KEYNOTE-564 at 5 Years: Adjuvant Pembrolizumab in Clear Cell RCC

In the adjuvant setting, managing the patient with high-risk clear cell renal cell carcinoma (ccRCC) remains challenging with conflicting trial results, high rates of adverse events, and a lack of reliable biomarkers to help identify appropriate patients. Although pembrolizumab (Keytruda) is an FDA-approved approach, other immunotherapies have shown minimal benefit.

The KEYNOTE-564 trial (NCT03142334)¹ established adjuvant pembrolizumab as a standard of care for patients with clear cell renal cell carcinoma (RCC) at high risk of recurrence following nephrectomy. The trial initially demonstrated a significant improvement in disease-free survival (DFS), leading to regulatory approval and adoption into clinical guidelines. With extended follow-up, KEYNOTE-564 has now shown a sustained overall survival (OS) benefit, further solidifying the role of adjuvant immunotherapy in this setting.

During a live event, Bradley McGregor, MD, director of clinical research at the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, and participants discussed their approach to patient selection, and their strategies for managing recurrence in patients who have received adjuvant pembrolizumab.

This article is part 2 of a 2-part series from a Case-Based Roundtable event. Part 1 is available here.

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CASE SUMMARY

A 48-year-old man visited his primary care physician because of persistent fatigue, nausea, and vomiting that developed after having “a cold,” with recent weight loss of 15 to 20 pounds and onset of hematuria.

Medical History/Surgical History/Family History

• Obesity, obstructive sleep apnea, appendectomy
• 40-lb total weight loss in past year
• Mother and sister with lung cancer
• Former smoker
• He underwent nephrectomy + limited lymph node dissection

CT of the abdomen/pelvis (w/o contrast): showed large right- sided renal mass (11.3 cm) with extension into the renal vein

CT chest: negative

Laboratory findings:

• Hemoglobin - 10.8 g/dL
• White blood count - 7.9 x 10⁹/L
• Platelet count - 316K
• Calcium - 9.8

Pathology/histology

• Clear cell renal cell carcinoma (ccRCC)
• Renal vein invasion
• Negative margins
• No coagulative necrosis
• Grade 4 (without sarcomatoid features)
• pT3a pN0 M0

ECOG PS 1

DISCUSSION QUESTIONS

• What is your reaction to the updated KEYNOTE-564 data?
• Do you consider them practice changing or confirming?
• If not, why not?

Bradley McGregor, MD: The KEYNOTE-564 trial enrolled patients with confirmed clear cell renal cell carcinoma (RCC). Eligible patients had T2 grade 4 or sarcomatoid features—though sarcomatoid is by definition grade 4, it was specified separately because sarcomatoid histology may predict differential response, at least in the metastatic setting. This approach helped enrich the population for sarcomatoid features, which may partly explain why the trial was positive.

Additional eligible criteria included T3 any grade, T4 any grade, node-positive disease, and M1 NED (no evidence of disease) following nephrectomy. Patients underwent nephrectomy within one year prior to enrollment and had no metastasectomy. Bone and brain lesions were excluded, and local treatment had to be surgical (not radiation or ablation). Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo for one year.

The primary end point was investigator-assessed disease-free survival (DFS), and the secondary endpoint was overall survival (OS).

After 5-years of follow-up, the investigators reported a clear benefit in overall survival (OS). The absolute benefit at the 6-year point is around 6%, with a hazard ratio below 0.7. There is also a clear improvement in disease-free survival, with the hazard ratio remaining around 0.7 with extended follow-up and an absolute benefit of approximately 10%. Notably, the Kaplan-Meier curves separated early and maintained separation over time without converging, suggesting that one year of therapy appears sufficient—patients who received pembrolizumab did not suddenly relapse after treatment cessation.

This benefit was consistent across all subgroups. The M1 NED (no evidence of disease) group represented a small proportion of the trial, less than 7%, while the majority of patients were in the intermediate-high risk group (T2 grade 4 or T3 patients), and the benefit was similar across these subgroups.

When considering the overall survival (OS) benefit, subsequent therapy becomes an important factor. Disease-free survival (DFS) is unaffected by second-line treatment, and a clear DFS benefit is evident. However, for OS benefit, the impact of second-line and subsequent therapies becomes more complex. This is often confusing because trials report these outcomes using different denominators at different time points.

