Cabozantinib in Kidney Cancer: Longest PFS Yet

Zosia Chustecka

September 25, 2015

UPDATED September 27, 2015 // VIENNA ― Renal cell carcinoma is in the spotlight here at European Cancer Congress (ECC) 2015, with the first presidential session featuring two trials reporting what are being hailed as practice-changing results.

Both trials were conducted in patients with advanced renal cell carcinoma who had already been treated with prior therapies, for whom the standard of care is everolimus (Afinitor, Novartis), and so this was used as the control. In one trial, an improvement in overall survival was seen in patients treated with nivolumab (Opdivo, Bristol-Myers Squibb). The other trial showed an improvement in progression-free survival (PFS) with cabozantinib (Cometriq, Exelisis, Inc), with a trend toward improved overall survival, although the data are still immature.

These two presentations are "definitely among the highlights of this congress," commented Peter Naredi, MD, PhD, the European CanCer Organisation (ECCO) scientific co-chair for the meeting. Dr Naredi, who is also professor of surgery at Sahlgrenska University Hospital, in Gothenburg, Sweden, was not involved with either trial.

"For patients with advanced kidney cancer who have progressed on earlier treatment, we now get two novel treatment options, both with different mechanisms of action," he said.

However, outside experts, writing in a New England Journal of Medicine editorial that accompanied the publication of both trials, highlight the data on nivolumab; they predict that the immunotherapy will become the treatment of choice for this patient population, whereas cabozantinib will compete with other VEGFR inhibitors as third-line or later therapy.

Longest PFS Yet Reported

Cabozantinib is an oral drug and is currently approved for use in the treatment of medullary thyroid cancer.

Dr Toni Choueiri

The new data in renal cell carcinoma come from the METEOR study, presented here by Toni Choueiri, MD, associate professor of medicine at Harvard Medical School and director of the Kidney Cancer Center at the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. The study was simultaneously published online in the New England Journal of Medicine.

The median PFS with cabozantinib was 7.4 months, compared with 3.8 months with everolimus (hazard ratio, 0.58; P < .0001).

This is the longest PFS yet seen in a second-line setting, Dr Choueiri noted. It compares with median PFS rates of 3.9 months for everolimus in the RECORD-1 trial (which led to that drug's approval) and of 4.8 months for axitinib (Inlyta, Pfizer Inc) and 3.4 months for sorafenib (Nexavar, Bayer HealthCare Pharmaceuticals) in the AXIS study, Dr Choueri noted.

The overall survival data from the METEOR study are still immature, but there is a "strong trend" favoring cabozantinib, with results from an interim analysis showing a hazard ratio of 0.67 (P = .005), which suggests a 33% decrease in the risk for death, he said.

The objective response rate was 21% for cabozantinib and 5% for everolimus.

"I am very excited about the outcome of the study since the results may change the standard of care in patients with advanced kidney cancer who have received prior standard therapy that targets the vascular endothelial growth factor receptor [VEGFR]," Dr Choueri said in a statement.

"Regaining tumor control after prior targeted therapy may reduce symptoms related to kidney cancer and eventually help patients live longer," he added.

However, outside experts were less enthusiastic about the prospects for the drug. "Cabozantinib is a salvage treatment for patients whose tumors progress during VEGF therapy," say David I. Quinn, PhD, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, and Primo N. Lara, Jr, MD, from the University of California Davis Comprehensive Cancer Center, Sacramento, writing in an editorial in the New England Journal of Medicine that accompanied the publication.

They compare the results seen with cabozantinib in the METEOR trial with those seen with nivolumab in the CheckMate-0225 trial and find in favor of the immunotherapy.

"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," they write.

They note that cabozantinib has not shown a significant overall survival benefit and had significant side effects that necessitated a dose reduction in 60% or more of patients ― for these reasons, they say it "will not precede nivolumab in the therapeutic sequence."

Overcoming Resistance

Drugs that target VEGFR, which include sunitinib (Sutent, Pfizer Inc), sorafenib, pazopanib (Votrient, Novartis Pharmaceuticals Corporation), and axitinib, have been very effective in the first line of therapy for patients with advanced kidney cancer, Dr Choueri commented. However, in many cases, tumor cells find ways to escape control by these drugs. Cabozantinib has a slightly different mechanism of action and targets possible escape mechanisms of tumor cells, including the tyrosine kinases MET, VEGFR, and AXL, he said.

"Overcoming mechanisms of tumor escape or resistance to standard therapies is critical for improving long-term outcome for our patients with advanced kidney cancer," Dr Choueri said.

However, the editorialists say it is uncertain whether the inhibition of MET, RET, or AXL drives clinical activity or whether the benefit is simply due to a VEGFR-inhibitory effect, and add that trials . comparing cabozantinib with other VEGF-targeted therapies are much needed.

The METEOR study included 658 patients, but the analysis for PFS that is being reported is based only on the first 375 patients who underwent randomization, whereas the safety data are reported on 653 patients who received study medications.

The incidence of adverse effects of grade 3 or 4 was 68% with cabozantinib and 58% with everolimus. The most common grade 3 or 4 adverse events with cabozantinib were hypertension (15%), diarrhea (11%), and fatigue (9%); with everolimus, they were anemia (16%), fatigue (7%) and hyperglycemia (5%). As noted by the editorialists, dose reductions because of adverse events were made for 60% of patients receiving cabozantinib, compared with 25% for patients receiving everolimus. The common adverse events (any grade) leading to dose reductions with cabozantinib were diarhea (16%), the palmar-plantar erythrodesia syndrome (11%), and fatigue (10%); for everolimus, they were pneumonitis (4%), fatigue (3%), and stomatitis (3%).

The study was funded by Exelisis. Dr Choeuiri reports that his institution received a grant from Exelisis for conducting the clinical trial. Dr Lare reports being on the independent Data Monitoring Committee for the METEOR trial and acting as a consultant for Novartis. Dr Quinn reports consultancy for Pfizer, Bayer, Genentech, and NovartisNippon Pharma.

European Cancer Congress (ECC) 2015. Abstract LBA 4. Presented September 26, 2015.

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