Illustration of a cross section of human kidneys to illustrate kidney disease
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For the first time in fifty years, a survival benefit has been demonstrated from an adjuvant therapy in patients with kidney cancer. The immunotherapy pembrolizumab (Merck’s Keytruda), given after nephrectomy, prolonged overall survival by 38% in patients with clear-cell renal-cell carcinoma (ccRCC) at high risk for recurrence, according to the latest analysis of data from the Phase III KEYNOTE-564 study. 

“We can now tell our patients that pembrolizumab after surgery not only delays recurrences but also helps them live longer,” says the study’s lead investigator Toni Choueiri, MD, of Dana-Farber Cancer Institute. Choueiri is director of the Lank Center for Genitourinary Oncology at Dana-Farber and presented the findings at the American Society of Clinical Oncology (ASCO) Genitourinary Cancer Symposium on January 27, 2024.

Kidney cancer affects more than 430,000 people worlwide each year. It is the sixth most common cancer for men in the U.S. But early diagnosis is not yet routine with this disease. 

We do not have a screening test to detect kidney cancer at the earliest stage,” Choueiri tells Inside Precision Medicine. “Another challenge is that it’s a cancer that does not respond to chemotherapy.

The KEYNOTE-564 trial was designed to evaluate adjuvant pembrolizumab following removal of the cancerous kidney. The study, which was carried out at hundreds of sites worldwide, enrolled 994 patients who were randomized to pembrolizumab once every three weeks for about a year, or a placebo. 

Pembrolizumab is a checkpoint inhibitor that targets a molecular pathway cancer cells use to evade attack by the immune system. By blocking this pathway, the drug helps free T cells to attack tumors. First approved by the FDA in 2014, pembrolizumab now has 35 approvals across 16 types of cancer and two tumor-agnostic indications. It was approved in 2021 as adjuvant treatment for patients with kidney cancer.

There been many previous efforts to find a useful adjuvant treatment for kidney cancer.

“Since 1973, more than 12,000 patients with kidney cancer participated in adjuvant studies versus a control arm and none of the studies showed the experimental arm extends lives until now with the KEYNOTE-564 study,” says Choueiri. “We showed pembrolizumab extends survival. It doesn’t only delay recurrence.”

In the first interim analysis of KEYNOTE-564, Choueiri and colleagues reported that adjuvant pembrolizumab improved disease-free survival in patients with kidney cancer at high risk of relapse. This third interim analysis was completed after a median of 57.2 months of follow up. Adjuvant pembrolizumab significantly prolonged overall survival versus placebo in trial participants. Overall survival benefits with pembrolizumab were consistent across subgroups, irrespective of stage, risk stratification, immunological biomarkers, and other characteristics.

Approximately 18% of patients stopped therapy due to side effects associated with pembrolizumab, but no treatment related deaths were reported with the drug. The investigators reported previously that adjuvant pembrolizumab did not result in clinically meaningful deterioration of health-related quality of life.

Prior to the approval of pembrolizumab, there was no accepted standard of care for patients with ccRCC after treatment with surgery. Choueiri and colleagues are now investigating whether adjuvant pembroizumab can be improved by adding the HIF-2 inhibitor belzutifan (Welireg/Merck) the to regimen. That drug was FDA approved for advanced renal cell carcinoma in December of 2023.

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