The Rationale for Cabozantinib After Progression of mRCC

Daniel J. George, MD: In our case, our 48-year-old gentleman who presented with bone metastasis in the primary tumor—who had a really good response to pazopanib following palliative radiation and debulking nephrectomy for over 1 year, but then, over time, required dose reduction and had disease progression that ultimately resulted in symptomatic progression in the bone—this is, I think, an ideal situation to consider cabozantinib.

First, this patient clearly has clinical progression. Not only is he developing evidence of new lesions and growth of existing lesions, but he’s having symptomatic disease progression in the bone. Cabozantinib showed response in all subgroups, with overall survival benefit greater than everolimus across all subgroups. But one subgroup in particular showed a more impressive overall survival in progression-free survival benefit, and that was in the patients with bone metastases. And mechanistically, this makes sense. MET appears to be an important growth factor in that bone microenvironment. And so, blocking that additional agent, in addition to VEGF, may really give cabozantinib a unique mechanism in controlling disease progression within renal cell osseous metastases. Renal cell osseous metastasis tends to be associated with significant symptomatic skeletal complications—cord compressions, fractures.

In our case, our patient had a lytic bone metastasis, meaning that those bones are being eaten away and are physically unstable. So, that’s a really important setting where we want to prevent those kinds of complications down the road, and cabozantinib is perhaps uniquely capable of doing that by blocking these additional targets. In this case, even though this patient maybe had slow progression, at first, on cabozantinib, he ultimately escalated into more of a clinical progression, particularly in the bone. But I think cabozantinib uniquely meets that particular medical need.

In addition, in this case, as this patient progressed and developed back pain, he had some decrease in his functional performance status—the back pain limiting his ability to maintain all of his activities of daily living and his functional status for work. When you see a change in functional status, a change in performance status, that’s one of the known independent poor prognostic factors in this second-line space. Other factors include anemia, and this patient had mild anemia associated with his chronic therapy, and then hypercalcemia, which he didn’t have. But having 2 poor prognostic factors puts him into what we consider to be a poor prognostic group for this second-line space. This is somebody that we would expect to not necessarily to be able to go through 4 or 5 lines of therapy. So, it’s really critical to use a therapy that’s going to work relatively quickly, work to control that disease, in particular, and any kind of physical complications and symptoms, and give him the best overall survival benefit in that setting.

Again, one of the nice things in this field is the flexibility we have, the variation we have, which in IV therapies in some patients is actually a real advantage for us. These are patients that sometimes won’t necessarily have significant co-pays. There are therapies that we know we can get high compliance for and we can get full dosing. The downside, of course, with IV therapy is that it really is tying patients to our clinics, and at least here at Duke, we have patients coming from long distances. For other places, this can be done locally, and it’s a real advantage for patients in the short term. But therapy every 2 weeks over the course of 1 year can also be incredibly draining on patients. It really limits their ability to travel, it limits their ability to work in some cases, when you’re taking that many days out of the office on a regular basis. It can eat into a lot of resources for patients.

Oral therapies, financially, can be variable in terms of cost coverage and offer greater flexibility for our patients. So, particularly for our chronic patients that we feel have a high likelihood of responding to second-line therapy and responding for a long period of time, in many respects, oral therapy gives us the greatest flexibility of dosing, of travel, and of economics. And, in general, from a patient’s perspective, it’s going to be a preferred mechanism of treatment, almost all the time, over an IV therapy.

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