Phase 3 KEYNOTE-564 Meets it Secondary Endpoint in RCC


Adjuvant pembrolizumab improved overall survival vs placebo in patients with renal cell carcinoma at intermediate-high or high risk of recurrence.

Phase 3 KEYNOTE-564 Meets it Secondary Endpoint in RCC

Phase 3 KEYNOTE-564 Meets it Secondary Endpoint in RCC

Merck has announced that adjuvant pembrolizumab (Keytruda) has met its key secondary end point of the phase 3 KEYNOTE-564 trial (NCT03142334), improving overall survival (OS) over placebo in patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Safety data for pembrolizumab were consistent with previously reported findings from other studies. Detailed OS data from the prespecified interim analysis will be presented at an upcoming medical meeting and shared with regulatory authorities.

“As we continue to evaluate the potential of [pembrolizumab] in earlier stages of disease across multiple types of cancer, we hope to reduce disease recurrence and ultimately, improve overall survival outcomes,” Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories, stated in a news release. “These new results from KEYNOTE-564 are notable and mark the first time a therapy has demonstrated a statistically significant survival benefit compared [with] placebo in patients with RCC at a higher risk of recurrence following surgery, building on the positive disease-free survival [DFS] findings from this study that led to approvals around the world for this [pembrolizumab]-based regimen.”

In November 2021, the FDA approved pembrolizumab for the adjuvant treatment of patients with RCC who are at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.2

The regulatory decision was based on prior data from KEYNOTE-564, which showed that treatment with the checkpoint inhibitor led to a statistically significant improvement in disease-free survival (DFS) vs placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0010). At the time of this prior prespecified interim analysis, 22% of patients experienced DFS events in the pembrolizumab arm vs 30% of patients in the placebo arm. The median DFS was not reached (NR) in either arm.

An updated analysis presented at the 2022 Genitourinary Cancers Symposium (ASCO GU) showed that at a median follow-up of 30.1 months (range, 20.8-47.5), pembrolizumab had sustained DFS benefit vs placebo (HR, 0.63; 95% CI, 0.50-0.80; P < .0001).3 The median DFS was still NR in both arms. In this updated analysis, OS data remained immature; however, a trend was observed favoring pembrolizumab (HR, 0.52; 95% CI, 0.31-0.86; P = .0048). The 24-month OS rates were 96.2% and 93.8% for pembrolizumab and placebo, respectively.

KEYNOTE-564 was a randomized, double-blind study that enrolled patients with RCC who had undergone nephrectomy within 12 weeks of randomization.3,4 Patients needed to have disease that was intermediate-high risk, high risk, or M1 no evidence of disease following surgery. Other key inclusion criteria included RCC with clear cell component with or without sarcomatoid features, no prior systemic therapy for advanced RCC, an ECOG performance status of 0 or 1, and adequate organ function.

Patients were excluded if they received prior radiotherapy for RCC; had preexisting brain or bone lesions; had residual thrombus post nephrectomy in the vena renalis or vena cava; had a history of pneumonitis that required steroids or had current pneumonitis; or had any prior treatment with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent, or any other agent directed to a co-inhibitory T-cell receptor.

Patients were randomly assigned to received 200 mg of intravenous pembrolizumab (n = 496) or placebo (n = 498) on day 1 of each 21-day cycle for up to 17 cycles.

Investigator-assessed DFS served as the trial’s primary end point. In addition to OS, secondary end points included recurrence-free survival, second disease recurrence–specific survival, event-free survival, DFS and OS based on PD-L1 status, quality of life, and safety.

Safety data from the updated analysis presented at ASCO GU showed that all-cause adverse effects (AEs) were experienced by 96.3% of those in the pembrolizumab arm vs 91.3% of those in the placebo arm; these effects were grade 3 to 5 for 32.2% and 17.7% of patients, respectively.3 AEs led to treatment discontinuation for 21.1% and 2.2% of patients, respectively.

The most common treatment-related any-grade AEs occurring in at least 5% of the as-treated population included fatigue (20.3%, pembrolizumab; 14.3%, placebo), pruritus (18.6%; 11.5%), hypothyroidism (17.4%; 2.6%), diarrhea (15.8%; 10.3%), rash (15.0%; 7.3%), hyperthyroidism (10.9%; 0%), arthralgia (9.2%; 8.7%), nausea (8.0%; 4.6%), myalgia (6.1%; 4.0%), and asthenia (5.7%; 4.6%).


  1. Keytruda (pembrolizumab) significantly improved overall survival (OS) versus placebo as adjuvant therapy for certain patients with renal cell carcinoma (RCC) following nephrectomy. News release. Merck. November 1, 2023. Accessed November 1, 2023.
  2. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed November 1, 2023.
  3. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab as post nephrectomy adjuvant therapy for patients with renal cell carcinoma: Results from 30-month follow-up of KEYNOTE-564. J Clin Oncol. 2022;40(suppl 6):290. doi:10.1200/JCO.2022.40.6_suppl.290
  4. Safety and efficacy study of pembrolizumab (MK-3475) as monotherapy in the adjuvant treatment of renal cell carcinoma post nephrectomy (MK-3475-564/​KEYNOTE-564). Updated June 29, 2023. Accessed November 1, 2023.
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