KEYNOTE-564 is the first global phase III clinical trial of adjuvant immunotherapy for renal cell carcinoma to achieve positive results. At the 2025 ASCO annual meeting, Dr. Naomi Balzer Haas from the Abramson Cancer Center, University of Pennsylvania presented the updated DFS (Disease-Free Survival) and OS (Overall Survival) results from the 5-year follow-up of the study. Oncology Frontier invited Dr. Naomi Balzer Haas to interpret the results at the conference site as follows.

— Overview: the updated results of KEYNOTE-564 —

The phase 3 KEYNOTE-564 study evaluated adjuvant pembrolizumab (pembro) for clear cell renal cell carcinoma (ccRCC) at high risk of recurrence. This study enrolled 994 patients who had undergone nephrectomy or metastasectomy, randomizing them 1:1 to pembro (200 mg IV Q3W) or placebo for approximately 1 year. The primary endpoint was disease-free survival (DFS), with overall survival (OS) as a key secondary endpoint. At a median follow-up of 69.5 months, DFS events occurred in 188 pembro patients vs. 241 placebo patients, with a median DFS of NR vs. 68.3 months (HR 0.71, 95% CI 0.59−0.86) and 5-year DFS rates of 60.9% vs. 52.2%. OS events occurred in 68 pembro patients vs. 99 placebo patients, with a median OS of NR in both arms (HR 0.66, 95% CI 0.48−0.90) and 5-year OS rates of 87.7% vs. 82.3%. No new serious treatment-related adverse events were reported after ≥3 years. These results confirm pembro’s sustained benefit in DFS and OS across all subgroups and solidify its role as a standard adjuvant therapy for high-risk ccRCC patients.

— Interview: insights from Dr. Naomi Balzer Haas —

Oncology Frontier: Before the approval of pembrolizumab, the only adjuvant treatment for renal cell carcinoma after surgery was TKI drugs. Based on clinical practice, can you please share what stages of adjuvant treatment this type of patient has gone through, and what unmet clinical needs still exist?

Dr. Naomi Balzer Haas: The development of adjuvant therapy for renal cell carcinoma began with vascular endothelial growth factor receptor inhibitors. Several studies were conducted in this area, but the only trial that showed a benefit was the S-TRAC trial, which evaluated adjuvant sunitinib for a year. However, the disease-free survival benefit was only observed for one year beyond that, and there was no overall survival benefit. This led to an interest in exploring the role of immune checkpoint inhibitor treatments, given their activity in advanced disease settings. Consequently, four or five perioperative immune checkpoint inhibitor trials were developed and studied. The only one that demonstrated a benefit so far was the KEYNOTE-564 trial, which compared adjuvant pembrolizumab for one year versus placebo. This study enrolled high-risk patients, including those intermediate-high (pT2 Gr 4 or sarcomatoid, or pT3 any Gr, N0 M0) or high (pT4 any Gr, N0 M0, or any pT and Gr, N+ M0) risk of recurrence or M1 with no evidence of disease (NED) who had nephrectomy and/or metastasectomy ≤12 wks.

The KEYNOTE-564 trial showed an improvement in disease-free survival several years ago, and more recently, an improvement in overall survival. With a follow-up of at least five years for all patients and a median follow-up of almost six years for many, the Kaplan-Meier curves for disease-free survival remain separated, indicating a continued benefit. The overall survival benefit also persists. The safety profile shows no new safety events after more than three years of follow-up. Importantly, we analyzed patients in both the pembrolizumab and placebo arms who had recurred and looked at their subsequent treatments. We found that around 60% of patients in both arms received some form of systemic therapy, with or without local therapy such as surgery or radiation. VEGF-targeted therapy was the most common subsequent treatment, and its use was similar between patients who received adjuvant pembrolizumab and those who received placebo.

One of the biggest challenges now is to determine which patients might be undertreated. This could include patients with metastectomy, as metastatic disease often requires combination therapy. Additionally, about 50% of patients in the placebo arm who did not recur may not have needed adjuvant therapy in the first place. These are areas where we still have unmet needs, and we need more data on biomarkers to better understand which patients will benefit most from adjuvant therapy. The overall survival continues to be stable, with hazard ratios remaining consistent. The most common serious side effects observed were hypertension, elevated liver enzymes (transaminitis), and diarrhea, with data on their duration and resolution also presented.

Oncology Frontier: KEYNOTE-564 is the first study on immunoadjuvant therapy for renal cell carcinoma to obtain positive results. How do you view the OS and safety results from this extended follow-up period?

Dr. Naomi Balzer Haas: The overall survival in the KEYNOTE-564 study remains pretty stable. The hazard ratio is consistent with what we have seen previously, and the Kaplan-Meier curves separate close to the completion of adjuvant therapy and remain separated. We have not observed any new safety signals over the long-term follow-up. In our presentation, we showed the frequency and duration of serious adverse events. The most common serious side effects were hypertension, transaminitis or elevation of liver enzymes, followed by diarrhea. We also demonstrated the duration of these events, showing the time it takes for serious adverse events to completely resolve. This data was also included in the presentation.

Oncology Frontier: For patients whose disease progresses during immunotherapy, what follow-up treatment options are available?

Dr. Naomi Balzer Haas: That’s a very good question. One of the most important questions still to be answered is whether there are patients who received adjuvant pembrolizumab that should still receive an immune checkpoint inhibitor in the future. There are a number of studies ongoing to look at this. Perhaps patients who were only on treatment for a very short period of time may not have reached the full benefit we typically see. Additionally, for patients who relapse several years after completing treatment, it’s worth considering whether they should still receive adjuvant therapy.

However, we know that it’s important to offer VEGF inhibitor therapy for these patients. The newer HIF-1 alpha inhibitors are also showing promise. Certainly, we need to identify new targets in kidney cancer as well.

Oncology Frontier: What impact do you think the results of the KEYNOTE-564 study will have on existing kidney cancer treatment guidelines and clinical practice?

Dr. Naomi Balzer Haas: I think having an available adjuvant therapy that shows a survival benefit, like the one demonstrated in the KEYNOTE-564 study, is very important for both patients and physicians. We hope that it will lead to curing more kidney cancer patients. However, I believe we need to continue improving in this area. The study results will likely be here to stay, but I think we need to better understand which patients might not need this therapy or might need more, because we’re still not curing everyone.

References:

[1]Ravaud A, Motzer RJ, Pandha HS, et al. Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy. N Engl J Med. 2016;375(23):2246-2254. doi:10.1056/NEJMoa1611406

[2]Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391

[3]Powles T, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2023 Jan;24(1):e10. doi: 10.1016/S1470-2045(22)00759-8.]. Lancet Oncol. 2022;23(9):1133-1144. doi:10.1016/S1470-2045(22)00487-9

[4]Naomi Balzer Haas, et al.Five-year follow-up results from the phase 3 KEYNOTE-564 study of adjuvant pembrolizumab (pembro) for the treatment of clear cell renal cell carcinoma (ccRCC).ASCO 2025;Abstract #5414