The Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of lenvatinib (Kisplyx) in combination with everolimus (Afinitor) for patients with advanced renal cell carcinoma (RCC) following one prior VEGF-targeted therapy.
The positive opinion 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 versus 5.5 months with everolimus (HR, 0.40; 95% CI, 0.24-0.68; P
The positive CHMP opinion will be sent to the European Commission for a final regulatory decision.
"Lenvatinib in combination with everolimus is the first proven combination treatment to treat patients following one prior vascular endothelial growth factor-targeted therapy," Gary Hendler, chief commercial officer of Eisai's Oncology Business Group, said in a statement. "The very real treatment benefit of the combination provides patients with an additional treatment option proven to have a beneficial impact on progression free survival."
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, 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 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.
"This is a positive step forward for people with advanced renal cell carcinoma," Hilary Glen, MB ChB, MSc, PhD, consultant medical oncologist, Beatson West of Scotland Cancer Centre, Scotland, UK, said in a statement. "The phase II trial was the first in which these two types of cancer drugs have been successfully combined in renal cell carcinoma, and the progression free survival results were statistically significant."
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 mRCC. Additionally, the FDA approved lenvatinib for patients with radioactive iodine refractory differentiated thyroid cancer in February 2015.
- 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.
- 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).