear cell RCC, with intermediate-high or high risk for recurrence (pT2, grade 4 or sarcomatoid, N0, M0; or pT3-4, any grade, N0 M0; or pT any stage, any grade, N+ M0) after nephrectomy, or after nephrectomy and resection of metastatic lesions (M1 NED), were randomly assigned 1:1 to receive pembrolizumab 200 mg IV or placebo Q3W for up to 17 cycles (̃1 y). Exploratory analyses of TFST and PFS2 were conducted. The Kaplan-Meier method was used to estimate TFST and PFS2. Hazard ratios (HRs) were estimated using a Cox regression model. Results: Of 994 patients, 496 were randomly assigned to receive pembrolizumab and 498 to placebo. Median time from randomization to the data cutoff date (June 14, 2021) was 30.1 months (range, 20.8-47.5). Overall, 67 patients (13.5%) in the pembrolizumab group and 99 patients (19.9%) in the placebo group received ≥1 line of subsequent anticancer drug therapy. Of patients who received ≥1 line of subsequent drug therapy, most in the pembrolizumab group (90.0% [60/67]) and placebo group (85.9% [85/99]) received a VEGF/VEGFR-targeted therapy; 23.9% of patients (16/67) in the pembrolizumab group and 59.6% (59/99) in the placebo group received an anti–PD-1/PD-L1 agent. Seventy-seven TFST events were observed in the pembrolizumab group; 110, in the placebo group. Compared with placebo, adjuvant treatment with pembrolizumab delayed TFST (HR, 0.67; 95% CI, 0.50-0.90; medians not reached). A total of 108 PFS2 events were observed, 40 (8.1%; 12 death events and 28 progression events) in the pembrolizumab group and 68 (13.7%; 14 death events and 54 progression events) in the placebo group. PFS2 was also delayed with pembrolizumab compared with placebo (HR, 0.57; 95% CI, 0.39-0.85; medians not reached). Conclusions: Treatment with adjuvant pembrolizumab reduced risk for TFST and PFS2 compared with placebo. Results of this exploratory analyses suggest sustained clinical benefit of adjuvant pembrolizumab and support the use of adjuvant pembrolizumab after nephrectomy as standard of care for patients with localized RCC at increased risk for recurrence. Clinical trial information: NCT03142334.