FDA Assigns Priority Review to Lenvatinib Plus Everolimus Combo in RCC


The combination of lenvatinib (Lenvima) and everolimus (Afinitor) has been given a priority review status by the FDA as a treatment for patients with metastatic renal cell carcinoma (RCC) following one prior VEGF-targeted therapy.

Lenvatinib Everolimus RCC

Lenvatinib Everolimus RCC

Kenichi Nomoto, PhD

The combination of lenvatinib (Lenvima) and everolimus (Afinitor) has been given a priority review status by the FDA as a treatment for patients with metastatic renal cell carcinoma (RCC) following one prior VEGF-targeted therapy.

According to a statement from Eisai, the company developing the multikinase inhibitor, the priority review was based on data from a phase II study presented at the 2015 ASCO Annual Meeting and published in Lancet Oncology.1,2This trial yielded results showing the combination of lenvatinib and everolimus reduced the risk of progression or death by 60%, as compared with the mTOR inhibitor everolimus alone. Median progression-free survival (PFS) with the combination was 14.6 versus 5.5 months with everolimus (HR, 0.40; 95% CI, 0.24-0.68;P<.001)

Under the priority review program, the FDA plans to make a decision on the lenvatinib plus everolimus combination within 6 months, as compared with the standard 10-month review. The accelerated review timeline follows a breakthrough therapy designation for lenvatinib that was granted by the FDA in July 2015.

&ldquo;With the FDA's acceptance of this supplemental application, we are one step closer to potentially providing the first tyrosine kinase and mTOR inhibitor combination therapy to patients with unresectable advanced or metastatic renal cell carcinoma,&rdquo; Kenichi Nomoto, PhD, president, Oncology Product Creation Unit, Eisai Product Creation Systems, said in a statement. &ldquo;We look forward to working with the FDA over the coming months as it considers this potential new option for patients with advanced RCC.&rdquo;

In the open-label phase II study that was the basis for the application, 153 patients were randomized in a 1:1:1 ratio to lenvatinib plus everolimus (n = 51), lenvatinib monotherapy (n = 52), or everolimus monotherapy (n = 50). In the combination arm, lenvatinib was administered at 18 mg per day with everolimus at 5 mg daily. In the single-agent groups, everolimus was given at 10 mg/day and lenvatinib was administered at 24 mg/day. Crossover was not permitted in 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. Overall, 10%, 8%, and 14% of patients in the combination, lenvatinib, and everolimus arms received cytokine therapy or a checkpoint inhibitor, respectively.

The median PFS was 14.6 months for lenvatinib plus everolimus, 7.4 months for lenvatinib alone, and 5.5 months for everolimus. Lenvatinib monotherapy improved PFS by 29% versus everolimus monotherapy (HR, 0.61; 95% CI, 0.38-0.98;P= .048). However, the combination did not show a statistically significant improvement in PFS compared with lenvatinib monotherapy (HR, 0.66; 95% CI, 0.30—1.10;P= .12).

Median overall survival 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) and there was a 49% improvement seen in survival for the combination versus everolimus (HR, 0.51; 95% CI, 0.30-0.88;P= .024).

The ORR was 43% in the combination arm, 27% with lenvatinib, and 6% with everolimus. The median duration of response was 13.1 months in the combination arm compared with 7.5 months and 8.5 months in the lenvatinib and everolimus monotherapy arms, respectively.

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.

The most frequently reported grade 3/4 treatment-emergent AE with the combination was diarrhea (20%). In the single-agent arms, the most common grade 3/4 AEs were proteinuria (19%) and anemia (12%) for lenvatinib and everolimus, respectively.

There were relatively few grade 4 events in any of the three arms; however, two grade 5 AEs were attributed to lenvatinib. Seventy-one percent of patients required a lenvatinib dose reductions in the combination arm compared with 62% in lenvatinib alone arm. Of those in the everolimus monotherapy arm, 26% required a dose reduction.

&ldquo;The high-response rate and the longer OS results speak to the high-level of efficacy observed in the study for the combination,&rdquo; lead investigator Robert Motzer, MD, an attending physician, Memorial Sloan Kettering Cancer Center, said when he presented the findings at ASCO. &ldquo;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.&rdquo;

In addition to the United States, a filing was submitted to the European Medicines Agency (EMA) in January 2016. The Committee for Medicinal Products for Human Use (CHMP) of the EMA granted the combination an accelerated assessment in October 2015. Under this program, the EMA will assess the application within 150 days, as compared with 210 days under a standard review.


  1. 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).
  2. Motzer RJ, Hutson TE, Michaelson MD, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.Lancet Oncol. 2015;16(15):1473—1482.
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