1. Goodwin, Peter M.

Article Content

AMSTERDAM, Netherlands-Patients with previously-treated metastatic kidney cancer given second-line therapy with cabozantinib lived a third longer than those in a comparator group receiving everolimus-the current standard-in the phase III randomized open-label METEOR trial reported at the 2017 European Cancer Conference (Lancet Oncol 2016;17(7):917-927).

kidney cancer. kidne... - Click to enlarge in new windowkidney cancer. kidney cancer

"This is the first trial that demonstrated statistically significant superiority in all three endpoints," said Manuela Schmidinger, MD, Professor of Medicine and Program Director for Kidney Cancer at the Medical University of Vienna, Austria, reporting significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).


"It's an excellent drug. It's a drug that's directed against pathways that become relevant at this time of the disease," she said.


Cabozantinib is an oral small-molecule tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR), MET, and AXL-each of which has been linked to the mechanisms of metastatic renal cell carcinoma or resistance to antiangiogenic drugs.


The study randomized 658 patients with clear cell renal cell carcinoma-who had one or more prior treatments with a VEGFR TKI-to treatment with cabozantinib or everolimus.


Study Results

After 18 months follow-up, there was a significant difference in median OS between the two groups. Patients receiving cabozantinib lived a median of 21.4 months compared to 16.5 months for patients treated with everolimus-a statistically significant hazard ratio (HR) of 0.66.


All subgroups treated with cabozantinib-including those defined by Memorial Sloan Kettering Cancer Center risk group, number, and type of prior VEGFR TKIs; prior anti-programmed death-1 (PD-1) and anti-PD-ligand 1 (PD-L1) treatment, location, and extent of tumor metastases; and tumor tyrosine kinase receptor MET expression level-lived longer than similar patients receiving everolimus.


Cabozantinib nearly doubled median PFS-the primary endpoint of METEOR-from 3.8 months to 7.4 months (HR 0.51) compared to everolimus. "That was highly statistically significant and-by indirect comparison-was the best achieved in second-line compared to former established agents axitinib or everolimus," Schimidinger said, adding that the proportion of patients with objective responses went up from 3 percent to 17 percent.


Schimidinger said that, although patients with bone metastases usually had very poor prognoses-because the bone was "a difficult organ to treat"-cabozantinib worked very well in the bone.


"We observed responses in the bone radiologically. And when we look at the OS benefit-or [at the] sub-group analysis in patients with bone mets-these patients derived similar benefits to others without bone mets," she explained.


Although toxicities were different for the two drugs, the overall incidence of grade 3 or 4 adverse events in each arm of the study was similar- about 40 percent of patients were affected irrespective of which drug was used.


To manage toxicities, doses were reduced in 60 percent of patients treated with cabozantinib and a quarter of those who received everolimus. The number of patients who needed to discontinue treatment "owing to adverse events" was similar in the two groups-9 percent of those who received cabozantinib and 10 percent for everolimus.


Schmidinger concluded that cabozantinib should be considered as a new standard-of-care for second-line treatment in this population.



When asked about patient selection for second-line therapy, Schmidinger said that-on current knowledge-every patient was a good candidate for cabozantinib, but immunotherapy was also an important option.


"We also have nivolumab, for example, the checkpoint inhibitor immunotherapy. So, of course, we ask the question: Which is the best second-line treatment-nivolumab or a tyrosine kinase inhibitor such as cabozantinib?"


And because there had been no head-to-head comparison yet between those two agents, she said we didn't know which agent was better.


"Probably there isn't any optimal sequence. It could easily be it doesn't matter, which is chosen first as long as the patient gets all of these strategies. Nivolumab is much better tolerated. On the other hand, patients experience TKI side effects. So, currently, I'd say it's based on a clinical decision."


Preferred Sequence

When she was asked about her preferences, Schmidinger noted that, while nivolumab also provided a survival benefit, it was different from cabozantinib which-the METEOR results show-was the first agent to demonstrate a robust benefit in all three efficacy endpoints PFS, ORR, and OS, while nivolumab had benefits with OS and response rate.


"My recommendation would be that if your patient has tolerated TKIs well during first-line treatment, [and] if you were able to manage side effects very well, then-of course-go for a TKI in the second line. And if the patient is exhausted from first-line treatment due to side effects, then give him a break with TKIs and treat with immunotherapy," she said.


Game Changer

Session chair at the ECCO conference Steven Joniau, MD, PhD, Professor in Urology at University Hospitals Leuven in Belgium, said METEOR was "a game-changer" and pointed to the data on OS.


"Here we see very significant benefit for any subgroup. There is a vast survival advantage for cabozantinib versus the old standard of care-everolimus-and I think that's probably going to move everolimus to second choice," he said.


When asked which patients could be candidates for therapy with cabozantinib, Joniau noted this included most patients who had previously failed VEGF receptor TKIs.


"Most of the patients [in METEOR] had one or two lines of VEGF receptor TKIs in the past as first-line treatment," he explained.


But Joniau also was impressed by the performance of immunotherapy in patients with advanced renal cancer.


"The immune checkpoint inhibitor niovolumab-also tested against everolimus-had quite similar overall survival outcomes," he said, adding that nivolumab was also a significant improvement over everolimus.


Peter M. Goodwin is a contributing writer.