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RCC: Two approvals expand options for TKI-refractory patients


FDA approval of second-line therapies could mean an “embarrassment of riches” in this field, according to one expert.

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.

Dr. Kutikov“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.

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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.

Next: Approval of cabozantinib based on results from phase III METEOR trial


The approval of cabozantinib was based on results from the phase III METEOR trial of subjects with advanced kidney cancer, in which treatment with cabozantinib tablets resulted in improved overall survival, progression-free survival, and objective response rate. In that study, which was published in the New England Journal of Medicine (2015; 373:1814-23), those randomized to cabozantinib, 60 mg daily, had a median progression-free survival of 7.4 months versus 3.8 months in a group of patients who received everolimus, 10 mg daily. Rate of progression or death was 42% lower in the cabozantinib group than with everolimus. Objective response was 21% with cabozantinib versus 5% with everolimus.

Read: What anti-PD-L1 immunotherapy approval means for urology

Exelixis announced in February 2016 that cabozantinib demonstrated, in that same trial, a 34% reduction in the rate of death compared to everolimus.

Dr. Choueiri“The efficacy profile demonstrated by CABOMETYX in the METEOR trial, now complemented by the overall survival benefit, is highly compelling,” said Toni Choueiri, MD, of Dana-Farber Cancer Institute, Boston in a press release from Exelixis. “CABOMETYX is distinct from other approved treatment options, as it targets multiple tyrosine kinases involved in the development of RCC, including MET, AXL, and three VEGF receptors.

“The approval of CABOMETYX is wonderful news for physicians who are looking for a new option for their previously treated patients with advanced kidney cancer.”

The most common adverse reactions (frequency ≥25%) in cabozantinib-treated patients include diarrhea, fatigue, nausea, decreased appetite, hand-foot syndrome, high blood pressure, vomiting, weight loss, and constipation. Dose reduction rates were 60% for CABOMETYX and 24% for everolimus. The treatment discontinuation rate was 10% in both the cabozantinib and everolimus arms of the trial. Rates of severe hemorrhage, gastrointestinal perforations and fistulas, thrombotic events, and hypertension and hypertensive crisis were higher with cabozantinib than with everolimus.

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More recently, METEOR subgroup analyses presented at the American Society of Clinical Oncology annual meeting in Chicago demonstrated that cabozantinib’s benefits in progression-free survival and overall survival were independent of the presence of bone metastases, prior anti-PD-1/PD-L1 therapy, and the type of prior VEGF receptor TKI therapy, according to a separate press release from Exelixis.

Next: Read more about lenvatinib


Lenvatinib was first approved in the U.S. on Feb. 13, 2015 for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer. Approval for the additional indication for lenvatinib was based on Study 205, a phase II study suggesting the once-daily combination of lenvatinib, 18 mg, and everolimus, 5 mg, improved progression-free survival, objective response rate, and clinically meaningful overall survival compared to everolimus alone. Findings from that study were published in The Lancet Oncology (2015; 16:1473-82).

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"Lenvatinib plus everolimus is the first and only FDA-approved regimen that successfully combines treatments that employ tyrosine kinase and mTOR inhibition, the primary targets of advanced [renal cell carcinoma] treatment for the past decade," principal investigator Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York said in a press release.

In Study 205, lenvatinib plus everolimus nearly tripled progression-free survival, compared to everolimus alone, with a 14.6-month median progression-free survival in patients treated with the combination. The objective response rate was 37% in the combination arm, compared to 6% in the single-treatment group.

Median overall survival increased 10.1 months in the combination group compared to the monotherapy arm.

Among the serious risks associated with the combination treatment: hypertension, cardiac dysfunction, arterial thromboembolic events, hepatotoxicity, proteinuria, diarrhea, renal failure and impairment, gastrointestinal perforation and fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhagic events, impairment of thyroid-stimulating hormone suppression/thyroid dysfunction, and embryo fetal toxicity.

Greater than 30% of those treated with lenvatinib and everolimus experienced diarrhea, fatigue, arthralgia/myalgia, decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral edema, cough, abdominal pain, dyspnea, rash, weight decreased, hemorrhagic events, and proteinuria. At least 5% of subjects treated with the combination had renal failure.

Dr. Choueiri has received honoraria from the National Comprehensive Cancer Network and UpToDate and is a consultant/adviser for Bayer, Bristol-Myers Squibb, Eisai, Foundation Medicine, GlaxoSmithKline, Merck, Novartis, Pfizer, Prometheus, and Roche/Genentech. Dr. Motzer is a consultant/adviser for Eisai, GlaxoSmithKline, Novartis, and Pfizer.

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