Renal carcinoma represents 3–5% of the incidence of adult malign tumors. The more common histologic subtype is clear cell carcinoma and it accounts for more than 75% of cases; several minor subtypes are diagnosed among the remaining 25% of cases. Papillary carcinoma, type I or II, is the most frequent of these minor subtypes and accounts for 10% of all cases. Surgery with partial or radical nephrectomies cures most patients and disease-specific survival at 5 years is between 70 and 80% [
1,
2]. Metastases often occur in the 2 to 5 years following surgery but are uncommon at initial diagnosis. Metastases are frequently located in lungs and lymph nodes, but also in bones and liver; brain metastases are unfrequently observed with an estimated incidence of 10% [
3,
4]. Brain metastases are generally associated with a limited survival time despite local specific treatments with neurosurgery or radiation therapy [
3,
5]. Significant progress in the treatment of metastatic renal cell carcinoma (mRCC) was achieved in the past decade; however, patients die after a survival period varying from 1 to 3–4 years depending on the prognosis factors [
1]. Due to specific gene alterations, the vascular endothelial growth factor (VEGF) pathway is a major driver of clear cell renal carcinoma development, which is the most frequent histologic subtype, and, as a consequence, VEGF or VEGF receptor (VEGFr) inhibitors are key in the treatment of these patients [
1]. Other genes, especially
MET, involved in the carcinogenesis of a number of tumors, were also found to be determinants for tumor progression and resistance to treatments. MET was first identified as a major driver for the development of papillary renal carcinoma, but was also shown to be involved in resistant clear cell carcinomas [
6‐
8]. Different MET or dual MET and VEGF-targeted therapies were recently investigated through clinical trials [
9,
10]. One of the most recently registered targeted therapies for the treatment of mRCC, cabozantinib, is a tyrosine kinase inhibitor (TKI) directed against VEGFrs, but also against other different genes: c-Met, RET, and AXL [
11].
We describe two cases of mRCC who developed resistant brain metastases despite several systemic treatments as well as stereotaxic radiation. Cabozantinib induced significant tumor reductions including the life-threatening brain metastases.