Activity of Cabozantinib in Radioresistant Brain Metastases From Renal Cell Carcinoma

Two Case Reports

Sylvie Négrier; Guillaume Moriceau; Valéry Attignon; Véronique Haddad; Daniel Pissaloux; Nicole Guerin; Christian Carrie


J Med Case Reports. 2018;12(351) 

In This Article

Case Presentation

Case 1 is a 51-year-old man of North African origin with a history of hypertension who had been diagnosed as having a right kidney tumor associated with one bulky pleural metastasis and some smaller metastatic lesions of the lung; Case 1 is summarized in Figure 1. No bone or brain metastases were observed at initial work up; he was classified in the poor risk group according to the International Metastatic RCC Database Consortium (IMDC).[12] A radical nephrectomy was performed in July 2012. A pathological report indicated a renal cell carcinoma (RCC) of 16 cm with a clear cell component and some degree of a more aggressive cellular component, giving a Fuhrman grade of 4, pT3a pN0 M1 according to the Union for International Cancer Control (UICC) classification. Sunitinib, 50 mg/day, then reduced to 37.5 mg due to side effects, was administered during 6 months. Because of the painful progression of the pleural metastasis in the upper part of his left lung, radiation therapy was delivered to this tumor. Systemic treatment was further modified for the approved second-line treatment everolimus. This latter treatment induced a significant tumor response in most metastatic sites for 15 months before re-progression. In March 2014, our patient complained of persistent headaches and brain magnetic resonance imaging (MRI) identified a single right frontal metastasis. Stereotactic radiotherapy was performed and a treatment with axitinib, a second-line TKI directed against VEGFrs, was started. Axitinib induced significant tumor shrinkage in the pleural and lung metastases; the brain metastasis was much improved because a brain MRI was considered almost normal. Axitinib was maintained for 18 months, but had to be completed because of a severe episode of angina pectoris. A coronary stent that required dual anti-platelet therapy for 6 months was indicated. Due to an increased hemorrhagic risk with this treatment together with a VEGFr inhibitor, axitinib was not resumed; nivolumab, a programmed death-1 (PD1) directed antibody recently approved for mRCC treatment, was administered as part of a compassionate program. Our patient was admitted with seizures and vertigo 4 months after immunotherapy initiation. A brain MRI evidenced the enlargement, with some hemorrhagic traits, of the previously treated metastasis. Further to therapeutic control of his neurological symptoms, a thoracic and abdominal computed tomography (CT) scan showed the progression of the disease at all metastatic sites. He then entered a genetic profiling experimental program (NCT 01774409) and sequencing of the primary tumor was performed. Due to the long duration of this analysis, cabozantinib that had been recently made available was administered after our patient gave consent. All neurological symptoms disappeared and his performance status (PS) score improved to 0 after 2 weeks of treatment with cabozantinib. A brain MRI and thoracoabdominal CT scan at 8 weeks indicated a significant shrinkage of the metastatic lesions including the brain metastasis (Figure 2). Treatment was rather well tolerated but had to be reduced to 40 mg per day instead of 60 mg, due to fatigue, stomatitis, and loss of weight. Cabozantinib is ongoing with a reduced dose of 40 mg/day with a maintained efficacy over 8 months. Meanwhile, results of the tumor sequencing indicated the expression of mutation of the MET gene.

Figure 1.

Case 1 timeline. CT computed tomography, MRI magnetic resonance imaging

Figure 2.

Brain magnetic resonance imaging of Case 1. a July 2016, b December 2016, c May 2017 4 months under cabozantinib

Case 2 is a 55-year-old European man with a history of hypertension who presented to the emergency room with seizures in December 2013; Case 2 is summarized in Figure 3. A brain CT scan and further MRI showed three tumors surrounded by cerebral edema. A left kidney tumor and two lung nodules were identified by CT scan and, finally, clinical examination found some hypervascularized lesions of his scalp. The cutaneous tumors were surgically removed and the pathological report identified metastases of a type 2 papillary renal tumor. This patient was classified in the favorable risk group according to the International Metastatic RCC Database Consortium (IMDC).[12] Brain metastases were all treated by stereotaxic radiation. Pazopanib another TKI directed to VEGFr was initiated at 800 mg/day. This treatment induced a partial response in lung metastases and in the primary renal tumor; the three brain metastases were also reduced. The disease remained stable for 2.5 years under pazopanib, except in his brain. In fact, two new brain metastases appeared 12 months later and three others after 24 months. Stereotaxic radiation was performed on each new brain tumor and pazopanib at 800 mg per day was resumed. Some neurological symptoms appeared with several transient episodes of aphasia together with some degree of mental confusion, 4 months after the last radiation treatment. Pazopanib treatment was completed and brain MRI indicated a radionecrosis with surrounding cerebral edema in one of the recently irradiated brain metastases. Two months after pazopanib completion, a CT scan showed significant progression in all other metastatic sites including previously irradiated brain metastases. Cabozantinib was started after our patient gave consent. Neurological symptoms rapidly resolved and a brain MRI at 2.5 months evidenced tumor regression of the different brain metastases (Figure 4). Cabozantinib was ongoing for 6 months but had to be reduced to 40 mg/day due to grade 3 diarrhea. Sequencing was performed on the metastatic tumor sample but no MET mutation was identified and no MET gene amplification was observed.

Figure 3.

Case 2 timeline. CT computed tomography, MRI magnetic resonance imaging

Figure 4.

Brain magnetic resonance imaging of Case 2, effect of cabozantinib after 2.5 months