Recent FDA approvals in the advanced renal cell carcinoma space could mean an “embarrassment of riches” in this field, according to one expert.
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In April, the FDA approved cabozantinib (CABOMETYX) as a treatment for advanced renal cell carcinoma patients who have received prior anti-angiogenic therapy. The agent had been granted granted fast track and breakthrough therapy designation by the FDA.
In May, the agency approved an additional indication for the multiple receptor tyrosine kinase inhibitor (TKI) lenvatinib (Lenvima) in combination with everolimus (Afinitor) for the treatment of advanced renal cell carcinoma patients treated previously with anti-angiogenic therapy. Like cabozantinib, lenvatinib was granted breakthrough therapy designation by the FDA.
“These are two agents that are now joining the immunotherapy agent nivolumab (Opdivo) and the second-line TKI axitinib (Inlyta) in the TKI-refractory space,” said urologist Alexander Kutikov, MD, of Fox Chase Cancer Center, Temple University Health System, Philadelphia. “Clearly, the established paradigm of TKI, followed by axitinib, followed by an mTOR inhibitor is being broken down.”
Dr. Kutikov was not involved in the trials leading to the approval of cabozantinib or lenvatinib and does not have disclosures related to these medications.
He told Urology Times that this may be a situation of an "embarrassment of riches," where with a multitude of active agents in the second-line space (ie, nivolumab, cabozantinib, lenvatinib/everolimus, and axitinib), clinicians don’t yet have data on how to best sequence these agents in patients who fail first-line TKI therapy.
“More importantly, we are all awaiting trials in the first-line space to see which of these agents dethrones pazopanib/sunitinib as the first-line go-to therapeutic,” he said.
Cabozantinib, according to Dr. Kutikov, blocks both the VEGF pathway and MET.
“MET, it is hypothesized, may potentiate signaling around the VEGF pathway, thus explaining the efficacy in TKI-resistant patients,” Dr. Kutikov said.
Regarding lenvatinib, Dr. Kutikov pointed out that, in the past, TKI plus mTOR combinations have not gotten very far off shore due to severe toxicities.
“This is the first example of a TKI working synergistically with an mTOR inhibitor (everolimus). Many suspect that this is foreshadowing emergence of combination therapies in the kidney cancer space,” Dr. Kutikov said.