Activity of cabozantinib in radioresistant brain metastases from renal cell carcinoma: two case reports

Renal cell carcinoma represents 3-5% of adult malignant tumors. Metastases are found in 30-40% of patients and brain metastases occurred in more than 10% of them. Despite significant progress in medical treatment, patients with brain metastases still have a limited survival. Cabozantinib, a tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors, was recently registered for the treatment of metastatic renal cell carcinoma. Almost no data are, however, available on patients with brain metastases.

Case 1 is a 51-year-old man of North African origin; Case 2 is a 55-year-old European man. Case 1 and Case 2 had metastases of renal carcinoma at initial diagnosis and were treated with vascular endothelial growth factor receptors tyrosine kinase inhibitors. Case 1 had clear cell renal carcinoma and underwent nephrectomy; he then received several lines of tyrosine kinase inhibitor directed against vascular endothelial growth factor receptors and the mTor complex. During the second treatment a brain metastasis was diagnosed and treated with radiosurgery with rapid efficacy. Two years later he received nivolumab, an antibody directed against the programmed death-1 and programmed death-ligand 1 complex, but disease progression was observed with the reappearance of the brain metastasis together with neurologic symptoms. Cabozantinib was administered and induced a rapid clinical improvement as well as tumor regression in all sites including his brain. Sequencing of his tumor evidenced a mutation of the MET gene. Case 2 had a papillary renal carcinoma with brain metastases at time of diagnosis. After radiation of the brain tumors, a vascular endothelial growth factor receptor tyrosine kinase inhibitor was administered for 3 years. The disease was under control in all sites except in his brain; several new brain metastases requiring new radiation treatments developed. The disease finally progressed at all metastatic sites including his brain and he had several neurological symptoms. Cabozantinib was administered and rapidly induced a clinical improvement; a further computed tomography scan and brain magnetic resonance imaging showed significant tumor regressions. No MET gene mutation or amplification was observed in the tumor analysis.

These case reports indicate that cabozantinib was able, first, to reach brain tumors and second, to induce significant regressions in renal carcinoma brain metastases that were resistant to radiation as well as to previous systemic vascular endothelial growth factor receptor tyrosine kinase inhibitors.