Oral agent improves survival in advanced RCC patients

Chicago-Once-daily treatment with cabozantinib (CABOMETYX), an oral tyrosine kinase inhibitor (TKI), significantly improves overall survival as well as progression-free survival and objective responses rates compared with everolimus (Afinitor) in previously treated patients with advanced renal cell carcinoma (RCC), according to final results from the phase III METEOR trial.  

The data were presented by Toni K. Choueiri, MD, at the American Society of Clinical Oncology annual meeting in Chicago and published simultaneously online in Lancet Oncology (June 5, 2016).

After a median follow-up of almost 19 months, cabozantinib prolonged median overall survival (OS) by almost 5 months compared to everolimus (21.4 vs. 16.5 months) and reduced the risk of death by 34% (p=.0003). Moreover, results from pre-specified and post-hoc subgroup analyses showed the survival benefit associated with cabozantinib was highly robust, being observed across all Memorial Sloan Kettering Cancer Center Risk Factor groups, in patients previously treated with just one or more than one vascular endothelial growth factor receptor (VEGFR) TKI agent, those with bone or bone and visceral metastases, whether the duration of prior VEGFR TKI therapy was up to 6 months or longer, and regardless of tumor MET status.

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Dr. Choueiri“Topline results from the randomized phase II CABOSUN study investigating first-line treatment for patients with locally advanced or metastatic kidney cancer showed that cabozantinib significantly improved progression-free survival [PFS] compared with sunitinib (Sutent), which has been the standard of care. And a previous analysis from METEOR showed cabozantinib met its primary endpoint for improving PFS compared with everolimus in patients with previously treated advanced kidney cancer (N Engl J Med 2015; 373:1814-23),” said Dr. Choueiri, lead investigator for CABOSUN and METEOR and clinical director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston.

“Recently approved by the FDA, cabozantanib is a new treatment standard for patients with advanced RCC after prior antiangiogenic therapy.”

METEOR randomized 658 patients 1:1 to receive cabozantinib, 60 mg daily, or everolimus, 10 mg daily. OS was a key secondary endpoint. Dr. Choueiri noted that treatment crossover was not allowed in METEOR in order to enable robust assessment of OS. Furthermore, patients in the two arms were well balanced for anticancer therapy received after study treatment discontinuation.

“Therefore, it is unlikely that the OS results were biased by subsequent therapy,” he said.

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Commenting on OS outcomes in subgroup analyses, Dr. Choueiri observed that cabozantinib showed a marked benefit in patients with bone metastases, reducing the risk of death by 46% compared with everolimus in patients with bone metastases and by 55% in patients with bone and visceral metastases.

“Bone metastases are associated with poor prognosis in patients with advanced RCC who receive targeted therapy. The survival benefit observed with cabozantinib in patients with bone metastases suggests further investigation of the underlying activity of cabozantinib in bones is warranted,” he said.

Next: Benefit regardless of MET expression

Benefit regardless of MET expression

Among patients with high, low, and unknown tumor MET status, cabozantinib reduced the risk of death by 45%, 28%, and 33%, respectively, compared with everolimus.

“These data suggest patients experience benefit with cabozantinib regardless of MET expression and could reflect the broader target profile of cabozantinib,” Dr. Choueiri said.

PFS results based on data from all 658 randomized patients were consistent with the results of the primary endpoint analysis that was conducted based on data from the first 375 patients treated and also highly consistent with the OS benefits, Dr. Choueiri said.

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In the primary endpoint analysis, median PFS was 7.4 months for cabozantinib and 3.8 months for everolimus, and cabozantinib reduced the rate of disease progression or death by 42%. In the secondary analysis based on all 658 patients, median PFS was 7.4 months for cabozantinib and 3.8 months for everolimus, and cabozantinib reduced the rate of disease progression or death by 49% (p<.0001).

The objective response rate based on independent radiology review was 17% for cabozantinib compared with 3% for everolimus (p<.0001).

Findings of the updated safety analysis for both treatments were similar to those previously reported at the time of the primary endpoint analysis of PFS.

“Treatment-emergent adverse events were effectively managed with dose modifications in both arms, and so the discontinuation rate due to adverse events was low in both treatment groups,” Dr. Choueiri said.

Dr. Choueiri is a consultant/adviser for Bayer, Bristol-Myers Squibb, Eisai, Foundation Medicine, GlaxoSmithKline, Merck, Novartis, Pfizer, Prometheus, and Roche/Genentech. His institution has received research funding from a number of pharmaceutical companies. Several of Dr. Choueiri’s co-authors have a financial or other relationship with Exelixis, Novartis, Pfizer, and/or other pharmaceutical companies.

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