Cabozantinib Displays Significant Intracranial Activity in Metastatic RCC

Cabozantinib (Cabometyx) demonstrated significant intracranial and extracranial responses in patients with metastatic renal cell carcinoma (RCC) who have brain metastases, according to results of a retrospective analysis presented at the 2021 Genitourinary Cancers Symposium.

Results showed that in patients with uncontrolled brain metastases at baseline (n = 25) who received cabozantinib, the intracranial response rate was 61% (95% CI, 39%-80%); this comprised a 13% complete response (CR) rate and a 48% partial response (PR) rate. Thirty percent and 9% of patients experienced stable disease (SD) and progressive disease (PD), respectively.

In those who had controlled brain disease at baseline (n = 44), the intracranial response rate was 57% (95% CI, 41%-72%), which included all PRs. The SD and PD rates were 31% and 12%, respectively.

“This is the largest cohort of patients with metastatic renal cell carcinoma with concomitant brain metastases treated by cabozantinib,” lead study author Laure Hirsch, MD, of the Department of Medical Oncology, Cochin Hospital, Paris Descartes University, in Paris, France, said in a poster presentation of the data. “Cabozantinib was associated with high intracranial activity with a considerable response rate in patients with uncontrolled intracranial disease.”

The FDA approved cabozantinib in December 2017 as a treatment for previously untreated patients with advanced RCC. Most recently, in January 2021, the FDA approved the combination of nivolumab (Opdivo) plus cabozantinib for the frontline treatment of patients with advanced RCC.

In the multicenter, international analysis, investigators identified 69 patients with metastatic RCC and brain metastases across 15 institutions who were treated with single-agent cabozantinib. The trial was stratified into 2 cohorts: those with progressing intracranial metastases (n = 25) and those with non-progressing/controlled intracranial metastases (n = 44).

Eighty-seven percent of patients were identified as International Metastatic RCC Database Consortium intermediate or poor risk, and 75% had received cabozantinib in the second- or later-line setting. Sixty-five percent of patients in cohort 1 received prior brain-directed therapy, such as radiation therapy or surgery, versus 93% of patients in cohort 2.

At the time of the analysis, 23% of patients remained on treatment; 52% had discontinued due to disease progression, while 9% stopped treatment for toxicity-related reasons.

Intracranial and extracranial responses were assessed by RECIST v1.1 criteria.

Additional data showed that the extracranial response rate in cohorts 1 and 2 were 52% and 41%, respectively. Two patients were unevaluable in each cohort due to lesion sizes being less than 5 mm.

In cohort 1, the median time-to-treatment failure (TTF) was 9.9 months (95% CI, 5.9-14.0) and the median overall survival (OS) was 14.7 months (95% CI, 7.7-23.0). In cohort 2, the median TFF and OS were 9.0 months (95% CI, 4.6-11.4) and 14.1 months (95% CI, 11.0-22.0), respectively.

Investigators also measured the cumulative incidence of brain progression and safety. In cohort 1, 16% (95% CI, 4%-33%) of patients had disease progression in the brain compared with 9% (95% CI, 3%-12%) in cohort 2.

Regarding safety, there were no unexpected adverse events (AEs); the most common AEs included fatigue (79%), diarrhea (46%), and nausea (32%). Nine patients (13%) experienced grade 3/4 AEs, but no neurological toxicities were reported. Thirty-eight patients (55%) required dose reductions.

Hirsch noted that central review of imaging and the addition of more patients to this trial is ongoing.

The ongoing, prospective, multicenter, phase 2 CABRAMETtrial (NCT03967522) is evaluating the efficacy and safety of cabozantinib in patients with metastatic RCC who have brain metastases. Additionally, the phase 3 COSMIC 313 trial (NCT) is looking at the combination of cabozantinib plus nivolumab and ipilimumab (Yervoy) in previously untreated patients with advanced RCC, including those with brain metastases.

Reference

Hirsch L, Chanza NM, Farah S, et al. Activity and safety of cabozantinib (cabo) in brain metastases (BM) from metastatic renal cell carcinoma (mRCC): An international multicenter study. J Clin Oncol. 2021;39(suppl; abstr 310). doi:10.1200/JCO.2021.39.6_suppl.310