Lenvatinib added to everolimus extended overall survival (OS) significantly compared with everolimus alone in patients with metastatic renal cell carcinoma (mRCC). 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 the international, randomized, open-label study in 153 patients with mRCC, reported Robert Motzer, MD, Attending Physician, Memorial Sloan Kettering Cancer Center, New York City.
“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.
In mRCC, activation of the fibroblast growth factor (FGF) 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 both VEGF receptors and FGF receptors.
Patients were randomized to lenvatinib (18 mg/day) plus everolimus (5 mg/day), lenvatinib monotherapy (24 mg/day), or everolimus monotherapy (10 mg/day), and were treated until disease progression or unacceptable toxicity.
The most common prior VEGF-targeted therapy was sunitinib, taken by 56% to 71% of patients. Therapy other than VEGF-targeted therapy was permitted, and 13% of the patients had received prior cytokine or checkpoint inhibitor therapy (on a clinical trial).
The median PFS was 14.6 months for the lenvatinib/everolimus combination, 7.4 months for lenvatinib alone, and 5.5 months for everolimus. The combination improved PFS compared with everolimus (hazard ratio [HR], 0.40; P <.001). Lenvatinib monotherapy also significantly improved PFS compared with everolimus (HR, 0.61; P = .048).
The highest objective response rate was observed with the combination (43%), compared with 27% for lenvatinib monotherapy and 6% for everolimus.
“Most of the responses were partial, although 1 complete remission was observed in the combination arm,” he said. “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, there was a trend favoring lenvatinib/everolimus versus everolimus (HR, 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 an updated OS analysis (data cutoff of December 10, 2014), 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).
In comparing 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).
Patients treated in each of the lenvatinib-containing arms had more grade 3 and a similar proportion of grade 4 adverse events compared with patients randomized to everolimus. “Most toxicities were managed by dose modification,” said Motzer.
Prominent grade 3 adverse events associated with lenvatinib alone or in combination included diarrhea, fatigue, nausea, vomiting, and hypertension. The incidence of 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,” said Motzer. There were relatively few grade 4 events in any arm and 1 grade 5 adverse event in each lenvatinib-containing arm.
