Adjuvant Pembrolizumab in Kidney Cancer: Dr Haas on KEYNOTE-564

3D render of human kidney on science background: © Rasi - stock.adobe.com

The 5-year follow-up results from the pivotal phase 3 KEYNOTE-564 study (NCT03142334) further underscore the significant and durable benefits of adjuvant pembrolizumab (Keytruda) for patients with high-risk clear cell kidney cancer.

In an interview with Targeted Oncology^TM, Naomi B. Haas, MD, professor of medicine at the Hospital of the University of Pennsylvania and an investigator on the study, emphasized the robust and sustained separation of overall survival (OS) curves, solidifying pembrolizumab's position as a standard of care in this setting.

KEYNOTE-564 investigated the use of adjuvant pembrolizumab for 1 year vs placebo in nearly 1000 patients with high-risk clear cell renal cell carcinoma (RCC) that had been completely resected. The primary end point was disease-free survival (DFS), with key secondary end points including OS and safety.

The 72-month DFS rate was 58.5% with adjuvant pembrolizumab vs 48.7% for those in the placebo group. At the 5-year analysis, the median DFS was not reached nor where either ends of the 95% confidence interval (CI) for those receiving pembrolizumab vs 68.3 months for patients in the placebo group (HR, 0.71; 95% CI, 0.59-0.86). At 72 months, the OS rate was 86.1% in the pembrolizumab group vs 79.4% in the placebo group. The median OS was not yet reached in either arm (HR, 0.66; 95% CI, 0.48-0.90).

"What is truly confirmatory from this data is that the Kaplan-Meier curves for overall survival continue to remain well separated," said Haas in the interview. "This is incredibly important because sometimes, as clinical trials are followed for longer periods, the initial benefits can become diluted. However, in KEYNOTE-564, the separation of the curves for overall survival continues to look very robust, and this is the first time we have reached a median follow-up of 6 years for this data."

The extended follow-up also provided reassuring insights into the long-term safety profile of pembrolizumab. Haas confirmed that "no new serious treatment-related safety signals were observed" in the past 3 years. While acknowledging that some immune-mediated toxicities can be permanent (e.g., diabetes, myocarditis, hypophysitis), she highlighted that these severe adverse events are occurring at a very low rate. Furthermore, increased familiarity among healthcare providers in managing immune-mediated toxicities has led to earlier recognition and more prompt intervention, ultimately improving patient outcomes.

Regarding patient selection, Haas reiterated that the contraindications for adjuvant pembrolizumab remain consistent with those for advanced disease. Patients with inflammatory bowel disorders (Crohn's disease, ulcerative colitis, celiac disease) or severe autoimmune disorders (rheumatoid arthritis, psoriatic arthritis, lupus) should generally avoid immunotherapy.

Biomarkers for Patient Selection Still Under Investigation

Currently, the landscape of RCC and immunotherapy still lacks reliable biomarkers for refining patient selection outside of the established eligibility criteria. Haas cautioned against the independent use of emerging biomarkers like kidney injury molecule-1, DNA methylation, and circulating tumor DNA for patient selection, stressing the need for further validation through retrospective and prospective studies.

Instead, Haas advocated for adhering to the KEYNOTE-564 eligibility criteria for treatment decisions, which include:

• Pathologic T2 disease that is high grade clear cell histology
• Any of the PT3 categories
• Any patient with node-positive disease
• A smaller number of patients who had metastasectomy within 1 year of their original primary kidney cancer surgery. While this last group was relatively small in the study, the forest plot data indicated a strong benefit for adjuvant pembrolizumab in this population.

The enduring positive outcomes observed in the KEYNOTE-564 study at its 5-year follow-up further solidify the critical role of adjuvant pembrolizumab in improving both disease-free survival and OS for patients with high-risk clear cell kidney cancer, reinforcing its status as a standard of care.

REFERENCE:

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 17):4514. doi:10.1200/JCO.2025.43.16_suppl.4514