according to expert opinion.
The high hopes have been generated by results from the randomized, phase 3 KEYNOTE-564 trial, showing that monotherapy with pembrolizumab (Keytruda, Merck) was associated with significantly longer disease-free survival (DFS) after nephrectomy than placebo (77.3% vs. 68.1%, respectively). Median follow-up was 24 months.
The results come from the trial’s first interim analysis of data from 994 patients with clear-cell renal cell carcinoma (RCC) at high risk of recurrence.
For the pembrolizumab group, the estimated percentage alive at 24 months was 96.6%, compared with 93.5% in the placebo group (hazard ratio for death, 0.54), said Toni Choueiri, MD, of the Dana-Farber Cancer Institute, Boston, and colleagues.
However, grade 3 or higher adverse events (any cause) occurred at almost twice the rate in the pembrolizumab versus the placebo group (32.4% vs. 17.7%). The new study was published online Aug. 18, 2021, in the New England Journal of Medicine.
The study results were first presented at the 2021 American Society of Clinical Oncology annual meeting and described as likely to be practice changing in this setting, as reported by this news organization.
Currently, this patient population has “no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence,” observed the authors.
That’s about to change, as the trial results “herald the dawn of a new era in the treatment of renal cell carcinoma,” Rana McKay, MD, University of California San Diego Health, wrote in an accompanying editorial.
Multiple studies have investigated potential adjuvant therapies in RCC since the 1980s, she observed.
“For the first time, we now have an effective adjuvant immunotherapy option for patients with resected renal cell carcinoma at high risk of recurrence,” Dr. McKay said in an interview.
To date, the lack of clinically beneficial adjuvant therapy options in RCC has been “humbling,” Dr. Choueiri said in an interview. “We hope we can push the envelope further and get more patients with RCC some good options that make them live longer and better.”
Although the standard of care for patients diagnosed with locoregional RCC is partial or total nephrectomy, nearly half of patients eventually experience disease recurrence following surgery, Dr. Choueiri noted.
“No standard, globally approved adjuvant therapy options are currently available for this population,” he said. Clinical guidelines recommend patients at high risk of disease recurrence after surgery be entered into a clinical trial or undergo active surveillance.
Researchers will continue to follow the results for overall survival, a secondary endpoint. “The very early look suggests encouraging results [in overall survival] with an HR of 0.54,” Dr. Choueiri noted.
In the meantime, the prolongation of DFS represents a clear clinical benefit, said Dr. McKay, “given the magnitude of the increase” and “the limited incidence of toxic effects.”
KEYNOTE-564 will alter the adjuvant treatment landscape for RCC as a positive phase 3 trial of adjuvant immunotherapy for the disease, she added.
A number of earlier studies have investigated the use of adjuvant vascular endothelial growth factor–targeting agents in RCC. Only the 2016 Sunitinib Treatment of Renal Adjuvant Cancer (S-TRAC) trial showed improved DFS with sunitinib, compared with placebo (6.8 vs. 5.6 years). Subsequently, sunitinib was approved for adjuvant use in the United States. However, the S-TRAC trial also showed that sunitinib therapy was associated with an increased incidence of toxic effects and lower quality of life scores, and researchers did not observe any benefit in overall survival.
“Despite regulatory approval in the U.S., sunitinib is not approved for adjuvant use by the European Medicines Agency and has limited utilization in clinical practice given the low benefit-risk ratio,” Dr. McKay pointed out.