The Rationale for Using Cabozantinib

Nizar M. Tannir, MD:If you look at the METEOR data and you look at sub-analysis, patients who had a visceral metastasis or a bone metastasis, patients who had intermediate risk, poor risk, high tumor burden, it supports that cabozantinib was shown to be superior to everolimus in all of these subgroups or these cohorts of patients. So, I think one of the attractive scenarios where cabozantinib is particularly effective is in patients who have a bone metastasis. We’ve seen that, this is my experience, and this was born from the trial, as well, when we talk about METEOR. Patients with a bone metastasis are particularly vulnerable and traditionally have not had good outcomes, but with cabozantinib, this is a scenario where cabozantinib is particularly the go-to agent and the drug that I would choose if a patient has poor-risk disease in the salvage setting and has a bone metastasis. But if they also have a liver metastasis, they can respond, as well, from the METEOR data.

I think we have treated patients who are in their 70s or even older with cabozantinib, and the management of the adverse events is nothing different than how you manage the adverse events with a VEGFR TKI, such as pazopanib or sunitinib, in the first-line setting. So, we manage with interruption for a few days to allow patients to improve, allow those adverse events to resolve, and we manage with dose reductions as well. I start with 60 mg, like in this patient. We chose to start with 60 mg and not 40 mg because she had progressive disease and already progressed after 2 months of therapy, including nivolumab in the second-line. And it was important for us to deliver the most powerful punch against the cancer. That’s why I think it’s important in my practice—when a patient has spine metastasis, has liver metastasis and already their performance status is declining—to really go with the highest dose that’s most efficacious. If, as in this case, they develop adverse events, that’s when you can reduce the dose down to 40 mg.

Now, if you look at the METEOR data, the phase III trial we alluded to, the discontinuation rate due to adverse events was only 12%, although the percentage of patients who required dose reduction was 60%. But again, management of adverse events with supportive care, as well as with brief interruptions, can maintain a response and maintain a patient on therapy for a good while. I think, in my experience, cabozantinib is an effective agent in patients, such as this lady, with visceral and bone metastases. If you also look at the METEOR data, 32 patients were previously treated with nivolumab. Those patients responded as well to cabozantinib, and they had better response to cabozantinib over everolimus. So, we have experience and there are data to support use of cabozantinib as second-line as well as third-line, even if they had prior nivolumab therapy.

I could have chosen to treat this patient with cabozantinib in the second-line. That would have been appropriate as well, but the oncologist in the community chose to use nivolumab. But she could also have received cabozantinib as a second-line and then nivolumab as third-line or vice versa. I think we have now the land of plenty. We have good news that we have many options for our patients, and many of our patients are receiving third- and fourth-line. And at MD Anderson, we have patients who are receiving even 7, 8, or 9 lines of therapy, and that’s good news for our patients. We have many options for them, and I think we can tailor the therapy to the scenario and particulars of the patient situation: performance status, age, comorbidities, and the sites of metastasis.

The METEOR trial actually did allow patients who had a brain metastasis to get on trial as long as the brain metastasis was treated and controlled. And we have experience that it would be appropriate to treat a patient with a brain metastasis with a TKI as long as you have the brain metastasis under control, meaning they received stereotactic radiation or they had surgery and resection of the brain metastasis. I think it would be appropriate as long as you feel that the brain metastasis is controlled, there is no hemorrhage, and there is no edema. Once you get the patient’s brain metastasis under control, it’s perfectly fine. And that’s the assuring thing from METEOR: they allow patients who had brain metastasis as long as the brain metastasis were controlled. So, I have no problem treating a patient with a brain metastasis or prior history of a brain metastasis with cabozantinib.

Now, do we know if somebody has a brain metastasis and you give them cabozantinib, will the brain metastasis regress? I think that is still under investigation. We are actually looking at what experience with cabozantinib there is to see if patients who have measurable or disease obvious on MRI of the brain, whether those will regress with cabozantinib. And then, I think this is something to be explored with immune checkpoint inhibitors, as well as with TKIs. We have reported in the past with sunitinib, some patients who had active brain metastasis but not threatening, not associated with edema or hemorrhage, that actually responded to a VEGFR TKI. So, that has been my experience in the past. It is appropriate to treat patients who have systemic disease and a brain metastasis with a TKI, such as cabozantinib.

Case Presentation

February 2016

• 70-year old female, presented to her physician with symptoms of nausea, fatigue, and weight loss
• Abdominal CT showed a 9-cm left renal tumor and a small solitary spot on the liver
• She was referred to urology and underwent left radical nephrectomy with removal of the liver lesion
• Post-surgical imaging showed multiple liver lesions
• She was then referred to medical oncology and was started on sunitinib 50 mg daily on a 4/2 schedule; stable disease was achieved within 6 weeks
• Moderate fatigue, diarrhea, and increasing severity of hand—foot syndrome were managed with treatment interruption and then dose reduction to

June 2016

• Four months later the patient reported increasing fatigue, nausea, and weight loss
• Abdominal CT showed progression of her liver metastasis
• She was then switched from sunitinib to nivolumab
• The patient reported that her symptoms had improved
• Imaging at 8 weeks showed a response in the liver
• She was maintained on nivolumab without any toxicity

February 2017

• Eight months later, the patient complained of fatigue, abdominal discomfort, and weight loss; she subsequently developed back pain
• CT scan of abdomen and chest showed new liver lesions and progression of previously identified lesions
• MRI of the spine showed multiple metastatic lesions of the thoracic and lumbar vertebrae, with no evidence of cord compression
• She sought a second-opinion at an academic center
• She was subsequently switched to cabozantinib 60 mg
• Her symptoms subsided within 4 weeks
• CT and MRI imaging at 8 weeks showed response with improvement of both liver and spine metastases.
• She was maintained on cabozantinib for approximately 4 months and developed diarrhea and hand-foot skin reaction
• Her dose of cabozantinib was reduced to 40 mg daily on which she was maintained for 13 months until she developed disease progression
• At this time the patient is being considered for enrollment into a clinical trial