As reported in The New England Journal of Medicine by Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, and colleagues, an interim analysis of the phase III KEYNOTE-564 trial has showed improved disease-free survival with adjuvant pembrolizumab vs placebo after nephrectomy in high-risk patients with clear cell renal cell carcinoma (RCC).¹

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 with or without metastasectomy 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 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 (NED). Randomization was stratified according to metastatic status (M0 vs M1-NED) and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1). The primary endpoint was investigator-assessed disease-free survival in the intent-to-treat population. Overall survival is a key secondary endpoint.  

For the pembrolizumab vs placebo groups, median age was 60.0 years (range = 27–81 years, 31.9% ≥ 65 years) vs 60.0 years (range = 25–84 years, 34.5% ≥ 65 years), and 70.0% vs 72.1% were male. ECOG performance status was 0 in most patients, but some patients had an ECOG performance status of 1 (15.1% vs 14.5%). Geographic location was North America for 26.8% vs 25.1%, Europe for 37.9% vs 37.6%, and the rest of the world for 35.3% vs 37.3%. Overall, 92.5% vs 92.4% had radical nephrectomy. Sarcomatoid features were present in 10.5% vs 11.8% and absent in 84.1% vs 83.3% (unknown status in 5.4% vs 4.8%). Disease risk status was M0-intermediate to high risk in 86.1% vs 86.9%, M0-high risk in 8.1% vs 7.2%, and M1-NED in 5.8% vs 5.8%. PD-L1 combined positive score (CPS) was < 1 in 25.0% vs 22.7% and ≥ 1 in 73.6% vs 76.9% (unknown in 1.4% vs 0.4%).

Disease-Free Survival

At the prespecified interim analysis of disease-free survival, median time from randomization 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). The rate at 12 months was 85.7% (95% CI = 82.2–88.5%) vs 76.2% (95% CI = 72.2%–79.7%).  Local recurrence alone was observed in 3.4% vs 6.4% of patients, and distant recurrence was observed in 17.3% vs 23.5%.

In subgroup analyses, hazard ratios for disease free-survival for the pembrolizumab vs placebo groups were 0.74 (95% CI = 0.57–0.96) for M0 disease and 0.29 (95% CI = 0.12–0.69) for M1-NED disease, 0.65 (95% CI = 0.49–0.85) for an ECOG performance status of 0 and 0.91 (95% CI = 0.50–1.63) for a performance status of 1, and 0.83 (95% CI = 0.45–1.51) for PD-L1 CPS  < 1 and 0.67 (95% CI = 0.51–0.88) for CPS ≥ 1.

Among 76 patients (15.3%) in the pembrolizumab group vs 112 (22.5%) in the placebo group who received subsequent therapy, 82.9% vs 76.8% received anticancer drugs (including anti–PD-L1/PD-1 antibodies in 18.4% vs 41.1% and VEGF-targeted therapy in 73.7% vs 67.9%), 18.4% vs 15.2% received radiation therapy, and 25.0% vs 28.6% had surgery. 

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%); the rate at 12 months was 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 of any grade with the greatest difference in incidence in the pembrolizumab vs placebo groups were hypothyroidism (21.1% vs 3.6%), hyperthyroidism (11.9% vs 0.2%), pruritus, and rash (20.1% vs 10.7%). Grade ≥ 3 adverse events occurred in 32.4% of the pembrolizumab group vs 17.7% of the placebo group; the most common adverse events 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 or 4 in 8.6% vs 0.6%).

Serious adverse events occurred in 20.5% vs 11.3% of patients; the most common adverse events in the pembrolizumab group included adrenal insufficiency (1.2%), pneumonia (1.2%), acute kidney injury (1.0%), and colitis (1.0%). Adverse events led to treatment discontinuation in 20.7% vs 2.0%; the most common causes in the pembrolizumab group were increased alanine aminotransferase (1.6%), adrenal insufficiency (1.0%), and colitis (1.0%). 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 was 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 and Dohme, a subsidiary of Merck. Dr. Choueiri reports a financial and/or nonfinancial relationship (including potential reimbursements for travel and meals) with Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, Heron, Ipsen, Kidney Cancer Journal, The Lancet Oncology, Lilly, Lpath, Merck, Janssen, Michael J. Hennessy Associates, Navinata Healthcare, NCCN, The New England Journal of Medicine, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, and UpToDate. He has received institutional research funding from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs, Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, Merck, National Cancer Institute, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and Tracon Pharma; holds international patents for biomarkers and has other relationships with ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, and Parexel (medical writing assistance). He holds stock or other ownership interests in Pionyr Immunotherapeutics and Tempest Therapeutics.

REFERENCE

1. Choueiri TK, Tomczak P, Park SH, et al: Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 385:683-694, 2021.