MOA and Management of Any Adverse Effects of Cabozantinib

The advent of renal cell carcinoma therapy really started almost 12 years ago when we took advantage of the fact that von-Hippel-Lindau syndrome is mutated in the majority of clear cell renal cell carcinomas, and targeting that VEGF pathway has been instrumental in advancing our therapy for renal cell carcinoma. Initially, we had sunitinib and pazopanib, axitinib. These are all different VEGF inhibitors. But we know that patients who receive sunitinib will ultimately progress through that therapy. And one of the things they noted was there are mutations in MET or AXL that sort of drive some of that resistance.

Cabozantinib is a multitargeted tyrosine kinase inhibitor [TKI] that goes against VEGF, as well as MET and AXL. So clearly, given the METEOR trial, we know that in patients who are refractory to VEGF therapy, cabozantinib is certainly active. And so in those patients who, where you’re worried that if you don’t get a response, they’re not going to get to that second-line therapy, there’s a hope that by attacking MET and AXL earlier on, you may avoid some of those resistant clones and lead to a better response rate. And that was the basis for the CABOSUN trial, which showed superiority of cabozantinib over sunitinib in those patients with intermediate- and poor-risk disease.

I think toxicity management of any TKI is certainly going to be something that needs to be addressed closely. When we look at the CABOSUN data, the toxicity profile was relatively comparable between the 2 with actually less severe fatigue with cabozantinib than sunitinib and less marrow complications with cabozantinib. I think this is an important thing. If you look at the CABOSUN data, the starting dose was 60 mg, although close to 50% required dose reduction. So as we pursue this therapy, it’s very important to assess the patient on a regular basis and control their adverse effects, give the medication to control those adverse effects. But also if there is a need to pursue dose reduction, pursue dose reduction, pursue it down to 40 mg. And if the patient isn’t able to tolerate, maybe go to 20 mg or even further tweaks along those lines.

Transcript edited for clarity.

Case: A 70-Year-Old Man with Intermediate-Risk RCC

A 70-year-old Caucasian man presented to ER complaining of blood in his urine and abdominal pain.

H & P

• History of ulcerative colitis, controlled hypertension, and controlled hypercholesterolemia
• Lower back tender to touch

Labs

• CBC: Hgb 12.5 g/dL, HCT, PLT, WBC all WNL
• BP: WNL
• Lipid panel: WNL

Imaging

• Bone CT scan of the chest, abdomen, and pelvis showed a bilateral renal mass, a small lytic lesion in the lumbar vertebrae, several pulmonary nodules, and mediastinal and right hilar lymphadenopathy.
• Diagnosis: stage IV clear-cell renal cell carcinoma; intermediate-risk

Treatment

• Received cytoreductive nephrectomy
• He was started on cabozantinib 60 mg daily

Follow-up

• At 3 weeks of therapy patient tolerated treatment well, with mild fatigue and diarrhea, HTN remains controlled; blood in urine and lower back pain resolved; ECOG 0
• At 6 weeks of therapy the patient shows PR and reduction in size of the renal masses and lymphadenopathy.