Patients with kidney cancer in Europe who are not responding to treatment will soon have two new options to try, as cabozantinib (Cabometyx, Ipsen Pharma) and lenvatinib (Kisplyx, Eisai Europe Ltd) have been recommended for approval by the European Medicines Agency (EMA).

Both of these drugs are tyrosine kinase inhibitors, and both are recommended for use in patients with kidney cancer who have been previously treated with a vascular endothelial growth factor (VEGF) inhibitor. Cabozantinib is to be used as monotherapy, whereas lenvatinib is to be used in combination with everolimus (Afinitor, Novartis).

The drugs are already approved for this indication in the United States.

In its announcement, the EMA notes that the most common form of kidney cancer in adults is renal cell carcinoma (RCC). Advanced RCC includes both metastatic disease and locally advanced disease that cannot be removed by surgery. Despite the recent approval of new therapies for advanced RCC, many patients who do not respond to the existing treatments have a poor prognosis. Therefore, new treatment options are needed, the agency comments.

The EMA considers the kidney cancer indications for cabozantinib and lenvatinib to be accelerated approvals because both drugs were felt to address an unmet medical need.

The EMA also notes that both of these drugs are also used in thyroid cancer but are marketed for that indication under different trade names. Cabozantinib (as Cometriq) was approved in the EU in December 2013 for adults with medullary thyroid cancer, while lenvatinib (as Lenvima) was recommended for approval for patients with thyroid carcinoma in March 2015.

Clinical Data to Support Approval

Cabozantinib was recommended for approval mainly on the basis of a phase 3 trial (known as METEOR) involving 658 patients with metastatic RCC that had progressed after prior VEGF receptor tyrosine kinase inhibitor therapy. As previously reported by Medscape Medical News, this study showed the longest progression-free survival (PFS) ever seen in this setting, with 7.4 months on cabozantinib compared with 3.8 months on everolimus, which is the usual standard second-line therapy. In addition, preliminary results show an improved overall survival, with a median of 21.4 months on cabozantinib vs 16.5 months on everolimus.
The EMA notes that the most frequent adverse reactions associated with cabozantinib include diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (hand and foot redness, swelling, and pain), hypertension, and vomiting.

Lenvatinib was recommended for approval mainly on the basis of a phase 1b/2 trial involving 153 patients with metastatic or unresectable RCC who received at least one prior VEGF targeted therapy and were treated with lenvatinib plus everolimus or with one of these agents used alone. In this study, progression-free survival was 12.8 months on average for patients receiving the combination of lenvatinib and everolimus, compared with 5.6 months for patients treated with everolimus alone, based on independent review of radiologic images. In addition, encouraging signs of prolonged overall survival were seen in patients given the combination therapy. The most frequent adverse reactions include diarrhea, fatigue, decreased appetite, vomiting, nausea, and hypertension. Severe diarrhea occurred at a higher frequency in the combination group than in the everolimus group.

When assessing these data, the EMA’s Committee for Medicinal Products for Human Use considered that the benefits of lenvatinib plus everolimus outweigh its risks but requested that postauthorization studies be conducted to collect further data to complement data from the phase 1b/2 trial.