Experience with Cabozantinib in mRCC

Daniel J. George, MD: Since its approval on the market in May of 2016, we’ve had about 8 to 9 months of access to cabozantinib. And fortunately, working in an academic medical center like Duke, we get to see a lot of patients with advanced refractory renal cell carcinoma. So, I’ve had a lot of experience in a relatively short window of time using this agent in a broad spectrum of patients. Prior to this, on clinical trials, including the METEOR trial that we participated in, I had experience using cabozantinib.

But my greatest experience has been in my real-world everyday practice treating patients. That’s where we see the greatest variety of our patient population. And in that population, I’ve treated patients old and young. I’ve treated patients in the second-line space to the fourth-line space. I’ve treated patients with renal cell carcinoma in bone, in lung, in liver, in soft tissues, even in patients with brain metastases. What struck me about the drug is that I see responses in multiple organ sites. There doesn’t seem to be any sanctuary, including the brain, where this drug doesn’t work. We’re able to see evidence of real tumor regression, evidence of seeing decrease in tumor edema; we’re able to see very long-term stable disease associated with this drug. It has been great to be able to use this in a variety of patients because I’ve also gotten to see a spectrum of toxicities associated with the drug.

What’s interesting about this agent, compared to maybe some other agents, is the toxicity tends to be a little bit more delayed in onset. So, a drug like, say, ceritinib or axitinib or pazopanib, where we might see within the first 2 or 3 weeks, significant toxicity, cabozantinib seems to build up over the course of more like 4 to 6 weeks. And I think that’s really important for our patients. We can sometimes see clinical benefit before we see cumulative toxicity. It allows us to get the patient comfortable with the agent, to get the patient back in the clinic to reassess toxicity, and to continue our education around symptom management.

These are also patients that have had prior VEGF inhibitors, so they know about how to manage diarrhea, hypertension, and things like that. We’re constantly reiterating that kind of education, but it’s really important to recognize that these are patients that already have some experience, so we can manage this. To me, dose interruptions are a key in maintaining the dose of cabozantinib. I really like to keep patients on the full dose if we can—60 mg—knowing we can drop down to 40 mg at any time. And in most of my patients who are on cabozantinib for months and months, I do drop down to 40 mg. Those first 1 to 2 months, I try as much as I can to manage them on 60 mg and use my dose interruptions before we see grade 3 toxicity, to manage that. And that’s different than what we do in clinical trials where we’re really not changing the dose or interrupting the dose until grade 3 toxicity.

In my practice, I’m able to do this in a much more proactive way. And what that allows me to do is treat patients who are more frail, patients who are more elderly, and patients who have had perhaps some other lingering toxicities or medical issues that may have excluded them from other clinical trials, but allow me to treat them off study. Those are the circumstances where I might consider starting at a lower dose. But when I can, as much as possible, I try to start at 60 mg and use my dose interruptions to allow me to maintain that dose for at least 1 to 2 months, if possible.

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