Which Kidney Cancer Drug on Progression? Surprising Answers

Nick Mulcahy

January 05, 2016

Clinicians who are concerned about the results of clinical trials being overhyped can take comfort in the balanced ways of cancer investigator Bernard Escudier, MD, from the Institut Gustave Roussy in Villejuif, France.

Dr Escudier presented data on the oral agent cabozantinib (Cometriq, Exelixis) that reaffirm that it provides an unprecedented benefit in slowing the progression of advanced kidney cancer in the second-line setting during a presscast held in advance of the Genitourinary Cancers Symposium 2016 in San Francisco.

He reported new results from the phase 3 METEOR trial, in which 658 patients with advanced renal cell carcinoma, who had previously experienced disease progression on first-line vascular endothelial growth-factor receptor (VEGFR) inhibitor therapy, were randomly assigned to receive cabozantinib or everolimus (Afinitor, Novartis), the current second-line standard of care.

Findings from the first 375 METEOR patients showed that median progression-free survival was significantly better with cabozantinib than with everolimus (7.4 vs 3.8 months; < .0001) (N Engl J Med. 2015;373:1814-1823). That progression-free survival was hailed as the longest yet seen in a second-line setting when presented at last year's European Cancer Congress, as reported by Medscape Medical News.

During the presscast, Dr Escudier reported that the median progression-free survival for the expanded number of patients was "exactly the same" as the earlier findings (7.4 vs. 3.9 months; < .001).

However, despite these precedent-setting results, Dr Escudier believes that "most" clinicians will eventually "reserve" cabozantinib for third-line treatment and use another treatment, the immunotherapy nivolumab (Opdivo, Bristol Myers-Squibb), as their treatment of choice in the second line.

Nivolumab has been shown to improve overall survival in this setting and is much less toxic, he explained.

This sentiment is echoed in an editorial published last year in the New England Journal of Medicine (2015;373:1872-1874).

"Cabozantinib is a salvage treatment for patients whose tumors progress during VEGF therapy [and] will compete with other VEGFR inhibitors as third-line or later therapy," according to editorialists David Quinn, PhD, from the University of Southern California Norris Comprehensive Cancer Center in Los Angeles, and Primo Lara, Jr., MD, from the University of California Davis Comprehensive Cancer Center in Sacramento.

They also note that nivolumab should be the choice for second-line treatment: "Given the overall survival advantage it confers and its relatively good side-effect profile, nivolumab is the choice for patients who have disease progression while they are receiving VEGF-targeted therapy."

"Data are Incredibly Compelling"

However, the moderator of the presscast, which was presented by the American Society of Clinical Oncology (ASCO), had other thoughts.

"The efficacy data...for cabozantinib are incredibly compelling," said Sumanta Pal, MD, from the City of Hope Comprehensive Cancer Center in Los Angeles, and an ASCO spokesperson.

Dr Pal was referring to the improvement in progression-free survival with cabozantinib and the trend toward improved overall survival reported last year. Specifically, there was a strong trend favoring cabozantinib; the interim results showed a hazard ratio of 0.67 (= .005), suggesting a 33% decrease in the risk for death.

Despite the overall survival benefit with nivolumab, the immunotherapy has not been shown to improve progression-free survival in this setting, Dr Pal pointed out.

"Personally, it makes a compelling argument for me as a practitioner to use cabozantinib in the second-line setting," he summarized.

Dr Pal emphasized that there is "no fair and direct comparison" in terms of toxicities between nivolumab and cabozantinib because neither of their clinical trials used the rival drug as a comparator.

Dr Escudier conceded that the forthcoming final overall survival data from METEOR will ultimately help clinicians decide to use "cabo before nivo or not," in the second line.

But the toxicity of the drug is considerable, he added.

"We have quite a few side effects," said Dr Escudier. "Toxicity has been an issue with this drug."

As previously reported, 60% of patients in the study underwent a dose reduction as a result of adverse events. Adverse effects are "certainly a very big difference between nivolumab and cabozantinib," he said.

Cabozantinib, which is approved for the treatment of medullary thyroid cancer, targets the VEGFR but has additional effects on other tyrosine kinases, including MET and AXL. It has been suggested that these additional activities allow it to overcome the resistance that develops with the first-line treatment of kidney cancer with drugs that target VEGFR, which include sunitinib (Sutent, Pfizer), sorafenib (Nexavar, Bayer), pazopanib (Votrient, Novartis), and axitinib (Inlyta, Pfizer).

Subgroup Analyses

Dr Escudier also presented subgroup analyses from METEOR, which he said is a statistical exercise that must be interpreted "very cautiously."

Nevertheless, he reported that the international team of investigators found that the progression-free survival improvements associated with cabozantinib were consistent in prespecified patient subgroups. The subgroups were defined by a Memorial Sloan Kettering Cancer Center risk category (favorable, intermediate, or poor risk), tumor burden, and previous therapy (type, number, and duration).

A total of 32 patients had been treated previously with programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) monoclonal antibodies, such as nivolumab, and progressed. The progression-free survival benefit had not yet been reached for the patients who were subsequently treated with cabozantinib; for patients treated with everolimus, median progression-free survival was 4.1 months, which translated into a hazard ratio of 0.22. Cabozantinib "is still very active after PD-1 or PD-L1 therapy," Dr Escudier explained.

This study received funding from Exelixis, Inc. Dr Escudier reports financial ties with multiple pharmaceutical companies, including Exelixis. Dr Pal reports multiple ties to the pharmaceutical industry, but not to Exelixis.

Genitourinary Cancers Symposium (GUCS) 2016: Abstract 499. To be presented January 9, 2016.

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