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

Abstract

BackgroundRenal 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 presentationCase 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.ConclusionsThese 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.

Brain Metastases from Lung Cancer: Is MET an Actionable Target?

“…Moreover, the “selective” occurrence of somatic mutations causes one to think that this subset of patients could benefit from small molecule inhibitors. Among the novel small inhibitors, cabozantinib, a MET, RET, and VEGFR2 inhibitor, has been reported to be effective in radioresistant MET-mutated brain metastases from renal cell carcinoma [53] and to show rapid intracranial response in crizotinib-resistant MET-exon14 positive NSCLC [54]. On the other hand, the concomitant activation of the MET receptor and the ALK fusion gene has been reported to be associated with a rapid response to crizotinib in NSCLC brain metastatic lesions [55].…”

Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases

“…Preclinical studies have implicated c-Met signaling in hypoxia- and radiotherapy-associated protection from apoptosis [71,72]. Supporting this, two case studies recently reported slower disease progression in brain metastasis patients treated with c-Met inhibitors, crizotinib or cabozantinib [73,74].…”

Cabozantinib in Renal Cell Carcinoma With Brain Metastases: Safety and Efficacy in a Real-World Population

“…Cabozantinib was administered orally at the initial dosage of 60 mg/d in 28 Safety and Efficacy of Cabozantinib in mRCC d. Dose reductions to 40 mg and then to 20 mg were performed in cases of adverse events (AEs), according to clinicians' decision.…”

“…21 Retrospective studies supported the activity of sunitinib and sorafenib in mRCC patients with BM with acceptable tolerability. [22][23][24][25][26] Cabozantinib intracranial penetration and direct activity on brain disease were proven in preclinical and clinical settings, 27,28 and the higher expression of MET in BM than in the primary site might represent the biological rationale. 29 Limited data on cabozantinib activity toward BM from RCC were derived from under-represented subgroups or small clinical record or case reports.…”

“…29 Limited data on cabozantinib activity toward BM from RCC were derived from under-represented subgroups or small clinical record or case reports. 11,28,30,31 In the setting of BM from RCC, local treatment has a pivotal role in obtaining brain disease control. Local treatments (surgery or radiotherapy) and systemic therapy showed efficacy in controlling brain disease and prolonging survival.…”