Upfront Cabozantinib vs Sunitinib in mRCC

Daniel J. George, MD: Cabozantinib has been a fantastic addition to our armamentarium of renal cell carcinoma. It has, as I mentioned earlier in the METEOR study, demonstrated an overall survival benefit, progression-free survival benefit, and response rate benefit over everolimus. But everolimus is an mTOR inhibitor. One of the questions that is really critical in this field is differentiating the class of VEGF TKIs, and how do we select a VEGF TKI? Are they all the same when it comes to efficacy or are there differences?

I mentioned earlier that the AXIS study, that compared axitinib to sorafenib, demonstrated a statistically significant improvement in progression-free survival, but no difference in overall survival. What is probably most important to us, however, with VEGF tyrosine kinase inhibitors, is the frontline space. The frontline space is where we’re currently using and treating 80% of our patients with VEGF TKIs, and right now, that’s primarily sunitinib and pazopanib. And they’ve done a head-to-head study, the COMPARZ study, that showed no difference in overall survival or progression-free survival between those 2 agents.

What we did with the CABOSUN trial was take one of those agents, sunitinib—which we consider to be probably the most common standard-of-care therapy, VEGF TKI, in renal cell carcinoma in America—and compared that to cabozantinib. And we did it for 2 reasons. As cabozantinib compares to a VEGF TKI, from a biologic standpoint, is there a difference between these drugs? Cabozantinib blocks 2 targets that sunitinib doesn’t—MET and AXL. How clinically significant are MET and AXL in this frontline patient population? And we hypothesized, in particular, that cabozantinib would be, in MET and AXL in particular, important targets in patients with intermediate- to poor-risk features. Why? Because those are the patients that have the worse prognosis, more likely to die within a short period of time, less likely to get to second- and third-line therapy and where you’d want to use your best VEGF TKI. So, if cabozantinib is superior to sunitinib, you’d want to use it first in a population of patients that might not get to the second- or third-line setting.

So, that’s the study we did—150 patients randomized 1:1, sunitinib versus cabozantinib. It demonstrated what we consider to be a clinically significant difference in the progression-free survival: for about 5.5 months with sunitinib—again, in this intermediate- to poor-risk population—compared to about 8 months with cabozantinib. In addition, we were able to demonstrate a significant difference in the overall response rate: with sunitinib, at about an 18% overall response rate, and with cabozantinib at a 46% overall response rate. It’s really astounding, in this frontline space, to see that degree of overall response rate in this population.

And lastly, overall survival is not mature yet, but there’s at least a trend suggesting that cabozantinib could be superior, at least over the first 12 months of overall survival events of cabozantinib versus sunitinib. So, across all 3 spectrums of outcome, we see a separation between these. Whether or not that is enough to justify cabozantinib, in this patient population, as the frontline agent of choice versus sunitinib is something for our regulatory bodies and payers to decide. I think these data have to continue to mature. But we find this incredibly important, incredibly provocative, and incredibly insightful for us to understand which patient populations and which mechanisms might be really differentiating these VEGF-targeted inhibitors from each other.

Case Scenario 1: A 50-year old male with relapse of metastatic RCC

January 2014

• A 48-year old Caucasian man presented to his physician complaining of right upper quadrant discomfort and back pain
• CT scan of the abdomen and pelvis showed a large right renal mass with retroperitoneal adenopathy, largest node measuring 2.5 cm on right axis; metastatic lesion to T9, lytic
• The patient underwent cytoreductive nephrectomy, retroperitoneal node biopsy
• He was diagnosed with stage IV renal cell carcinoma, clear-cell histology, with metastases to bone and contralateral adrenal gland
• After radiation therapy to T8, he was then started on pazopanib 800 mg
• The first follow up scan showed a decrease in size of the adrenal lymph node
• The patient reported moderate diarrhea and mild fatigue which was controlled with antidiarrheal medication and rest
• He continues to do well with improved tolerance after dose adjustment to 600 mg

April 2016

• Imaging shows slow but steady progression in the adrenal lesion
• The patient complains of increasing back pain. He reports nausea and
• Pazopanib was discontinued and the patient was started on cabozantinib 60 mg