In this trial, more patients had documented recurrence in the placebo arm than in the pembrolizumab arm. Among those with recurrence, not all patients underwent surgery—some received systemic therapy alone, and others received radiation alone. Overall, in the placebo arm, 109 patients received some form of PD-1–directed therapy. Of those, 30 patients received only surgery or radiation without specific systemic therapy, and for 42 patients, no specific therapy was reported. The majority of patients who received systemic therapy did so with a checkpoint inhibitor in the second-line or frontline setting.

What are your thoughts on this updated data of KEYNOTE-564?

Walid El Ayass, MD: Any data demonstrating a survival benefit in the adjuvant setting is highly compelling across cancer types. In this trial, the hazard ratio benefit was approximately 30%, which is very appealing. Additionally, pembrolizumab is a widely used medication, and we are all familiar with its potential side effects as well as how to manage and monitor them, making us very comfortable using it in this setting.

Yiwu Jim Huang, MD: The data are available, and if a patient meets the criteria, treatment should be offered—unless there is a contraindication to immunotherapy.

McGregor: Is anyone offering it to patients who don't meet the criteria—for example, those with T1a or T1b grade 4 disease? Is that a situation where you might consider it, or are you strictly following the KEYNOTE-564 data?

Ilmana Fulger, MD: I would consider it for grade 4 disease, but it is difficult to get it covered. That is a challenge, which is why the clinical trial recommendation stands. Of course, we also have to remember that option is always available.

El Ayass: I would not consider it outside of a clinical trial. Immunotherapy can cause very severe side effects in some patients, and you do not want to put yourself in that situation. So no, I would not use it outside of what is recommended by guidelines.

McGregor: And do you view all patients the same—for example, a patient with T3 grade 2 disease? Would you treat them the same as other patients who were enrolled in the trial?

Sahil Doshi, MD: I think there are definitely patients I would consider higher risk—for example, those with positive lymph nodes, grade 4 disease, or other concerning risk features. Depending on those factors, as well as the patient's age and comorbidities, the strength of my recommendation may vary. However, I do at least offer it to anyone who meets the criteria, though I may provide a stronger recommendation for certain patients based on those features.

McGregor: Anyone have experience with patients who recur on checkpoint blockade and what you do in that situation?

Minas Economides, MD: Yes, we have been using adjuvant therapy for a couple of years now, so we are familiar with it. I think a lot depends on the timing. Often, for oligometastatic recurrence, we try to use local approaches, either with radiation or surgery. For more disseminated disease, I typically go with a TKI [tyrosine kinase inhibitor] alone, and I usually use cabozantinib in that setting.

Peter Gregos, MD: I would say the same, almost exactly. I have a patient right now who is eight or nine months into adjuvant pembrolizumab, and he developed a new, biopsy-proven para-aortic lymph node. That is the only area of disease, but it is new while he has been on treatment. We are still in the process of figuring out what to do, but I think we are going to offer him either local therapy or surgery, just as one of our colleagues mentioned.

McGregor: If a patient receives pembrolizumab and 18 months later has a relapse, do you consider the fact that they had adjuvant therapy when deciding what to offer, or do you consider that patient for a frontline trial?

Neenos Alnoor, MD: I may keep it in the back of my mind. I'm not going to not use it, but just keep it in the back of my mind, okay, yes, they received immunotherapy and maybe I need to consider that in my decision.

McGregor: I think this is a tough question. It always matters to some extent. One of the key considerations is the time point at which you consider rechallenging with immunotherapy. Some people say as short as 6 months after the last dose, while others may say up to 2 years—so there is no right answer. There are trials currently in development that are looking at rechallenge ranging from while on therapy to two years after completion, so hopefully we will have some answers in the future.

DISCLOSURES: McGregor has provided consulting or advisory services to: Seattle Genetics/Astellas, Exelixis, Astellas Pharma, Pfizer, Eisai, Bristol Myers Squibb, Gilead Sciences, Arcus Biosciences, Loxo/Lilly, Daiichi Sankyo/Astra Zeneca, Genmab, AVEO, Hexagon; Research Funding: Bristol Myers Squibb (Inst), Exelixis (Inst), Calithera Biosciences (Inst), Seattle Genetics/Astellas (Inst), Pfizer/EMD Serono (Inst).

REFERENCES

1. Choueiri TK, Tomczak P, Park SH, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695