Results from a phase 3 trial of patients with advanced renal cell carcinoma (RCC) presented this week at the American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium and simultaneously published in The New England Journal of Medicine demonstrated that the first-line treatment regimen of lenvatinib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, plus pembrolizumab, an anti–programmed cell death protein 1 (PD-1) monoclonal antibody, lengthened progression-free survival and overall survival compared with the standard-of-care treatment, sunitinib, a VEGFR tyrosine kinase inhibitor.
"This trial is a step forward in that it provides data that will assist in determining which combination of anti–PD-1 drug and VEGFR tyrosine kinase inhibitor may be effective as an alternative to nivolumab and ipilimumab for some patients," commented Dr. Alain Ravaud, MD, PhD, of Saint-André Hospital at the University Hospital Center Bordeaux, France, in his recent editorial published in The New England Journal of Medicine. "To date, scientific guidelines on this question have been lacking."
The phase 3 trial enrolled 1,069 patients with advanced RCC who had not received previous systemic therapy. Patients were randomized in a 1:1:1 ratio to receive 20 mg lenvatinib once daily in combination with 200 mg pembrolizumab once every 3 weeks; 18 mg lenvatinib once daily plus 5 mg everolimus once daily; or 50 mg sunitinib once daily, alternating four weeks receiving treatment and two weeks without treatment. The primary end point was progression-free survival, with secondary end points of overall survival, objective response rate, and safety.
Median progression-free survival was significantly longer with lenvatinib/pembrolizumab compared with sunitinib (23.9 vs. 9.2 months), as was overall survival (hazard ratio for death, 0.66). Median progression-free survival with lenvatinib/everolimus was also significantly longer compared with sunitinib (14.7 vs. 9.2 months); however, overall survival with lenvatinib/everolimus was not improved compared with sunitinib (hazard ratio for death, 1.15; 95% confidence interval, 0.88 to 1.50; P=0.30). Lenvatinib/pembrolizumab was superior to sunitinib for both objective response rate (71% vs 36%) and complete response rate (16% vs 4%), as was lenvatinib/everolimus compared with sunitinib (objective response rate, 54% vs 36%; complete response rate, 10% vs 4%).
Grade 3 or higher treatment-related adverse events occurred in 82.4% of the patients who received lenvatinib/pembrolizumab, 83.1% of those who received lenvatinib/everolimus, and 71.8% of those who received sunitinib. The most common grade 3 or higher adverse events experienced by at least 10% of patients in any group included hypertension, diarrhea, and elevated lipase levels.
"Lenvatinib plus pembrolizumab group demonstrated significant improvements in progression-free survival, overall survival, and objective response rate versus sunitinib. Lenvatinib plus everolimus demonstrated significant improvements in progression-free survival and objective response rate versus sunitinib," concluded the study investigators, led by first author Robert J. Motzer, MD, Head of the Kidney Cancer Section at Memorial Sloan Kettering Cancer Center, in their abstract presented at the ASCO Genitourinary Cancers Symposium. "Safety was manageable and consistent with the known single-agent profiles."
For More Information
Motzer RJ, Porta C, Eto M, et al (2021). Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). J Clin Oncol (Genitourinary Cancers Symposium Abstracts). Abstract 269. DOI:10.1200/JCO.2021.39.6_suppl.269
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