NEJM Data Underscore DFS Benefit With Adjuvant Pembrolizumab in Post-Nephrectomy RCC

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Partner | Cancer Centers | <b>Dana-Farber Cancer Institute</b>

Adjuvant treatment with pembrolizumab led to a significant improvement in disease-free survival compared with placebo after nephrectomy in patients with renal cell carcinoma who are at high risk for recurrence, as underscored by data from the pivotal phase 3 KEYNOTE-564 trial.

Adjuvant treatment with pembrolizumab (Keytruda) led to a significant improvement in disease-free survival (DFS) compared with placebo after nephrectomy in patients with renal cell carcinoma (RCC) who are at high risk for recurrence, as underscored by data from the pivotal phase 3 KEYNOTE-564 trial (NCT03142334) that was recently published in the New England Journal of Medicine.1

Both the median DFS and overall survival (OS) were not reached in either study group, and the risk of disease recurrence or death was 32% (HR, 0.68; 95% CI, 0.53-0.87; two-sided P = .002) with adjuvant pembrolizumab therapy vs placebo. At a median follow-up of 24 months, the DFS rate was 77.3% (95% CI, 72.8%-81.1%) for pembrolizumab vs 68.1% (95% CI, 63.5%-72.2%) for placebo.

OS was still trending favorably with pembrolizumab, demonstrating a 46% reduction in the risk of death (HR, 0.54; 95% CI, 0.30-0.96). Moreover, 96.6% (95% CI, 94.3%-98.0%) of patients in the pembrolizumab arm remained alive at 24 months vs 93.5% (95% CI, 90.5%-95.6%) in the placebo group.

Local recurrence was only observed in 3.4% of pembrolizumab-treated patients vs 6.4% of those on placebo; distant recurrence rates were reported in 17.3% and 23.5%, respectively. Moreover, 51 total deaths were reported on the study, with 18 occurring on pembrolizumab group, and 33 occurring in the placebo group.

Data presented from KEYNOTE-564 were presented at the 2021 ASCO Annual Meeting and served as the basis for a priority review application in this setting that was granted by the FDA in August 2021.

“VEGF-targeted therapies and other approaches have not shown a consistent benefit in patients with such disease,” lead study author Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, and coinvestigators wrote in the NEJM publication. “The results of this phase 3 trial support the use of pembrolizumab as adjuvant immunotherapy in patients with renal cell carcinoma and an intermediate-to-high or high risk of disease recurrence.”

Although partial or radical nephrectomy is a standard-of-care treatment for locoregional clear-cell RCC, nearly half of patients who undergo the procedure will experience disease recurrence. Oftentimes, patients who recur do so with metastatic disease, which has suboptimal survival outcomes.

No standard-of-care systemic adjuvant treatment is recommended for patients with RCC, and various VEGF-targeted treatments have shown mixed results. However, PD-1 inhibitors, such as pembrolizumab, have shown activity as monotherapy and in combination as treatment for patients with advanced RCC; investigators theorized it could also be an intriguing agent in the adjuvant setting.

“We conducted the KEYNOTE-564 trial to evaluate whether treatment with pembrolizumab after nephrectomy, with or without metastasectomy, would result in improved outcomes, as compared with placebo, in [this population],” the authors wrote.

In the double-blind, phase 3 trial, 994 patients were randomized 1:1 receive either adjuvant pembrolizumab (n = 496) at 200 mg or placebo (n = 498) intravenously (IV) once every 3 weeks for up to 17 cycles, which was approximately 1 year, or until disease progression. The primary end point was DFS; key secondary endpoints included OS and safety.

Patients eligible to enroll on the trial were at least 18 years old and had a confirmed diagnosis of locoregional RCC with clear cell histology. Additionally, patients must have undergone either partial or radical nephrectomy within 12 weeks of randomization with negative surgical margins. Those who had received prior systemic treatment for RCC were excluded from enrollment.

The median age was 60 years (range, 25-84), and 71% were male. Most patients (92.4%) underwent radical nephrectomy and presented with intermediate- to high-risk disease (86.5%).

Overall, 61.1% of patients randomized to the pembrolizumab arm completed all 17 cycles of treatment; 38.9% discontinued therapy. Among the patients who discontinued, the most common reasons were due to adverse effects (AEs; 21.3%) or disease progression (10.5%). Moreover, 73.6% of patients randomized to the placebo arm completed all treatment, with disease recurrence being the most common reason for discontinuation (20.4%).

The median duration of the trial regimen was 11.1 months in both the pembrolizumab (range, 0.0-14.3) and placebo (range, 0.0 to 15.4) arms.

In terms of safety, 96.3% and 91.1% of patients experienced at least 1 any-grade AE in the pembrolizumab and placebo arms, respectively. Moreover, AEs that ranged from grade 3 to 5 in severity were reported in 32.4% of patients receiving pembrolizumab and 17.7% receiving placebo.

Two deaths occurred in the pembrolizumab group, which were due to multiple organ dysfunction syndrome and pneumonia (n = 1 each); there was 1 death in the placebo group, which was due to intracranial hemorrhage.

Moreover, at least 1 serious AE was reported in 20.5% of patients receiving pembrolizumab, and 11.3% receiving placebo. The most common AEs of any grade reported were fatigue (29.7% with pembrolizumab vs 24.2% with placebo), diarrhea (25.4% vs 22.4%, respectively), pruritus (22.7% vs 13.1%), and arthralgia (22.1% vs 18.8%).

“As expected, the incidences of grade 3 to 5 adverse events of any cause, of serious adverse events, and of treatment-related adverse events of any grade, or of grade 3 or 4, were higher in the pembrolizumab group than in the placebo group,” the authors wrote. “Adverse events with the greatest risk difference between the pembrolizumab group and the placebo group, such as hyperthyroidism, hypothyroidism, and pruritus, were all known and expected with pembrolizumab monotherapy and were manageable.”

The FDA is expected to decide on the application for pembrolizumab as an adjuvant treatment for patients with RCC at an intermediate-high or high risk of recurrence after nephrectomy or following nephrectomy and resection of metastatic lesions by December 10, 2021.


  1. 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