The oral multitargeted tyrosine kinase inhibitor cabozantinib is more efficacious than everolimus as therapy for advanced renal cell carcinoma across a wide range of patients, suggests a subgroup analysis of the phase III METEOR trial being reported at the genitourinary cancers symposium.
Trial participants were 658 patients with advanced renal cell carcinoma and clear cell histology who had experienced progression on a tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptor (VEGFR). There was no limit on the number of prior therapies.
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The patients were randomized evenly to cabozantinib (Cometriq), which inhibits the VEGFR, MET, and AXL tyrosine kinases – all of which are up-regulated in this cancer – or to everolimus (Afinitor), an inhibitor of the mammalian target of rapamycin that is considered a standard of care. (At present, cabozantinib is approved by the Food and Drug Administration for the treatment of medullary thyroid cancer.)
Results for the entire trial population showed that patients in the cabozantinib group were about half as likely as were their counterparts in the everolimus group to experience progression-free survival events, lead author Dr. Bernard Escudier reported in a press briefing held before the 2016 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology. All patients appeared to derive benefit, with the reduction in risk ranging from 16% to 78% depending on the specific subgroup.
“Cabozantinib improved progression-free survival, compared to one of our standard therapies, everolimus, in advanced renal cell carcinoma,” concluded Dr. Escudier, who is chair of the Genitourinary Oncology Committee at the Institut Gustave Roussy in Villejuif, France. “Benefit was observed across prespecified subgroups,” including a small subgroup who had previously received immunotherapies targeting the programmed death 1 (PD-1) signaling pathway.
Toxicity was somewhat problematic with cabozantinib, despite starting the drug at a lower dose than has typically been used in the past, he acknowledged. The most common side effects were diarrhea, fatigue, nausea, decreased appetite, and hand-foot syndrome, and they often necessitated further dose reductions.
“Benefit with cabozantinib treatment is supported by a trend in overall survival, and hopefully, we will give this final overall survival analysis at ASCO this year,” Dr. Escudier added. Findings of an interim analysis reported last year were very promising with respect to this outcome (hazard ratio, 0.67; P = .005) (N Engl J Med. 2015 Nov 5;373:1814-23).
“This study is unique compared to others in that it allowed a broad range of patients: Patients could have had spread of cancer to the brain, they could have received any number of prior therapies, and they could have been exposed to immune-based treatments,” commented ASCO spokesperson and moderator of the press briefing Dr. Sumanta K. Pal. “The magnitude of benefit that patients got from cabozantinib far exceeds, in my opinion, what we have seen to date in this setting in terms of both delay in tumor growth and improving survival.”
In fact, for some oncologists, the findings may be strong enough to prompt use of cabozantinib as second-line therapy, according to Dr. Pal, who is a medical oncologist at the City of Hope in Duarte, Calif.
“Given the fact that cabozantinib has a very compelling benefit in terms of both delay in tumor growth and a hint toward a benefit in terms of overall survival, I would perhaps tend to favor that as a second-line option as compared to other comparators, such as nivolumab (Opdivo), in that setting,” he said, referring to an antibody that targets the cell surface receptor PD-1. “Now that’s a personal opinion. I certainly think there are some merits with nivolumab, such as the toxicity profile. But, in broad terms, patients are very focused on clinical efficacy, and with that in mind, the data for cabozantinib truly speaks for itself.”
But Dr. Escudier offered a more-reserved perspective. “I think what people are going to do will be to use nivolumab as second-line [therapy] in most patients and keep cabozantinib for nivolumab failure,” he predicted. “Based on that, this subgroup, although small, is of importance. I don’t think it’s good enough to say we should use cabozantinib or nivolumab in second line based on the subgroup analyses we have.”
The eagerly awaited overall survival results will also help determine cabozantinib’s position in treatment sequence, he added. “If we get a survival advantage [that] is the same magnitude that we have with nivolumab, with such an impressive improvement in progression-free survival, maybe despite the toxicity with cabozantinib, people will be willing to use cabozantinib early on.”
In the new analysis, median progression-free survival in the entire trial population was 7.4 months with cabozantinib and 3.9 months with everolimus, translating to a near halving of the risk of events (hazard ratio, 0.52; P less than .001).