5-Year Analysis of KEYNOTE-564 Reinforces Role of Adjuvant Pembrolizumab as SOC in ccRCC

Naomi B. Haas, MD

Adjuvant pembrolizumab (Keytruda) demonstrated improved disease-free survival (DFS) and overall survival (OS) after 5 years of minimum follow-up in patients with clear cell renal cell carcinoma (ccRCC), reinforcing its role as the standard of care for patients with an increased risk of recurrence, according to Naomi B. Haas, MD.

Updated data from the phase 3 KEYNOTE-564 trial (NCT03142334) were presented at the 2025 ASCO Annual Meeting, and showed that at a median follow-up of 69.5 months (range, 0.59-0.86), the updated median DFS in the intention-to-treat (ITT) population was not reached (NR; 95% CI, NR-NR) vs 68.3 months (95% CI, 51.7-NR) in the adjuvant pembrolizumab and placebo arms, respectively (HR, 0.71; 95% CI, 0.59-0.86). 1 Additionally, the median OS in the ITT population was NR in both arms (HR, 0.66; 95% CI, 0.48-0.90).

In November 2021, the FDA approved adjuvant pembrolizumab for the treatment of patients with RCC at intermediate- or high-risk of recurrence after nephrectomy with or without resection of metastatic lesions based on data from KEYNOTE-564. 2

“KEYNOTE-564 specifically included patients who had pT2 high grade, all pT3 disease and pT4 as well as node-positive disease, and even up the ante a little bit by including patients who had metastasectomy of their ccRCC, provided that it was within the first year after their primary tumor was resected because that was considered to be a very high-risk population,” Haas explained in an interview with OncLive®.

During the interview, Haas highlighted the rationale for investigating adjuvant pembrolizumab in ccRCC, updated efficacy data from the KEYNOTE-564 trial, the safety profile of adjuvant pembrolizumab, its application in clinical practice, and the role of a risk-adapted approach during treatment decision-making.

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.

OncLive: What was the rationale for evaluating adjuvant pembrolizumab in ccRCC in the KEYNOTE-564 trial?

Haas: A number of adjuvant trials were designed several years ago, and this was based on a lot of excitement that everybody shared in the activity of immune checkpoint inhibitors [ICIs] in advanced kidney cancer. Most of the studies were conducted in advanced kidney cancer with clear cell histology; the focus of most of the adjuvant and perioperative trials [was on] patients with clear cell histology. A lot of the [trials were] based on previous adjuvant therapy designs that were conducted in the period of about 2007 to 2011, using the VEGF TKIs. The design was fairly similar to that, [except], based on some of the OS data from those studies, these trials tended to be slightly [more focused in the] higher-risk population. The majority of the trials included, at a minimum, patients with pT2 high-grade disease. There was some variability in some of the trials that were a little bit more inclusive to all grades. The PROSPER EA8143 trial [NCT03055013], for example, was based on clinical histology, not pathologic histology. However, virtually all of the other ones were based on pathologic histology because these were patients who had already had their kidney surgery, and we knew what the pathologic staging was.

The designs [of KEYNOTE-564 and other similar trials] generally had some other differences, in that some of them looked at duration of therapy that was only 6 months, or combinations of ICIs with CTLA-4 inhibitors. KEYNOTE-564 looked specifically at an ICI, pembrolizumab, in which patients received that for a year vs placebo of pembrolizumab. In the KEYNOTE-564 trial, roughly 1000 patients were enrolled, with [DFS per] investigators assessment being the primary end point, and OS and safety were considered key secondary end points.

What were the updated efficacy data presented at the meeting?

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. 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.

What was the overall safety profile of adjuvant pembrolizumab, and were there any new safety signals observed?

The safety results remain consistent with the prior analysis. There have been no new serious treatment-related [adverse effects (AEs)] for the past 3 years…and no new safety signals observed. The predominant AEs—serious [grade 3] AEs—that were experienced by patients who participated in this trial and received adjuvant pembrolizumab were hypertension and elevated transaminase, followed by diarrhea. These are all reversible AEs. The permanent AEs that people have focused on were in a continued small group of patients, but were serious AEs. They included diabetes, hypophysitis, myocarditis, and myasthenia gravis. These AEs have been observed both in advanced disease clinical trials, as well as in the adjuvant setting, and they've been observed in many different trials, many different drugs, not just pembrolizumab, but other ICIs as well.

How do these updated data contribute to ongoing discussions about the application of adjuvant pembrolizumab for the treatment of ccRCC in clinical practice?

There are a lot of questions that remain. There is enthusiasm to better understand how patients who've had metastasectomy relatively soon after surgery should be treated. Should they be treated with a single-agent ICI or should they be treated with a combination of ICIs or VEGF ICIs?

This trial was also stratified by United States [US] vs non-US sites. The question has come up about whether the non-US sites have had sufficient access to ICIs. Although there continue to be some cases where we just don't know what happened because it hasn't been sufficiently reported, as far as whether patients who recurred had received additional treatment, we don't always get all of the information. We've tried to be pretty transparent about this, and we do a good job of showing that in the long run, patients in both non-US and US sites did have access to ICI therapy.

How can a more risk-adapted approach support treatment decision-making when selecting adjuvant pembrolizumab for patients with ccRCC?

We have patients that we might be under-treating and patients that we might be over-treating. [We saw] a large group of patients who were never going to [experience disease recurrence] anyway. That's another big challenge that we have to better understand right now. What we have is access to nomograms—I helped develop the ASSURE nomogram. There are about 5 or 6 other nomograms that are somewhat useful. There is a lot of excitement about some of the emerging [biomarkers we could leverage] to determine this, such as KIM-1. I want to emphasize that these are tools that need further both retrospective and prospective validation, because many different assays can be used. I would discourage anybody from trying to use this to determine whether patients should get adjuvant therapy or not. This needs to be further studied, and there's a lot of excitement and design being incorporated into these kinds of markers in future adjuvant trials, as well as looking at them retrospectively.

In addition, although the label is fairly broad for pembrolizumab, the use of this in non–clear cell histology has never been studied or reported in the adjuvant setting, I will say that the cooperative groups are moving forward with the non–clear cell [RCC] trial of adjuvant pembrolizumab vs close active surveillance. Hopefully we'll get some data for that group as well.

References

1. Haas NB, Powles T, Tomczak P, 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). J Clin Oncol. 2025;43(suppl 16):4514. doi: 10.1200/JCO.2025.43.16_suppl.4514
2. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed June 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-adjuvant-treatment-renal-cell-carcinoma