Two new combination regimens as first-line treatments for patients with advanced renal cell carcinoma (RCC), lenvatinib plus pembrolizumab and lenvatinib plus everolimus, may prolong survival as compared with the current standard of care, sunitinib.
An open-label, randomized Phase III trial to assess these two treatment combinations found that treatment with lenvatinib plus pembrolizumab was associated with significantly greater overall survival (OS), longer progression-free survival (PFS), and a higher percentage of patients with objective response rates (ORR) versus sunitinib. Treatment with lenvatinib plus everolimus was also associated with a higher ORR and longer PFS than sunitinib, but did not have a significantly greater effect on OS.
"We are encouraged by all the data," said lead author Robert Motzer, MD, Kidney Cancer Section Head in the Genitourinary Oncology Service, and the Jack and Dorothy Byrne Chair in Clinical Oncology at Memorial Sloan Kettering Cancer Center. "As physician-researchers, we consistently strive to provide our patients with the most effective therapies and give those with advanced disease more options. These results could lead to a change in the standard of care for these patients."
Levantinib and pembrolizumab have shown activity as monotherapies for the treatment of patients with advanced RCC. Levantinib plus everolimus prolonged PFS compared to everolimus alone as second-line therapy in patients with advanced RCC. Results from a Phase I/II RCC study of levantinib plus pembrolizumab showed antitumor activity in previously treated RCC patients.
At the 2021 ASCO Genitourinary Cancers Symposium, Motzer reported on the results of CLEAR, a large, international trial involving 200 sites across 20 countries of first-line therapy, either with levantinib plus pembrolizumab or levantinib plus everolimus versus sunitinib in 1,069 patients with advanced RCC (Abstract 296). The study's findings were also published simultaneously on February 13, 2021, in the New England Journal of Medicine (doi: 10.1056/NEJMoa2035716).
Patients were randomized to receive lenalidomide 20 mg orally once daily plus pembrolizumab 200 mg IV every 3 weeks (355 patients), lenalidomide 18 mg plus everolimus 5 mg orally once daily (357 patients), or sunitinib 50 mg orally once daily, 4 weeks on and 2 weeks off (357 patients). The primary endpoint was PFS by Independent Review Committee per RECIST v1.1. Secondary endpoints included OS, ORR, and safety.
After a median follow-up of 27 months, PFS was significantly improved with levantinib plus pembrolizumab versus sunitinib (median 24 months vs. median 9 months), and was longer with lenvatinib plus everolimus than with sunitinib (median 14.7 vs. 9.2 months). OS was significantly longer with levantinib plus pembrolizumab versus sunitinib (HR 0.66), but was not significantly longer with lenvatinib plus everolimus than with sunitinib (HR 1.15).
ORR was significantly greater with levantinib plus pembrolizumab-ORR at 71 percent, including 16 percent complete response (CR)-as compared to sunitinib (ORR 36%; CR 4%). Similarly, lenvatinib plus everolimus had a higher ORR (54%) and CR (10%) than sunitinib.
Grade 3 or higher adverse events emerged or worsened during treatment in 82.4 percent of the patients who received lenvatinib plus pembrolizumab, 83.1 percent of those who received lenvatinib plus everolimus, and 71.8 percent of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10 percent of the patients in any group included hypertension, diarrhea, and elevated lipase levels. More patients had experienced treatment-related adverse events that led to dose reductions with lenvatinib plus pembrolizumab (67.3%) and lenvatinib plus everolimus (69.3%) than with sunitinib (49.7%).
In conclusion, Motzer said: "Lenvatinib plus pembrolizumab achieved significant improvements in PFS, OS, and ORR versus sunitinib in the first-line treatment of patients with advanced RCC. Lenvatinib plus everolimus demonstrated significant improvements in PFS and ORR, but not OS, versus sunitinib. The safety profiles of lenvatinib plus pembrolizumab and lenvatinib plus everolimus were consistent with each drug's known profile and were manageable, as needed, through dose modifications. These results support lenvatinib plus pembrolizumab as a potential first-line treatment for patients with advanced RCC."
Mark L. Fuerst is a contributing writer.