Selecting Therapy for Progressive mRCC

Nizar M. Tannir, MD:There are many considerations to select a salvage therapy. One of those considerations is efficacy. We discussed that. We already reviewed the efficacy of these agents that we spoke about in the salvage setting. But tolerability is important and so is, in my opinion, cost, and that brings us to value-based care, which is very important now. We need to take into account our cost, take into account tolerability. So, when I look at choosing a salvage agent, I have to look at the patient—age and comorbidities—and look at their prior history of exposure to the first-line therapy with a VEGFR TKI and whether they had good tolerance or poor tolerance of the initial agent. Now, it’s not always the case that if they had adverse events in the first-line, that that necessarily is going to carry over and have produced the same adverse event in the second-line. So, if you have a patient who had prior VEGFR TKI with sunitinib or pazopanib and had hand-foot skin rash, diarrhea, and fatigue, it doesn’t necessarily imply that they’re going to have the same adverse events when you switch to an agent, another VEGFR TKI, cabozantinib. They may have that; they may not have that. We’ve seen that when we go from one TKI to another TKI.

But if a patient already received a VEGFR TKI in the first-line and they developed hypertension, and they’re on 3 or 4 antihypertensive medications and they have had proteinuria, then I think this is a patient where I might select nivolumab for second-line to give them a break from the VEGFR TKI that they received first-line and for the hypertension and proteinuria before. But there are considerations where I would go with cabozantinib over nivolumab in the second-line setting, like if a patient has history of an autoimmune disorder, has prior history of Guillain-Barré, or has a history of a neuromuscular disorder, such as Myasthenia gravis. This is where I would go with cabozantinib because of real risks of developing toxicity with an immune checkpoint inhibitor. I think the other thing I talked about is the cost, and that’s important. So, when you look at giving, in the salvage setting, a combination of 2 agents that are more expensive and produce more adverse events, that, in my algorithm, would be a further line of usage rather than up front.

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