As reported in The New England Journal of Medicine by Toni K. Choueiri, MD, and colleagues, an interim analysis of the phase III KEYNOTE-564 trial showed improved disease-free survival with adjuvant pembrolizumab vs placebo after nephrectomy in high-risk patients with clear cell renal cell carcinoma (RCC).  

As stated by the investigators, “Patients with RCC who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence.”

Toni K. Choueiri, MD

Study Details

In the double-blind trial, 994 patients from sites in 21 countries who had undergone nephrectomy were randomly assigned between June 2017 and September 2019 to receive pembrolizumab at 200 mg (n = 496) or placebo (n = 498) once every 3 weeks for up to 17 cycles. High risk of disease recurrence was defined as tumor stage II with nuclear grade 4 or sarcomatoid differentiation, tumor stage III or higher, regional lymph node metastasis, or stage M1 with no evidence of disease.

The primary endpoint was investigator-assessed disease-free survival in the intent-to-treat population; overall survival was a key secondary endpoint.  

Disease-Free Survival

At the prespecified interim analysis of disease-free survival, median time from random assignment to data cutoff (December 2020) was 24.1 months (range = 14.9–41.5 months). At 24 months, disease-free survival was 77.3% (95% confidence interval [CI] = 72.8%–81.1%) in the pembrolizumab group vs 68.1% (95% CI = 63.5%–72.2%) in the placebo group (hazard ratio [HR] = 0.68, 95% CI = 0.53–0.87, P = .002). Rates at 12 months were 85.7% (95% CI = 82.2%–88.5%) vs 76.2% (95% CI = 72.2%–79.7%). Local recurrence only was observed in 3.4% vs 6.4% of patients, and distant recurrence was observed in 17.3% vs 23.5%.

At data cutoff, death had occurred in 18 patients in the pembrolizumab group vs 33 patients in the placebo group (HR = 0.54, 95% CI = 0.30–0.96). Estimated 24-month overall survival was 96.6% (95% CI = 94.3%–98.0%) vs 93.5% (95% CI = 90.5%–95.6%); rates at 12 months were 98.6% (95% CI = 97.0%–99.3%) vs 98.0% (95% CI = 96.3%–98.9%).

Adverse Events

The most common adverse events of any grade in both the pembrolizumab and placebo groups were fatigue (29.7% vs 24.2%), diarrhea (25.4% vs 22.4%), pruritus (22.7% vs 13.1%), and arthralgia (22.1% vs 18.8%). Adverse events with the greatest difference in incidence in the pembrolizumab vs placebo group were hypothyroidism, hyperthyroidism, pruritus, and rash. Grade ≥ 3 adverse events occurred in 32.4% of the pembrolizumab group vs 17.7% of the placebo group; the most common in the pembrolizumab group included diarrhea (1.6%) and rash 0.8%). Immune-mediated adverse events occurred in 34.6% vs 5.8% of patients (grade 3–4 in 8.6% vs 0.6%).

Serious adverse events occurred in 20.5% vs 11.3% of patients. Adverse events led to treatment discontinuation in 20.7% vs 2.0%. Adverse events led to death in two patients in the pembrolizumab group (due to multiple organ dysfunction syndrome and pneumonia) and in one patient in the placebo group (due to intracranial hemorrhage); none of the deaths were considered related to treatment.

The investigators concluded, “Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence.”

Disclosure: The study was funded by Merck Sharp & Dohme, a subsidiary of Merck. For full disclosures of the study authors, visit nejm.org.