Lenvatinib added to everolimus extended overall survival (OS) significantly compared with everolimus alone in patients with metastatic renal-cell carcinoma (RCC). This phase 2 study also demonstrated improved progression-free survival (PFS) with lenvatinib alone and in combination with everolimus compared with everolimus alone.
The OS finding was a secondary end point in this international, randomized, open-label study in 153 patients with metastatic RCC, reported Robert J. Motzer, MD, Attending Physician, Memorial Sloan Kettering Cancer Center, NY, at ASCO 2015.
“Although improved PFS benefit was observed in both lenvatinib-containing arms, the magnitude of the PFS, 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.
In metastatic RCC, the activation of the fibroblast growth factor pathway has been proposed as a mechanism of escape from vascular endothelial growth factor (VEGF)-targeted therapies. Lenvatinib is a potent tyrosine kinase inhibitor of the VEGF receptors and fibroblast growth factor receptors.
The patients were randomized to lenvatinib 18 mg plus everolimus 5 mg daily; lenvatinib monotherapy 24 mg daily; or everolimus monotherapy 10 mg daily, and were treated until disease progression or unacceptable toxicity.
The median PFS was 14.6 months for lenvatinib plus everolimus, 7.4 months for lenvatinib alone, and 5.5 months for everolimus alone. The combination significantly improved PFS compared with everolimus, with a hazard ratio (HR) of 0.40 (P <.001). Lenvatinib monotherapy also significantly improved PFS compared with everolimus alone (HR, 0.61; P = .048).
The objective response rate was 43% with the combination of lenvatinib plus everolimus compared with 27% for lenvatinib alone and 6% for everolimus alone.
“Most of the responses were partial, although one complete remission was observed in the combination arm,” Dr Motzer noted. “The duration of objective response was quite long in the combination arm; the median was 13 months.”
At the planned OS analysis for the primary data cutoff in June 2014, the median OS was 25.5 months for the combination, 18.4 months for lenvatinib alone, and 17.5 months for everolimus alone.
In an updated OS analysis, the median OS was 25.5 months in the combination arm, 19.1 months with lenvatinib alone, and 15.4 months with everolimus alone.
The patients in the lenvatinib-containing arms had more grade 3 adverse events and similar grade 4 adverse events compared with everolimus. “Most toxicities were managed by dose modification,” he said.
Prominent grade 3 events associated with lenvatinib were diarrhea, fatigue, nausea, vomiting, and hypertension. Grade 3 diarrhea was 20% in the combination arm, “which highlights the need for recognition and management of this toxicity for the combination, in particular,” Dr Motzer pointed out.