FDA Grants Priority Review to Adjuvant Pembrolizumab for Post-Nephrectomy RCC


The FDA has granted priority review to a new supplemental biologics license application for pembrolizumab as an adjuvant treatment in patients with renal cell carcinoma.



The FDA has granted priority review to a new supplemental biologics license application (sBLA) for pembrolizumab (Keytruda) as an adjuvant treatment in patients with renal cell carcinoma (RCC) who are at intermediate-high or high risk of recurrence after nephrectomy or following nephrectomy and resection of metastatic lesions.1

The application is supported by data from the pivotal phase 3 KEYNOTE-564 trial (NCT03142334), in which the immunotherapy significantly improved investigator-assessed disease-free survival (DFS) over placebo in the intent-to-treat population (HR, 0.68; 95% CI, 0.53-0.87; P = .0010). The median DFS had not yet been reached in either arm at a median follow-up of 24.1 months (range, 14.9-41.5).2

The estimated DFS rates at 12 months in the investigative and control arms were 85.7% and 76.2%, respectively; at 24 months, these rates were 77.3% and 68.1%, respectively.

The regulatory agency is expected to reach a decision on the sBLA by December 10, 2021, under the Prescription Drug User Fee Act.

“The acceptance of our application demonstrates the progress we are making in earlier lines and earlier stages of certain cancers across our oncology portfolio,” Scot W. Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “We look forward to working with the FDA toward the goal of bringing the first adjuvant immunotherapy option to appropriate patients with RCC in the United States.”

KEYNOTE-564 enrolled patients with histologically confirmed clear cell RCC who had undergone nephrectomy up to 12 weeks before randomization. Patients had an ECOG performance status of 0 or 1 and did not previously receive systemic therapy.

A total of 994 participants were randomized 1:1 to receive either pembrolizumab at a dose of 200 mg every 3 weeks for approximately 1 year (n = 496) or placebo for the same schedule (n = 498). Patients were stratified based on M0 vs M1 NED, and they were further stratified by ECOG performance status (0 vs 1) and country (United States vs non–United States).

The primary end point of the trial was investigator-assessed DFS, and a key secondary end point was overall survival (OS). Another important end point of the trial was safety.

The median age of study participants was 60 years, 85.2% had an ECOG performance status of 0, 86.5% had a disease risk category of M0 intermediate high risk, 37.7% were from the European Union, and most patients did not have sarcomatoid features (83.7%). Regarding PD-L1 status, 23.9% of patients had a combined positive score (CPS) of less than 1, 75.2% had a CPS of 1 or higher, and 0.9% of patients had this information missing.

Additional data from the trial presented during the 2021 ASCO Annual Meeting demonstrated that the median OS had not yet been reached in either arm (HR, 0.54; 95% CI, 0.30-0.96; P = .0164). The 12- and 24-month OS rates in the investigative and control arms were 98.6% vs 98.0%, respectively, and 96.6% vs 93.5%, respectively.

Regarding safety, all-cause adverse effects (AEs) were reported in 96.3% of those who received adjuvant pembrolizumab vs 91.1% of those who were given placebo; these effects were grade 3 to 5 in 32.4% and 17.7% of patients, respectively. All-cause toxicities resulted in treatment discontinuation in 20.7% of those on the investigative arm and 2.0% of those on the control arm. These effects resulted in death for 2 patients who received pembrolizumab and 1 patient who was given placebo.

Treatment-related AEs (TRAEs) were experienced by 79.1% and 53.4% of patients on the investigative and control arms, respectively; these effects were grades 3 to 5 in 18.9% and 1.2% of patients, respectively. TRAEs resulted in discontinuation in 17.6% and 0.6% of patients on the pembrolizumab and placebo arms, respectively. No TRAEs resulted in death across the arms.

The most frequently reported TRAEs in the pembrolizumab and placebo arms, respectively, included fatigue (20.3% vs 14.3%), pruritus (18.6% vs 11.5%), hypothyroidism (17.6% vs 2.6%), diarrhea (15.8% vs 10.3%), rash (15.0% vs 7.3%), hyperthyroidism (10.2% vs 0%), arthralgia (9.4% vs 8.7%), nausea (8.0% vs 4.6%), myalgia (6.1% vs 4.0%), and asthenia (5.7% vs 4.6%).

Pembrolizumab has received regulatory approval for use in combination with axitinib (Inlyta) for the frontline treatment of patients with advanced RCC in the United States, Europe, and Japan. The immunotherapy is under investigation as monotherapy and as part of novel combinations across several stages and settings of RCC, including adjuvant and advanced or metastatic disease.


  1. FDA grants priority review to Merck’s supplemental biologics license application for KEYTRUDA (pembrolizumab) as adjuvant therapy in certain patients with renal cell carcinoma (RCC) following surgery. News release. Merck. August 10, 2021. Accessed August 10, 2021. https://bit.ly/3jEcyMt
  2. Choueiri 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):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5
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