First-Line Targeted Therapy in mRCC

Daniel George, MD:Our patient with metastatic kidney cancer presenting to his spine has his kidney removed and then develops lung metastasis. This is a fairly classic presentation of an intermediate-risk patient. The disease burden is increasing, although the burden isn’t severe. He had some symptoms, although they were manageable with radiation. The question then becomes, how are we going to manage this patient?

For the last few years, we’ve been conducting studies in the frontline space, looking at combinations or single-agent therapies compared to sunitinib. Sunitinib has been our standard of care, along with pazopanib, for frontline metastatic kidney cancer. One of those studies was the CABOSUN study. It was one that I was involved in. It ran through our cooperative group—the Alliance Cooperative Group. This was a 152-patient randomized study of cabozantinib versus sunitinib, open-label, with intermediate and poor risk defined by the IMDC criteria—the same criteria that we talk about with things like performance status, anemia, thrombocytosis, and lymphocytosis.

These are the factors that help us define these intermediate-risk and high-risk patients. That’s who we focused on for CABOSUN. We did that for 2 reasons. First, because that’s where sunitinib is probably coming up a little bit short. Historically, we’ve known that patients with good risk features do really well on TKIs. That’s going to be hard to improve upon. But, the intermediate, poor risk is where these patients have had accelerated time to progression—historically, somewhere around 5 or 6 months, for that group.

So, we studied that population in a cooperative group setting. These are largely community centers around the country. So, in many respects, this is a real-world study. This is different than many of the industry-sponsored studies run from top academic centers in Europe and, maybe, here in the United States. This is strictly a US community population, looking at real live patients, who you’re going to see in your community, with kidney cancer. Patients were randomized to these 2 oral agents. Cabozantinib was given 60 mg daily. Sunitinib was given through the traditional 50-mg daily dose, for 4 weeks on and 2 weeks off. Patients were treated until disease progression or unacceptable toxicity. And the results were clear. By our investigator assessments, we saw about an 8-month median progression-free survival for cabozantinib, and 5.6 months for sunitinib. These results also suggested a big difference in the overall response rates—a 33% objective response rate for cabozantinib versus 12% for sunitinib.

A significant finding was published. Because of the frontline status, because cabozantinib was already approved in the second-line status, it was taken to the FDA. An independent radiographic committee re-reviewed the data, and it came out very similar. Again, we saw this sort of 8-month versus 5.3-month difference in the median progression-free survival between the arms. We saw little bit more strict criteria for objective response and confirmed response—lowering both arms down to 20% objective response for cabozantinib and just 9% for sunitinib. But really, again, this showed the sort of double response rate, this almost doubling of progression-free survival, and I think a really clinically and statistically significant difference between these 2 arms.

So, for me, getting back to our case, this is exactly how, for TKIs, we want to treat patients who have intermediate- and poor-risk features. And to me, cabozantinib is a new standard of care for that population.

Transcript edited for clarity.

Case Scenario: A 52-year old male with mRCC

February 2018

• A 52-year old Caucasian man presented to his physician complaining of severe left-sided back pain
• Laboratory findings: mild anemia, otherwise WNL
• CT scan of the abdomen and pelvis showed a large left renal mass, several small lytic lesions in the lumbar and thoracic vertebrae, and a small pulmonary nodule
• The patient underwent cytoreductive nephrectomy
• Diagnosis; stage IV clear-cell renal cell carcinoma; good-risk
• He received radiation therapy to his spinal lesions and was then started on cabozantinib 60 mg daily
• The patient reported moderate nausea and vomiting and diarrhea after 6 weeks on therapy; he continues to do well with improved tolerance after dose adjustment to 40 mg
• Imaging at 3 months showed a significant decrease in size of the pulmonary nodule