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The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of single-agent pembrolizumab for use as an adjuvant treatment in adult patients with renal cell carcinoma who are at increased risk of recurrence after nephrectomy, or following nephrectomy and the resection of metastatic lesions.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of single-agent pembrolizumab (Keytruda) for use as an adjuvant treatment in adult patients with renal cell carcinoma (RCC) who are at increased risk of recurrence after nephrectomy, or following nephrectomy and the resection of metastatic lesions.1
The positive opinion was supported by data from the phase 3 KEYNOTE-564 trial (NCT03142334), in which the immunotherapy significantly improved disease-free survival (DFS) compared with placebo.2 Pembrolizumab reduced the risk of disease recurrence or death by 32% vs placebo (HR, 0.68; 95% CI, 0.53-0.87; P = .0010).
The median DFS had not yet been reached in either treatment arm. However, the DFS rates at 24 months in the investigative and control arms were 77% (95% CI, 73%-81%) and 68% (95% CI, 64%-72%), respectively.
At the time of the interim DFS analysis, the overall survival (OS) findings were not yet mature, with 5% of deaths in the overall population (n = 994). At a median follow-up of 24.1 months (range, 14.9-41.5), 3.6% of those who received the immunotherapy experienced an OS event compared with 6.6% of those given the placebo (HR, 0.54; 95% CI, 0.30-0.96; P = .0164). The OS rates at 24 months in the investigative and control arms were 96.5% and 93.5%, respectively.
The recommendation will now be reviewed by the European Commission for marketing authorization in the European Union. A final decision is anticipated to be made in the first quarter of 2022.
“Patients in Europe with earlier-stage RCC, who are at increased risk of recurrence following nephrectomy, have not had an approved treatment option in the adjuvant setting that can help reduce the risk of their cancer returning, Scot Ebbinghaus, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “This positive CHMP opinion for [pembrolizumab] is an important step forward in bringing adjuvant immunotherapy to these patients and demonstrates Merck’s progress in providing new options to treat earlier stages of cancer.”
For the multicenter, double-blind, placebo-controlled trial, investigators set out to evaluate whether treatment with pembrolizumab after nephrectomy would significantly improve outcomes in 994 patients with clear cell RCC who are at intermediate-high or high risk of recurrence, and those who are M1 with NED.
The median age of study participants was 60 years in the investigative (range, 27-81) and control (range, 25-84) arms of the trial. At baseline, 86.1% of patients in the pembrolizumab arm (n = 427) were at intermediate-high risk of disease recurrence, 8.1% were high risk, and 5.8% were M1 with NED; these rates were 86.9%, 7.2%, and 5.8%, respectively, in the placebo arm (n = 433). Moreover, 92.5% of patients had a radical nephrectomy in the immunotherapy arm vs 92.4% of those in the placebo arm; 7.5% and 7.6% of patients, respectively underwent a partial nephrectomy.
Twenty five percent of patients who received pembrolizumab had a PD-L1 combined positive score (CPS) of less than 1, and 73.6% had a score of 1 or higher; 1.4% of patients had missing PD-L1 status. Moreover, 22.7% of those in the placebo arm had a CPS of less than 1, 76.9% had a score of 1 or higher, and 0.4% had missing status.
The median time from randomization to cutoff was 24.1 months (range, 14.9-41.5). Participants were randomized 1:1 to receive pembrolizumab at 200 mg or placebo every 3 weeks until disease recurrence, intolerable toxicity, or for up to 12 months.
After 15 months of minimum follow-up, 260 DFS events were reported, this equated to 78% of the number of events planned for the final analysis. Moreover, 51 OS events occurred, which translates to 26% of the planned number for the final analysis.
No new safety signals were reported with adjuvant pembrolizumab. Treatment-related toxicities were experienced by 79.1% of those who received pembrolizumab vs 53.4% of those in the placebo arm; 18.9% and 1.2% of patients, respectively, experienced grade 3 to 5 toxicities. Notably, none of these effects resulted in death.
The most frequently reported treatment-related adverse effects in the investigative and control arms were fatigue (20.3% and 14.3%, respectively), pruritus (18.6% vs 11.5%), hypothyroidism (17.6% vs 2.6%), diarrhea (15.8% vs 10.3%), and rash (15.0% vs 7.3%).
In November 2021, the FDA approved pembrolizumab as an adjuvant treatment for patients with RCC who are at intermediate-high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.3 Data from KEYNOTE-564 supported the regulatory decision.