The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for lenvatinib in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy.

The opinion was issued following the evaluation of results from a pivotal Phase II trial published in The Lancet, which show lenvatinib plus everolimus significantly extends progression-free survival in patients with unresectable advanced renal cell carcinoma versus everolimus alone.

Clear cell renal cell carcinoma accounts for approximately 80-90% of all kidney malignancies, and (RCC) represents 2-3% of all cancer cases, with the highest incidence in Western countries.

During the last two decades, until recently, there has been about a 2% increase in incidence of RCC worldwide.

Lenvatinib was granted an accelerated assessment by the European Medicines Agency in October 2015, and the combination with everolimus to treat RCC was approved in America by the FDA this May.

Lenvatinib selectively inhibits the kinase activities of several different receptors including vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), RET, KIT and platelet-derived growth factor receptors (PDGFR).

“This is a positive step forward for people with advanced renal cell carcinoma. 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,” comments Dr Hilary Glen, Beatson West of Scotland Cancer Centre, Glasgow, UK.

The Phase II study, on which the CHMP opinion is based, shows that people with advanced renal cell carcinoma who progressed on previous VEGF therapy treated with the combination of lenvatinib plus everolimus experienced a median progression-free survival of 14.6 months compared with 5.5 months for those who received everolimus alone (HR 0.40; 95% CI: 0.24-0.68; p=0.0005).

In subgroup analyses of the Phase II study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2016, progression-free survival benefit is maintained across all subgroups regardless of high-risk poor prognosis renal cancer subgroups (MSKCC risk, baseline tumour size, metastasis site).

Watch an interview from the preceding ASCO 2015, in which lenvatinib with everolimus was found to be more effective than solo everolimus, here

For the secondary endpoints, updated median overall survival in the intent-to-treat study population was 25.5 months in the lenvatinib plus everolimus group compared with 15.4 months in the everolimus group (HR 0.59; 95% CI 0.36 - 0.97; P=0.065).

Adverse events were generally higher for the lenvatinib plus everolimus combination compared with everolimus alone.

The most common grade 3 treatment emergent adverse events in the lenvatinib plus everolimus group included constipation (37%), diarrhoea (20%), fatigue or asthenia (14%) and hypertension (14%).

The most commons grade 3 TEAEs in the everolimus group included anaemia (12%), dyspnoea (8%), hypertriglyceridaemia (8%) and hyperglycaemia (8%).

The effect of the combination of lenvatinib plus everolimus in human renal cell carcinoma xenograft models (a graft of tissue or cells from one species to an unlike species) was also demonstrated in a second study presented at the American Association of Cancer Research in April 2016.

Results indicate that lenvatinib in combination with everolimus causes significant antitumour effects through the potent antiangiogenic activity of lenvatinib and direct antitumour activity of everolimus.

Lenvatinib, discovered and developed by Eisai, is an oral molecular targeted therapy that possesses a potent selectivity and a new Type V binding mode of kinase inhibition different to that of other tyrosine kinase inhibitors (TKI).

Lenvatinib has been approved for the treatment of refractory thyroid cancer in the United States, Europe, Russia, Switzerland, Australia, Canada, Singapore, Japan and South Korea and has been submitted for regulatory approval in Brazil. Lenvatinib was granted Orphan Drug Designation in Japan for thyroid cancer, in the United States for treatment of follicular, medullary, anaplastic, and locally advanced papillary thyroid cancer and in Europe for follicular and papillary thyroid cancer.

“Eisai continues to be committed to the discovery and development of treatments for cancers like advanced renal cell carcinoma. Lenvatinib in combination with everolimus is the first proven combination treatment to treat patients following one prior vascular endothelial growth factor (VEGF)-targeted therapy. 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.” comments Gary Hendler, Chief Commercial Officer Oncology Business Group, Chairman and CEO EMEA.

Source: CHMP