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Impressive disease-free survival seen with adjuvant pembrolizumab in clear cell RCC


“Although numbers of participants with certain disease risk features were small, the DFS benefit was consistent across subgroups,” said lead study author Toni K. Choueiri, MD.

Data presented at the 2021 American Urological Association Annual Meeting showed that adjuvant pembrolizumab (Keytruda) improved disease-free survival (DFS) vs placebo across all prespecified subgroups, including region, type of nephrectomy, sarcomatoid features, disease risk category, tumor grade, and PD-L1 status.1

The benefit was most significantly pronounced in patients who underwent partial nephrectomy (HR, 0.22; 95% CI, 0.05-1.04) and those who had M1 no evidence of disease (NED; HR, 0.29; 95% CI, 0.12-0.69). The data were derived from the phase 3 KEYNOTE-564 trial (NCT03142334).

Toni K. Choueiri, MD

Toni K. Choueiri, MD

“Although numbers of participants with certain disease risk features were small, the DFS benefit was consistent across subgroups,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, said in a virtual presentation during the meeting. “Safety results were in line with expectations and no new safety signals were observed.”

Earlier findings from the KEYNOTE-564 study were presented during the 2021 ASCO Annual Meeting. Based on these data, the FDA granted a priority review designation to a new supplemental biologics license application for adjuvant pembrolizumab as a treatment for patients with RCC who are at intermediate-high or high risk of recurrence after nephrectomy or following nephrectomy and resection of metastatic lesions.2 The agency is expected to decide on the application by December 10, 2021.

In the double-blind, multicenter, phase 3 KEYNOTE-564 study, investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Specifically, patients’ disease had to meet criteria that categorized them as intermediate-high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; high-risk pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with NED after surgery.

Stratification factors included metastatic status (M0 vs M1 NED), as well as ECOG performance status (0 vs 1) and region (US vs non-US), both in the M0 group only.

To be eligible for enrollment, patients must have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic therapy, had to have an ECOG performance status of 0 or 1, and a tissue sample must have been obtainable for PD-L1 testing.

All patients underwent 1:1 randomization to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year.

The primary end point of the trial was investigator-assessed DFS; secondary end points were overall survival (OS) and safety.

The first prespecified interim analysis was planned following approximately 265 DFS events and a 12-month minimum follow-up. Following a minimum 15-month follow-up, 260 DFS events had occurred, and 51 OS events occurred. DFS and OS were estimated via Kaplan-Meier.

The median age of study participants was 60 years (range, 25-84), 71% of patients were male, and 73.5% had an ECOG performance status of 1. Moreover, 25.95% of patients were from North America, 37.7% were from the European Union, and 37.3% were from the rest of world. Most patients (92.4%) underwent radical nephrectomy and 83.7% had absent sarcomatoid features.

The majority of patients (86.5%) had M0 intermediate-high risk disease, 7.6% had M0 high-risk disease, and 5.8% had M1 NED. Moreover, 88.6% of patients had a primary tumor stage of T3; 3.5%, 30.4%, 43.5%, 22.3% of patients had tumor grade 1, 2, 3, and 4, respectively. Additionally, 93.8% of patients had N0 disease. Seventy-five percent of patients had a PD-L1 combined positive score of at least 1.

The data cutoff date was December 14, 2020. At a median follow-up of 24.1 months (range, 14.9-41.5), the median DFS in the intent-to-treat population was not reached with either pembrolizumab (n = 496) or placebo (n = 498) per investigator assessment (HR, 0.68, 95% CI, 0.53-0.87; P = .0010). The estimated 1-year DFS rates were 85.7% and 76.2% with pembrolizumab and placebo, respectively; the 2-year rates were 77.3% and 68.1%, respectively.

When examined across subgroups, additional factors that were associated with a more significant DFS benefit with pembrolizumab was patients of the European Union (HR, 0.49; 95% CI, 0.32-0.74), present sarcomatoid features (HR, 0.56; 95% CI, 0.29-1.06), and grade 4 tumors (HR, 0.57; 95% CI, 0.37-0.87).

OS data remain immature and the median OS has not yet been reached in either arm. However, there is a trend toward improved survival with pembrolizumab (HR, 0.54; 95% CI, 0.30-0.96; P = .0164). Eighteen events (3.6%) have occurred in the pembrolizumab arm compared with 33 events (6.6%) in the placebo arm. The 1-year DFS rates were similar at 98.6% and 98.0% with pembrolizumab and placebo, respectively; at 2 years, these rates were 96.6% and 93.5%, respectively.

Safety findings showed that all-cause adverse events (AEs) occurred in 96.3% of patients on pembrolizumab and 91.1% of those on placebo; grade 3 to 5 AEs occurred in 32.4% and 17.7% of patients, respectively, and 20.7% and 2.0% of patients, respectively, had AEs led that led to treatment discontinuation. Two patients on pembrolizumab had AEs that led to death compared with 1 patient on placebo.

Serious all-cause AEs occurred in 20.5% of patients on pembrolizumab and 11.3% of patients on placebo; these AEs led to treatment discontinuation in 10.0% and 1% of patients, respectively. Treatment-related AEs (TRAEs) that were all-grade and grades 3 to 5 occurred in 79.1% and 18.9% of pembrolizumab-treated patients and 53.4% and 1.2% of placebo-treated patients, respectively. A total 17.6% of patients on pembrolizumab had AEs led to treatment discontinuation vs 0.6% on placebo. No TRAEs on either arm led to death.

Grade 3/4 AEs that occurred in more than 5% of patients on pembrolizumab were fatigue, diarrhea, rash, pruritis, hypothyroidism, hyperthyroidism, arthralgia, myalgia, and asthenia. A total 7.4% of patients on pembrolizumab received high-dose (≥40 mg/day) of systemic corticosteroids for immune-mediated AEs compared with 0.6% of those on placebo.


1. Choueiri T, Pembrolizumab (pembro) vs placebo as post nephrectomy adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): randomized, double-blind, phase 3 KEYNOTE-564 study. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Plenary session. https://bit.ly/392XAL7

2. 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 September 14, 2021. https://bit.ly/3jEcyMt

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