Lenvatinib Plus Everolimus Improves Survival in Metastatic RCC

A combination of the multiple tyrosine kinase inhibitor lenvatinib plus the mammalian target of rapamycin (mTOR) inhibitor everolimus improved survival and overall response rate compared with everolimus alone in patients with metastatic renal cell carcinoma (RCC) following prior vascular endothelial growth factor (VEGF)-targeted therapy, according to the results of an open-label, multicenter, phase II trial (abstract 4506) presented at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 29 to June 2, in Chicago.

“The progression-free survival was longer for lenvatinib plus everolimus and lenvatinib compared to everolimus. The response rate was higher in both lenvatinib-containing arms. The highest rate and longer duration of response was observed with the combination. Study results suggest an overall survival benefit for lenvatinib/everolimus over everolimus,” said lead author Robert Motzer, MD, of the Memorial Sloan Kettering Cancer Center in New York.

There is an unmet need for improved treatment outcomes in metastatic RCC patients after VEGF-targeted therapies and mTOR inhibitors. Fibroblast growth factor pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Lenvatinib is a highly potent, oral tyrosine kinase inhibitor. In combination with everolimus, it showed a manageable toxicity profile and antitumor activity in a phase I metastatic RCC trial, said Motzer.

This phase II trial compared lenvatinib 24 mg/day (52 patients), everolimus 10 mg/day (50 patients), and lenvatinib 18 mg/day plus everolimus 5 mg/day (51 patients) in 28 day cycles in patients with metastatic RCC. There was good balance of patient characteristics, he said. Only 13% of patients had previous cytokine or checkpoint inhibitor therapies.

Median duration of response was 7 months in the lenvatinib arms and 4 months in the everolimus arm. One-quarter of the everolimus-alone patients required dose modifications. The most common reason for discontinuation was progression.

The study met its primary endpoint of progression-free survival. The median progression-free survival was 14.6 months in the lenvatinib/everolimus group, 7.4 months in the lenvatinib group, and 5.5 months in the everolimus group. “The combination improved progression-free survival compared to everolimus (hazard ratio [HR] = 0.40),” he said, as did lenvatinib alone compared with everolimus (HR = 0.61).

Objective response rates followed a similar pattern: 43% in the combination arm, 27% in the lenvatinib arm, and 6% in the everolimus arm.

An update of overall survival showed a significant difference between the combination arm as compared with the everolimus arm (25.5 months vs 15.4 months; HR = 0.51). Disease-free survival also trended in favor of the combination arm as compared with the lenvatinib arm.

Adverse events were generally higher for the lenvatinib-containing arms, but “these were predictable and manageable with dose modification,” he said. Grade 3 adverse events were higher in the combination arm.  “We need to recognize diarrhea, in particular,” he said, which occurred in 20% of those taking the combination.

In conclusion, Motzer said: “The improvement in progression-free survival benefit in both lenvatinib arms, and the magnitude of progression-free survival, response rate, and longer overall survival, speak to the high level of efficacy for the combination,” Motzer said.

A phase III randomized trial of the combination therapy in metastatic RCC is planned.