Optimizing Adjuvant IO in Renal Cell Carcinoma Post-Nephrectomy

Following nephrectomy, patients with high-risk clear cell renal cell carcinoma (ccRCC) face a meaningful risk of disease recurrence, even when the cancer appears to be completely resected. Factors that predict a higher likelihood of recurrence include large tumor size, high tumor grade, invasion of the renal vein or surrounding structures, and the presence of sarcomatoid differentiation.

For many years, patients in this situation were managed with surveillance alone after surgery; however, the KEYNOTE-564 trial (NCT03142334) shifted the paradigm by showing that adjuvant treatment with the PD-1 inhibitor pembrolizumab (Keytruda) significantly reduced the risk of disease recurrence or death compared with placebo in patients with high-risk ccRCC following nephrectomy.¹ These findings led to the FDA approval of the immunotherapy in this setting for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy.²

In a live event, Thomas Hutson, DO, PharmD, PhD, director of Genitourinary Oncology Program and co-director of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center, and participants discussed the results and clinical significance of the KEYNOTE-564 trial and the optimal management of patients with high-risk ccRCC post-nephrectomy.

This is the second of 2 parts. Read part 1.

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CASE SUMMARY

• A 57-year-old man who received radical nephrectomy for a 9-cm left renal mass.
• Pathology: ccRCC with sarcomatoid features 0/3 lymph nodes; renal vein invasion; no coagulative necrosis; negative margins; grade 4
• Diagnosis: stage III (pT3aN0M0) ccRCC
• ECOG performance status: 1
• The patient received adjuvant pembrolizumab.

DISCUSSION QUESTIONS

• How do you assess the risk of recurrence following nephrectomy in patients with ccRCC?
• When these patients are referred by their urologist, are they aware of their recurrence risk and the potential use of adjuvant immunotherapy?

Thomas Hutson, DO: Do you assess risk using a nomogram, such as ASSURE, or do you guesstimate? Or do patients who come into your practice…already know they have a risk of recurrence risk of say 30% to 40% [based on a discussion with their urologist]? Or are they asking you to calculate that for them?

Rebecca Yarborough, MD: Mine typically know that I'm going to give them something. They don't ask a specific percentage, I guess. And I don't know if the urologist I work with ever used the ASSURE nomogram. I don't use it specifically myself.

Donald Richards, MD: Generally, the urologist doesn’t review the [KEYNOTE-564] data, and I don't think the patient knows [what we’re going to recommend].

Ananth Arjunan, MD: Mine's like 50/50, some people come in expecting to discuss [recurrence risk and adjuvant treatment]. I usually use the UCLA integrated staging system.

Hutson: Clearly there's been good penetrance into the urology community at some level, where many urologists realize that there is a role for adjuvant therapy [in high-risk ccRCC post-nephrectomy] now that didn't exist before, so at least they're sending those patients to us.

DISCUSSION QUESTION

• Would you recommend adjuvant immunotherapy for this patient?

Hutson: I think we all agree that the answer is, “yes.” And so, the NCCN guidelines for kidney cancer Version 3.2025 have adjuvant pembrolizumab as a category 1 recommendation for patients with stage III clear cell disease whwo have had radical nephrectomy or partial nephrectomy, if clinically indicated.³ Remember that non-clear cell histology is not an indication for this treatment.

What is interesting to note is that in the most recent version of the guidelines, there was the removal of sunitinib (Sutent) as an option in this scenario.

DISCUSSION QUESTION

• What clinical data support your choice of treatment approach for a patient presenting with this clinical profile?

Hutson: In the KEYNOTE-564 trial, patients with ccRCC with no prior systemic therapy were randomized to pembrolizumab or placebo for up to 17 cycles or 1 year. The primary end point was disease-free survival by investigator assessment and overall survival was the key secondary end point.

We have a hazard ratio for disease-free survival of 0.71 and a hazard ratio for overall survival of 0.66—so a 34% reduction in the risk of death at 5 years if you receive 1 year of adjuvant pembrolizumab.¹ So those are amazing results. And this benefit held up across the subgroups in the intent-to-treat population.

DISCUSSION QUESTION

• What is the window of time after nephrectomy in which you would still consider it clinically appropriate to offer adjuvant pembrolizumab to one of your high-risk patients?

Manny Mangat, MD: I think a question that often comes up is that sometimes patients “get lost,” meaning they don't get to see us right away, and some time goes by after their nephrectomy. So then how long is reasonable after surgery for a patient to still get a benefit from post-nephrectomy pembrolizumab?

Hutson: Being an academician, I'm pretty stringent on what the data say. In KEYNOTE-564, you needed to start receiving adjuvant pembrolizumab within 90 days from surgery. And I've had it happen to me just recently—someone came in 9 months after their surgery and they wanted to do adjuvant therapy…At some point you have to draw the line. Because if I’m starting adjuvant therapy after 90 days, I have no evidence that there’s a benefit for the patient.

DISCUSSION QUESTION

• When patients received adjuvant pembrolizumab and experience disease progression is rechallenging with a PD-1/PD-L1 inhibitor an option you consider?

Hutson: So, for the patients in KEYNOTE-564 who were randomly assigned to adjuvant pembrolizumab and subsequently progressed, did they end up getting anti–PD-1/PD-L1 inhibitors? The answer is that only about 28% did and I think that's a reflection of the time the trial was being conducted. At that time, we didn't really know what to do in those patients. So, if you went to any of the medical meetings at the time, kidney cancer aficionados would say, “If you had adjuvant pembrolizumab and progressed, what would you give next?” And some of them were saying single-agent TKI. I remember distinctly people saying that because we really didn't know any better; we had not defined yet what it looked like to progress in the adjuvant setting.

Now, I think we still don't have that firmly defined, but a lot of physicians are looking at how long the treatment-free interval was before the patient progressed. So, if a patient progresses immediately on adjuvant immunotherapy or even up to 6 months after the immunotherapy, the physician is less likely to want to use an immunotherapy again; however, if it's been longer than that—say a year or two—then they'll just treat the patient like they've never been exposed to immunotherapy. So, I think we'll see more of this being defined as we move forward.

DISCUSSION QUESTION

What patient factors present a clinical scenario in which you would you would almost always use adjuvant pembrolizumab?

Hutson: The M1 [distant metastases], no evidence of disease (NED) group—so those are patients that had metastatic disease and they were resected at the time of the nephrectomy to an NED status. They have the highest risk of recurrence. Their hazard ratio benefit with pembrolizumab is [about 0.3]…If you get something down in the 0.3 range, that's kind of like winning the lottery, right? You wouldn't expect a 70% improvement in something in general. So, I think anyone who's M1 NED needs to be getting adjuvant therapy, for sure.

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DISCLOSURES: Hutson reported receiving research support from Bayer/Onyx, Pfizer, and GlaxoSmithKline, and he is an advisory board/consultant for Bayer/Onyx and Pfizer and on the speaker's bureau for Bayer/Onyx, Pfizer, Amgen, Novartis, and Genentech.

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 for the treatment of clear cell renal cell carcinoma. J Clin Oncol. 2025;43(16 suppl):4514. doi:10.1200/JCO.2025.43.16_suppl.4514

2. Merck. FDA approves Merck's KEYTRUDA (pembrolizumab) as adjuvant therapy for certain patients with renal cell carcinoma (RCC) following surgery. News release. Merck; November 17, 2021. Accessed May 19, 2026. https://tinyurl.com/mr3pzksv

3. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 3.2026. Accessed May 19, 2026. https://tinyurl.com/yakm62w6