Michael R. Harrison, MD
The multikinase inhibitor cabozantinib (Cabometyx) remains to be the sole oral drug to meet 3 clinical trial endpoints of progression-free survival (PFS), overall survival (OS), and overall response rate (ORR) in patients with advanced renal cell carcinoma (RCC), Michael R. Harrison, MD, noted in a presentation at the 35th Annual CFS®
The benefit with cabozantinib was seen in the pivotal phase III METEOR trial, which led to the FDA approval of cabozantinib in April 2016 for patients with advanced renal cell RCC who have received prior therapy.
The FDA approval timeline of tyrosine kinase inhibitors (TKIs) for patients with advanced RCC in the “post-cytokine era” started with sorafenib (Nexavar) in December 2005, followed by sunitinib (Sutent), pazopanib (Votrient), axitinib (Inlyta), cabozantinib, and lenvatinib (Lenvima) plus everolimus (Afinitor). The RCC paradigm also includes mTOR inhibitors temsirolimus (Torisel) and everolimus (Afinitor), the anti-VEGF therapy bevacizumab (Avastin) and the PD-1 inhibitor nivolumab (Opdivo).
“It’s a pretty complex landscape,” said Harrison, a medical oncologist at Duke Cancer Institute.
Cabozantinib’s indication is specifically for patients with advanced RCC who have received prior treatment with an antiangiogeneic agent. Resistance to VEGFR inhibitors is also associated with increased MET and AXL signaling, which promotes tumor growth, angiogenesis, metastasis, and invasion into nearby tissues.
“We also know that when VEGF is inhibited, resistance to those VEGF inhibitors is driven by increased MEK and AXL signaling,” said Harris.
Preclinical models have shown that cabozantinib is designed to inhibit the MET and AXL receptors.
In the open-label, phase III METEOR trial, 658 patients with advanced clear cell RCC who progressed on or within 6 months of a prior VEGF TKI were randomized 1:1 to receive cabozantinib at 60 mg once daily (n = 330) or everolimus at 10 mg once daily (n = 328).2
Crossover was not permitted; the primary endpoint was PFS confirmed by an independent radiology review committee (IRRC), with secondary endpoints being OS and ORR.
"Importantly, this trial was powered to demonstrate an OS benefit if there was one to be seen,” Harris explained.
In the primary PFS analysis, which was conducted in the first 375 patients randomized to treatment, the median PFS was nearly doubled with cabozantinib over everolimus, at 7.4 months and 3.8 months, respectively (HR, 0.58; 95% CI, 0.45-0.74; P
“Of course, findings showed a 42% risk reduction in progression, and that was highly statistically significant,” he added.
Additionally, there was a median improvement in OS with cabozantinib versus everolimus at 21.4 and 16.5 months, respectively, leading to a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.53-0.83; P
= .0003). The ORR confirmed by IRRC was 17% with cabozantinib and 3% with everolimus (P
There were a number of hypothesis-generating subgroup analyses of the METEOR trial published in Lancet Oncology
that were generally consistent with overall results from the phase III study, Harris said. Some of the subgroup populations were small, he noted, and are not considered substantial evidence of efficacy.
Key differences, however, can be found in patients with varying levels of MET
status. In comparison of cabozantinib with everolimus, the HRs for OS were 0.55 for patients with high levels of MET
expression (95% CI, 0.31-0.99) and 0.72 for low MET
status (95% CI, 0.52-1.00). HRs for PFS for high MET
expression was 0.41 (0.24-0.68) and 0.58 for low MET
expression (95% CI, 0.43-0.79).
The HRs for OS were also noticeably different overall in patients with bone and visceral metastases (HR, 0.45; 95% CI, 0.28-0.72) and without (HR, 0.73; 95% CI, 0.57-0.93). It was a similar trend for PFS—for those with both metastases, the HR was 0.26 (95% CI, 0.16-0.43) and 0.56 without them (95% CI, 0.45-0.70).
“The caveats, of course, are that we are not supposed to make definitive conclusions based on subgroup analyses, but I think they are interesting to think about when we're thinking about the patient sitting in front of us and what might be the most beneficial choice for that patient,” he said.
The piece of data to focus on, Harrison added, would be the overall HRs of 0.66 for OS and 0.51 for PFS.
“Are there any groups that appear to be better? You focus your eyes on the OS column,” he said. “You can see that nothing really stands out in this group. The key thing in all of these is that cabozantinib appears, pretty uniformly, to benefit all patients no matter what characteristic you looked at.”