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EC Approves Lenvatinib/Everolimus Combo for RCC

The European Commission has approved lenvatinib (Kisplyx) in combination with everolimus for patients with advanced renal cell carcinoma following 1 prior VEGF-targeted therapy.

Hilary Glen, MB ChB, FRCP, MSc, PhD

The European Commission (EC) has approved lenvatinib (Kisplyx; EU) in combination with everolimus (Afinitor) for patients with advanced renal cell carcinoma (RCC) following 1 prior VEGF-targeted therapy.

The approval was based on findings from a phase II study, which showed a 60% reduction in the risk of progression or death with the combination versus single-agent everolimus. Median progression-free survival (PFS) with the combination was 14.6 months versus 5.5 months with everolimus (HR, 0.40; 95% CI, 0.24-0.67; P = .0005).1 The EC’s approval decision followed a positive recommendation from the Committee for Medicinal Products for Human Use. Cabozantinib is now approved for use in this setting in the 28 countries of the European Union, Norway, and Iceland.

“This is a positive milestone in the clinical management of advanced renal cell carcinoma in Europe. Lenvatinib in combination with everolimus is the first and only proven regimen in Europe to combine treatments that inhibit receptor tyrosine kinases and mammalian target of rapamycin, key targets of advanced renal cell carcinoma treatment,” Hilary Glen, MB ChB, FRCP, MSc, PhD, consultant medical oncologist, Beatson West of Scotland Cancer Centre, Scotland, UK, said in a statement.

In the open-label phase II study, 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 (Sutent), 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 age of patients in the combination arm was 61 years, with the majority being males (69%). Thirty-nine percent of patients were at poor risk, by MSKCC criteria. The most common sites of metastases were the visceral organs (80%), lung (67%), and lymph nodes (57%).

The objective response rate 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.

The benefits observed with the combination remained consistent across subgroups of patients, according to findings presented at the 2016 ASCO Annual Meeting.2 Those with favorable risk disease experienced the greatest benefit, with a median PFS of 20.1 months with the combination versus 9.8 months with everolimus alone (HR, 0.25; P = .009). In those with metastases to the lymph nodes, median PFS with the combination was 14.7 versus 5.5 months with everolimus (HR, 0.28; P <.001).

The median overall survival (OS) with lenvatinib plus everolimus was 25.5 months compared with 15.4 months with everolimus alone (HR, 0.59; 95% CI, 0.36-0.97; P = .065). The median OS was 19.1 months with single-agent lenvatinib.

All patients experienced at least 1 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.

“This marketing authorization underscores Eisai's ongoing commitment to delivering and developing advances in the fight against cancer. We remain committed to exploring the potential of lenvatinib for people with cancer, their family and carers,” Gary Hendler, chief commercial officer Oncology Business Group, Chairman and CEO EMEA.

In the United States, the FDA approved the combination of lenvatinib (Lenvima; US) and everolimus for patients with advanced RCC following a VEGF agent in January 2016. Prior to this approval, lenvatinib received a breakthrough therapy designation from the FDA for patients with metastatic RCC. Additionally, the FDA approved lenvatinib for patients with radioactive iodine refractory differentiated thyroid cancer in February 2015.


  1. American Lung Association. Lung Cancer Fact Sheet. http://goo.gl/EvuNfo. Updated 2015. Accessed August 26, 2016.
  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.
  3. Hutson TE, Dutcus CE, Ren M, et al. Subgroup analyses and updated overall survival from the phase II trial of lenvatinib (LEN), everolimus (EVE), and LEN+EVE in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2016;34 (suppl; abstr 4553).