Lenvatinib alone and in combination with everolimus significantly improved progression-free survival compared with everolimus alone in a phase II study of patients with metastatic renal cell carcinoma.
Robert Motzer, MD
Lenvatinib alone and in combination with everolimus significantly improved progression-free survival (PFS) compared with everolimus alone in a phase II study of patients with metastatic renal cell carcinoma (mRCC). The combination of lenvatinib and everolimus also extended overall survival (OS), a secondary endpoint, compared with everolimus monotherapy in an updated OS analysis. The findings support further study of lenvatinib in the treatment of RCC, said study author Robert Motzer, MD, at the 2015 ASCO Annual Meeting.
“The study met each of the two primary endpoint analyses,” said Motzer, an attending physician, Memorial-Sloan Kettering Cancer Center (MSKCC), New York City. The combination improved PFS compared with everolimus, with a hazard ratio (HR) of 0.40 (P<.001). As well, lenvatinib monotherapy improved PFS compared with everolimus, with an HR of 0.61 (P= .048). “Most of the responses were partial, although one complete remission was observed in the combination arm. The duration of objective response was quite long in the combination arm; the median was 13 months,” he said.
In mRCC, fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Lenvatinib is a highly potent tyrosine kinase inhibitor of both VEGF receptors and FGF receptors. A phase I study in patients with RCC established a maximum tolerated dose of lenvatinib at 18 mg/day and everolimus at 5 mg/day, with an objective response rate of 30%.
The phase II study was an international, randomized, open-label study in 153 patients that compared lenvatinib plus everolimus and lenvatinib alone to everolimus in patients with RCC following progression after one prior VEGF-targeted therapy.
Patients were randomized 1:1:1 to lenvatinib, 18 mg/day, plus everolimus, 5 mg/day; lenvatinib monotherapy, 24 mg/day; or everolimus, 10 mg/day. Patients were treated until disease progression or unacceptable toxicity. No crossover was permitted within the context of the study.
The cut-off for the PFS and OS primary analysis was June 13, 2014, but the OS analysis was updated to December 10, 2014 following a review of the primary data by the steering committee, which had requested more mature survival data, according to Motzer.
The proportion of patients with favorable, intermediate, and poor risk status by MSKCC stratification was similar in the three randomized groups. The most common prior VEGF-targeted therapy was sunitinib, in 56% to 71% of patients, followed by pazopanib in 18% to 26%. Therapy other than VEGF-targeted therapy was allowed, but only 13% of the patients had prior cytokine or checkpoint inhibitor therapy on a clinical trial.
At the time of the primary endpoint analysis, treatment was ongoing in 23 patients. Dose reduction of lenvatinib in the combination and the monotherapy arms was common, 71% and 62%, respectively. Dose modification of everolimus was necessary in 26%.
The number of PFS events at the time of the analysis was 101. The median PFS was 14.6 months for lenvatinib/everolimis combination, 7.4 months for lenvatinib alone, and 5.5 months for everolimus.
At the planned OS analysis for the primary data cutoff in June 2014, there was a trend favoring lenvatinib/everolimus versus everolimus in OS, with an HR of 0.55 (P= .062). The median OS was 25.5 months for the combination, 18.4 months for lenvatinib alone, and 17.5 months for everolimus.
In the updated OS analysis, the median OS was 25.5 months in the combination arm, 19.1 months in the lenvatinib monotherapy arm, and 15.4 months in the everolimus arm, with the difference between the combination arm and the everolimus arm statistically significant (HR = 0.51;P= .024).
“Although improved PFS benefit was observed in both lenvatinib-containing arms, the magnitude of the progression-free survival, the high response rate, and the longer OS results speak to the high level of efficacy observed in this study for the combination,” he said.
A secondary objective was to compare the efficacy of lenvatinib/everolimus with lenvatinib alone. The median PFS and OS trended in favor of the combination, and the objective response rate was also higher in the combination arm compared with lenvatinib monotherapy (43% vs 27%:P= .101).
All patients experienced at least one treatment-emergent adverse event (AE). Patients treated in each of the two lenvatinib-containing arms had more grade 3 and a similar proportion of grade 4 AEs compared with patients in the everolimus arm. Prominent grade 3 AEs associated with lenvatinib alone or in combination included diarrhea, fatigue, nausea, vomiting, and hypertension.
“Notably, there was a 20% incidence for grade 3 diarrhea in the combination arm, which highlights the need for recognition and management of this toxicity for the combination, in particular,” said Motzer. There were relatively few grade 4 events in any of the three arms. Two grade 5 AEs were attributed to study drug, one in each lenvatinib-containing arm.
Motzer R, Hutson T, Glen H, et al. Randomized phase 2 three-arm trial of lenvatinib (LEN), everolimus (EVE), and LNE+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC).J Clin Oncol2015;33 (suppl; abstr 4506).