“Practice-Changing” Results Seen for Pembrolizumab in Adjuvant Setting in Renal Cell Carcinoma

The study's lead author said researchers have searched for a generation for an effective therapy to give to high-risk patients with renal cell carcinoma after initial surgery for the tumor.

Treating patients with a common type of kidney cancer with the checkpoint inhibitor pembrolizumab (Keytruda, Merck) after surgery cut the risk of disease recurrence or death by 32% over a 2-year period, according to results presented Sunday during the annual meeting of the American Society of Clinical Oncology (ASCO).

The KEYNOTE-564 interim results, which capped the meeting’s plenary session, were described as “practice changing” by a scientist asked to comment, although more time is needed to learn whether a clear benefit in disease-free survival (DFS) fully extends to overall survival (OS).

Merck funded the study.

Renal cell carcinoma (RCC) kills 175,000 people worldwide each year, and its incidence has been slowly rising, due to an aging population and better detection. Half of patients who have surgery to remove an initial tumor see their cancer return, so the search has been on for treatment that could prevent cancer from reaching an advanced stage. Until now, adjuvant studies have inconsistent or negative. However, pembrolizumab’s effectiveness in metastatic RCC raised the possibility that the PD-1 inhibitor could work in the adjuvant setting.

The phase 3 study is the first with a checkpoint inhibitor in the adjuvant setting to improve DFS in patients with high-risk, clear cell renal cell carcinoma (RCC) who have had surgery to remove a tumor or the entire kidney. Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and lead author of the study, characterized how long researchers in the field have searched for an adjuvant treatment for high-risk RCC patients after surgery.

“The first randomized control trial to my knowledge of adjuvant immunotherapy in renal cell cancer was interferon, and this was presented at the 1992 ASCO meeting. At that time, I wasn't done with high school,” he said. “Now, 29 years later finally—finally—we have a positive adjuvant event study in renal cell cancer.”

Details of KEYNOTE-564

The study randomized 994 patients 1:1 to receive either pembrolizumab or placebo at least 12 weeks after surgery. The primary endpoint was DFS, with OS as a secondary end point. Patients at various risk levels were enrolled: intermediate-high risk, high risk, or no evidence of disease after a primary tumor and soft tissue metastases completely resected at least year from nephrectomy. Results showed:

  • The 24-month DFS rate was 77.3% with pembrolizumab, compared with 68.1% with placebo; the hazard ratio (HR) was 0.68; 95% CI, 0.53-0.87, P = .001. The benefit was consistent across subgroups.
  • Estimated preliminary OS rate at 24 months was 96.6% with pembrolizumab, compared to 93.5% with placebo; however, the number of events was small, and Choueiri said the results “should be interpreted with caution.” The HR was 0.54; CI 95%, 0.30-0.96, P = .0164.
  • Adverse events (AEs) of grade 3 or higher were more common with pembrolizumab than placebo — 32.4% vs 17.7%. No treatment-related deaths were seen in the pembrolizumab group.

Commentator Rana McKay, MD, associate professor of medicine and urology at the University of California San Diego, and Genitourinary Oncology co-lead at Moores Cancer Center, said that while it will be important to wait for overall survival data to mature, she did not hesitate to describe the results as “practice changing.”

“The data represent a paradigm shift as the first positive phase 3 study of adjuvant immunotherapy in RCC,” McKay said. “DFS prolongation represents clinical benefit given the magnitude of benefit and limited toxicity.”

If pembrolizumab after surgery is adopted as the new standard of care for these patients, she said, “New questions will arise, including, ‘Will there be broad implementation for all patients? What about the application for non-clear cell patients? And if recurrence does develop, how does this alter first-line treatment for advanced disease?”

“Ultimately,” McKay said, “this is a quantum leap forward for our patients and provides additional options for individuals with renal cell carcinoma.”


Choueriri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. J Clin Oncol 2021; 39: (suppl 15; abstr LBA5) DOI: 10.1200/JCO.2021.39.15_suppl.LBA5

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