Adjuvant Pembrolizumab Prolongs Overall Survival in Clear Cell RCC – Renal and Urology News

Adjuvant pembrolizumab prolongs overall survival in patients with clear cell renal cell carcinoma (RCC) at intermediate to high risk for recurrence after nephrectomy with or without metastasectomy, investigators reported in the New England Journal of Medicine.

Highly anticipated results from the phase 3 KEYNOTE-564 trial demonstrate that adjuvant pembrolizumab significantly decreased the risk for all-cause mortality by 38% compared with placebo at a median follow-up of 57.2 months, Toni K. Choueiri, MD, of Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, and colleagues reported. The estimated survival curves for the pembrolizumab group and placebo group began separating at 15 months. Estimated overall survival at 48 months was 91.2% in the pembrolizumab group compared with 86.0% in the placebo group. Patients who were younger and had less-adverse prognostic features, such as nonmetastatic disease, an ECOG performance-status score of 0, and absence of sarcomatoid features had significant survival benefits with use of the PD-1 inhibitor, according to unplanned subgroup analyses. Black patients comprised only 1.9% of the trial population, which is a limitation.

These overall survival data further support the use of adjuvant pembrolizumab as a standard of care after nephrectomy in clear cell RCC, according to Dr Choueiri’s team. Of the 994 randomized patients, 496 received intravenous pembrolizumab (at a dose of 200 mg) every 3 weeks for up to 17 cycles (approximately 1 year) or until disease recurrence, unacceptable toxic effects, or discontinuation. Surgery could include partial or radical nephrectomy, including complete metastasectomy within 1 year.

At a median follow-up of 57.2 months, pembrolizumab continued to show a 28% decreased risk for recurrence, confirming the disease-free survival benefit observed at 24 months.

Serious adverse events occurred in 20.7% of the pembrolizumab group compared with 11.5% of the placebo group. Grade 3 or 4 adverse events also affected a higher proportion of the pembrolizumab group: 18.6% vs 1.2%. No deaths were attributed to the treatment, but 1 in 5 patients treated with pembrolizumab discontinued therapy. Immune-mediated adverse events and infusion reactions were observed starting at 2.1 months in the pembrolizumab group and lasted a median 2.9 months per episode.

Patient-reported outcomes indicated no clinically meaningful deterioration in health-related quality of life, but validated instruments are needed.

“The appropriate strategy for adjuvant treatment should be determined on a case-by-case basis, by weighing efficacy benefits against safety risks, including the possibility of a serious adverse event … as part of the discussion and informed consent,” Dr Choueiri’s team cautioned.

Documented recurrence occurred 161 patients in the pembrolizumab monoclonal antibody group and 210 patients in the placebo group. The vast majority of patients in the pembrolizumab group (88.8%) had distant metastases. Subsequent therapy was administered to 79.5% of the pembrolizumab group and 81.4% of the placebo group. Overall, systemic anticancer drug therapy was administered to 79.5% vs 84.3%, including subsequent anti-PD-1 or anti-PD-L1 antibody-based therapy to 41.0% vs 69.7% and subsequent VEGF- or VEGFR-targeted therapy to 92.4% vs 84.8%, respectively. Subsequent radiation therapy was administered to 24.2% vs 19.8% of the intervention and placebo groups, respectively, and further surgery to 27.3% vs 29.1%, respectively.

“The anticipated effect of KEYNOTE-564 as the first trial of adjuvant therapy that has shown a benefit with regard to overall survival after nephrectomy cannot be overstated,” Martin H. Voss, MD, and Robert J. Motzer, MD, from Memorial Sloan Kettering Cancer Center in New York, New York, wrote in an accompanying editorial. “The lack of such success in phase 3 trials that have investigated other adjuvant immunotherapies may relate to differences in mechanism of action, trial design, population risk, and dose exposure.”

The editorialists observed that patient selection needs to be refined for use of adjuvant pembrolizumab. How adjuvant pembrolizumab will affect subsequent use of immunotherapy combinations in relapsed patients are among the outstanding questions.

Disclosure: This research was supported by Merck Sharp and Dohme. Please see the original reference for a full list of disclosures.