FDA Approves Adjuvant Pembrolizumab for RCC

The FDA has approved pembrolizumab for the adjuvant treatment of patients with renal cell carcinoma who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

The FDA has approved pembrolizumab (Keytruda) for the adjuvant treatment of patients with renal cell carcinoma (RCC) who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.1

Data supporting the decision were from the phase 3 KEYNOTE-564 trial (NCT03142334), which demonstrated that the immunotherapy resulted in a statistically significant improvement in disease-free survival (DFS) compared with placebo. Specifically, 109 (22%) events were reported in the pembrolizumab arm at the time of an interim analysis vs 151 events (30%) in the placebo arm (HR 0.68; 95% CI, 0.53-0.87; P = .0010). The median DFS had not yet been reached in either arm.

At the time of the DFS analysis, overall survival (OS) data were not mature.

“Despite decades of research, limited adjuvant treatment options have been available for earlier-stage renal cell carcinoma patients who are often at risk for recurrence. In KEYNOTE-564, pembrolizumab reduced the risk of disease recurrence or death by 32%, providing a promising new treatment option for certain patients at intermediate-high or high risk of recurrence,” Toni K. Choueiri, MD, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School, stated in a press release.2 “With this FDA approval, pembrolizumab may address a critical unmet treatment need and has the potential to become a new standard of care in the adjuvant setting for appropriately selected patients.”

The double-blind, international, phase 3 KEYNOTE-564 trial enrolled 994 patients with histologically confirmed locoregional RCC with a clear cell component who met protocol for a high risk of recurrence.3 Patients needed to be at least 18 years of age and could not have previously received systemic therapy for their disease; they also must have undergone surgery and had negative margins within 12 weeks prior to randomization. Patients with active autoimmune disease or a medical condition requiring immunosuppression were excluded.4

Study participants were randomized 1:1 to receive adjuvant pembrolizumab (n = 496) or placebo (n = 496) following nephrectomy, with or without metastasectomy. Patients were stratified based on metastatic status (M0 vs M1 NED). Within the M0 subset, they were further stratified based on ECOG performance status (0 vs 1) and geographic location (United States vs outside the United States).

Patients received pembrolizumab at a dose of 200 mg or placebo intravenously once every 3 weeks for up to 1 year or until recurrence, intolerable toxicity, intercurrent illness preventing further treatment of either agent, investigator decision, a new cancer resulting in active treatment, pregnancy, or nonadherence.

The primary end point of the trial was DFS, and OS was a key secondary end point.

The median age of study participants was 60 years (range, 25-84), with 33% of patients aged 65 years or older. Moreover, 71% of patients were male, 75% were White, and 85% had an ECOG performance status of 0. The majority of patients, or 94%, had N0 disease, 11% had sarcomatoid features, 86% were intermediate-high risk, 8% were high risk, and 6% were M1 NED. Additionally, 92% of patients had a radical nephrectomy and 8% underwent a partial nephrectomy.

The median duration of exposure to pembrolizumab was 11.1 months (range, 1 day to 14.3 months). Additional data showed that the 24-month DFS rate with pembrolizumab was 77% (95% CI, 73%-81%) vs 68% (95% CI, 64%-72%) with placebo.

Regarding safety, 20% of patients who received the immunotherapy reported serious adverse reactions, which included acute kidney injury (1.0%), adrenal insufficiency (1.0%), pneumonia (1.0%), colitis (1.0%), and diabetic ketoacidosis (1.0%). Moreover, 0.2% of patients who received pembrolizumab experienced fatal adverse reactions; this included 1 case of pneumonia.

Twenty-one percent of patients discontinued pembrolizumab because of a toxicity, the most common of which was increased alanine aminotransferase (ALT; 1.6%), followed by colitis (1.0%), and adrenal insufficiency (1.0%).

Additionally, 26% of patients required dose interruptions of the immunotherapy because of an adverse effect such as increased aspartate aminotransferase (2.3%), arthralgia (1.6%), hypothyroidism (1.6%), diarrhea (1.4%), increased ALT (1.4%), fatigue (1.4%), rash (1.0%), decreased appetite (1.0%), and vomiting (1.0%).


  1. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. News release. FDA; November 17, 2021. Accessed November 18, 2021. https://bit.ly/3FrJpND
  2. FDA approves Merck's KEYTRUDA (pembrolizumab) as adjuvant therapy for certain patients with renal cell carcinoma (RCC) following surgery. News release. Merck; November 18, 2021. Accessed November 18, 2021. https://bit.ly/3oFqiZJ
  3. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391
  4. Keytruda. Prescribing information. Merck; 2021. Accessed November 18, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s113lbl.pdf