As reported at the 2019 Genitourinary Cancers Symposium (Abstract 543) and in The New England Journal of Medicine, Rini et al found significant benefits in overall and progression-free survival with the combination of pembrolizumab plus axitinib vs sunitinib in the first-line treatment of advanced renal cell carcinoma.
The open-label phase III KEYNOTE-426 trial included 861 patients with previously untreated, advanced clear-cell renal cell carcinoma from 124 sites in 16 countries. Patients were randomly assigned between October 2016 and January 2018 to receive pembrolizumab at 200 mg once every 3 weeks plus axitinib at 5 mg twice daily (n = 432), or sunitinib at 50 mg once daily for the first 4 weeks of 6-week cycles (n = 429). Randomization was stratified according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group and geographic region.
The coprimary endpoints were overall survival and progression-free survival in the intention-to-treat population.
On first prespecified interim analysis, after a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-plus-axitinib group vs 78.3% in the sunitinib group (hazard ratio [HR] = 0.53, P < .0001). Median progression-free survival was 15.1 months vs 11.1 months (HR = 0.69, P < .001). A benefit of pembrolizumab plus axitinib in both overall survival and progression-free survival was observed across all subgroups examined, including all IMDC risk groups and programmed cell death ligand 1 (PD-L1) expression subgroups (combined positive score ≥ 1 or < 1). The objective response rate was 59.3% vs 35.7% (P < .001), including complete response in 5.8% vs 1.9%.
Grade ≥ 3 adverse events were observed in 75.8% of the pembrolizumab-plus-axitinib group vs 70.6% of the sunitinib group. Grade 3 or higher adverse events that occurred in ≥ 10% of patients were hypertension and increased alanine aminotransferase in the pembrolizumab-plus-axitinib group and hypertension in the sunitinib group. Adverse events of special interest occurred in 51.3% vs 36.2%, including grade ≥ 3 events in 11% vs 2%.
Adverse events led to discontinuation of either drug in 30.5% and both drugs in 10.7% of patients in the combination group and to 13.9% of patients in the sunitinib group. Death due to treatment-related adverse events occurred in 4 patients in the combination group (0.9%; due to myasthenia gravis, myocarditis, necrotizing fasciitis, and pneumonitis) and in 7 patients in the sunitinib group (1.6%; due to acute myocardial infarction, cardiac arrest, fulminant hepatitis, gastrointestinal hemorrhage, intracranial hemorrhage, malignant neoplasm progression, and pneumonia).
The investigators concluded, “Among patients with previously untreated advanced renal cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib.”
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