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Adjuvant pembrolizumab delivers sustained clinical benefits across ccRCC subgroups with no new long-term safety signals.
Adjuvant pembrolizumab (Keytruda) continued to improve disease-free survival (DFS) and overall survival (OS) vs placebo with benefits consistent in the overall population and across prespecified subgroups of patients with clear cell renal cell carcinoma (ccRCC), according to 5-year follow-up results from the phase 3 KEYNOTE-564 study.1 The immunotherapy also prolonged distant metastasis-free survival (DMFS) and time to recurrence vs placebo.
At a median follow-up of 69.5 months (range, 60.2-86.9) and at a data cutoff date of September 25, 2024, the median DFS was not reached (NR; 95% CI, NR-NR) with pembrolizumab (n = 496) vs 68.3 months (95% CI, 51.7-NR) with placebo (n = 498; HR, 0.71; 95% CI, 0.59-0.86). The estimated 2-, 3-, 4-, 5-, and 6-year DFS rates in the immunotherapy arm were 78.2%, 72.5%, 65.0%, 60.9%, and 58.5%; in the control arm, these respective rates were 67.2%, 62.8%, 56.5%, 52.2%, and 48.7%.
The median OS was NR in either arm (HR, 0.66; 95% CI, 0.48-0.90). At the 2-, 3-, 4-, 5-, and 6-year time points, the estimated OS rates with pembrolizumab were 96.3%, 93.9%, 91.2%, 87.7%, and 86.1%, respectively; with placebo, these rates were 93.9%, 89.5%, 86.0%, 82.3%, and 79.4%.
Subgroup analyses showed that the DFS benefits achieved with the immunotherapy over placebo were consistent across subgroups, irrespective of risk category and whether sarcomatoid features were present. Specifically, the HR for DFS in those with M0 intermediate-high risk was 0.75 (95% CI, 0.61-0.93); in those with M0 high risk, the HR for DFS was 0.61 (95% CI, 0.35-1.08), and in those with M1 NED risk, the HR was 0.48 (95% CI, 0.25-0.92). In those with sarcomatoid features, the HR for DFS was 0.56 (95% CI, 0.33-0.96); in those without, the HR was 0.75 (95% CI, 0.60-0.92).
The immunotherapy also improved OS spanning risk categories. In those with M0 intermediate-high risk, the median OS was NR with pembrolizumab or placebo (HR, 0.71; 95% CI, 0.59-0.86). The estimated 2-, 3-, 4-, and 5-year OS rates with the immunotherapy in this group were 97.1%, 95.0%, 92.6%, and 89.2%, respectively; with placebo, they were 95.4%, 91.2%, 87.7%, and 83.9% at these respective time points. In those with M0 high risk, the median OS was NR in both arms (HR, 0.86; 95% CI, 0.37-1.98). Estimated OS rates with pembrolizumab in this category were 90.0%, 87.5%, 80.0%, and 75.0% at 2, 3, 4, and 5 years, respectively; with placebo, these respective rates were 86.5%, 78.4%, 73.0%, and 73.0%. Lastly, in the M1 NED subgroup, the median OS was NR in either arm (HR, 0.36; 95% CI, 0.11-1.18). The estimated OS rates with pembrolizumab at 2 years were 93.1%, 89.7% at 3 years, 89.7% at 4 years, and 86.1% at 5 years; with placebo, these rates were 81.7%, 78.0%, 78.0%, and 70.2%, respectively
The median DMFS with pembrolizumab was NR (95% CI, NR-NR) vs 80.7 months (95% CI, 64.5-NR) with placebo (HR, 0.73; 95% CI, 0.60-0.89), and the median time to recurrence in the respective arms was NR (95% CI, NR-NR) and 80.9 months (95% CI, 58.8-NR; HR, 0.69; 95% CI, 0.57-0.84). Subsequent therapies were given at comparable rates in those with recurrence in the pembrolizumab (n = 171) and placebo (n = 226) arms, with 64.3% and 68.1% of patients receiving any systemic therapy, respectively. In the pembrolizumab arm, 19.3% received surgery and/or radiation therapy only, 59.1% received a VEGF or VEGFR inhibitor, and 28.7% received an anti–PD(L)1 therapy; these rates in the placebo arm were 13.3%, 58.8%, and 48.2%. Moreover, 16.4% of those in the immunotherapy arm and 18.6% of those in the placebo arm did not receive subsequent treatment.
The randomized, double-blind, placebo-controlled, phase 3 study enrolled patients with histologically confirmed ccRCC who were at least 18 years of age and had not received systemic therapy for advanced disease. Patients needed to have intermediate-high or high risk of recurrence or M1 with NED who had nephrectomy and/or metastasectomy within 12 weeks before randomization.
Patients were randomly assigned 1:1 to receive pembrolizumab intravenously (IV) at 200 mg every 3 weeks (Q3W) for approximately 1 year or up to 17 cycles or IV placebo Q3W for the same duration and number of cycles. Treatment continued until disease recurrence, intolerable toxicity, or decision to withdraw. Patients were stratified based on M stage (M0 vs M1 NED), and M0 group was further stratified based on ECOG performance status (0 vs 1) and region (United States vs the rest of the world).
The primary end point of the study was investigator-assessed DFS, and secondary end points were OS and safety. Exploratory analyses focused on DMFS and time to recurrence per investigator assessment.
At the time of the prespecified interim analysis of the study, a significant improvement in DFS was observed with the immunotherapy over placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0010).2 At the time of the DFS analysis, OS data were still immature. These earlier findings from KEYNOTE-564 supported the FDA’s decision to approve adjuvant pembrolizumab for use in patients with RCC at intermediate-high or high risk of recurrence after nephrectomy or after nephrectomy and resection of metastatic lesions in November 2021.
Other data from the 5-year analysis were previously shared at the 2025 ASCO Annual Meeting.3 In a prior exclusive interview with OncLive®,4 Naomi B. Haas, MD, discussed the significance of the data: “This is the first time that the results from the study have reached a median landmark analysis of 6 years. This is the longest data [we’ve seen] presented for adjuvant ICI therapy—that's the main [point] that I wanted to emphasize here,” she said. “There are some key takeaways. For example, we know that DFS continues to remain robust. The curves separate early in this trial and remain separated between the patients who received adjuvant pembrolizumab vs those who received placebo. The OS remains separated. However, looking at the OS curve, this continues to look very robust. DFS and OS benefit [has been] observed across all key subgroups.”
Haas is a professor of medicine at the Hospital of the University of Pennsylvania and the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center in Philadelphia, Pennsylvania.
The updated findings supported the long-term safety of the immunotherapy in the population. The median duration of treatment with pembrolizumab was 11.1 months (range, 0.03-14.3), and treatment-related adverse effects (TRAEs) occurred in 79.1% of patients; these effects were grade 3 or 4 in 18.6% of patients. Moreover, TRAEs were classified as serious in 11.9% of patients and led to discontinuation for 18.2% of patients. Immune-mediated toxicities and infusion reactions were observed in 36.7% of patients, and they were grade 3 or 4 for 9.6% of patients.
No new serious TRAEs have been reported for more than 3 years, Haas said in the presentation at SUO.
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