Lenvatinib Plus Everolimus Improves Survival in mRCC

Robert Motzer, MD

The combination of lenvatinib (Lenvima) and everolimus (Afinitor) more than doubled progression-free survival (PFS) and extended overall survival (OS) by 10.1 months compared with everolimus alone as a second-line treatment for patients with metastatic renal cell carcinoma (mRCC), according to a phase II study presented at the 2015 ASCO Annual Meeting.

In the study, the addition of lenvatinib resulted in a median OS of 25.5 versus 15.4 months for everolimus alone (HR = 0.51; 95% CI, 0.30-0.88; P = .024). The median PFS with the combination was 14.6 months compared with 5.5 months with everolimus (HR = 0.40; 95% CI, 0.24-0.68; P <.001). The objective response rate (ORR) was 43% with the combination versus 6% with single-agent everolimus (P <.001).

"The high-response rate and the longer OS results speak to the high-level of efficacy observed in the study for the combination," said Robert Motzer, MD, an attending physician, Memorial Sloan Kettering Cancer Center. "Adverse events were generally higher for the lenvatinib-containing arms compared with everolimus. These adverse events were predictable, and generally managed with dose modifications."

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%. Lenvatinib is FDA-approved as a treatment for patients with radioactive iodine refractory differentiated thyroid cancer.

In the phase II open-label study, 153 patients were randomized in a 1:1:1 ratio to lenvatinib (18 mg/day) plus everolimus (5 mg/day), lenvatinib monotherapy (24 mg/day) or everolimus monotherapy (10 mg/day). No crossover was permitted within the context of the study.

The most common prior VEGF therapy received by patients in the trial was sunitinib, at 71%, 67%, and 56% in the combination, lenvatinib, and everolimus arms, respectively. The remaining patients had received either pazopanib or sorafenib. Thirteen percent of patients had received a prior cytokine or checkpoint inhibitor therapy, at 10%, 8%, and 14%, in the combination, lenvatinib, and everolimus arms, respectively.

The median PFS was 14.6 months for lenvatinib plus everolimus (n = 51), 7.4 months for lenvatinib alone (n = 52), and 5.5 months for everolimus (n = 50). Lenvatinib monotherapy improved PFS by 29% versus everolimus monotherapy (HR = 0.61; 95% CI, 0.38-0.98; P = .048).

At the planned OS analysis for the primary data cutoff in June 2014, there was a trend favoring lenvatinib plus everolimus versus everolimus for OS, with a hazard ratio 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.

At the longer updated 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. The difference between the single-agent lenvatinib arm and the everolimus arm was 32% (HR = 0.68; P = .118).

The ORR in the combination arm was 43%, with lenvatinib it was 27%, and with everolimus it was 6%. “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,” Motzer said.

All patients experienced at least one treatment-emergent adverse event (AE) across all treatment arms. Treatment-related grade 3 AEs occurred in 71% of patients in the combination arm, 83% in the single-agent lenvatinib arm, and 52% in the everolimus arm.

“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 lenvatinib.

Lenvatinib dose reductions were required for 71% of patients in the combination arm compared with 62% in lenvatinib alone arm. Of those in the everolimus monotherapy arm, 26% required a dose reduction.

"Further study of lenvatinib therapy is warranted in RCC," Motzer concluded.

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 Oncol. 2015;33 (suppl; abstr 4506).

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