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The tyrosine kinase inhibitor (TKI) cabozantinib (Cabometyx) showed promising activity against brain metastases from renal cell carcinoma (RCC), researchers reported.

In a retrospective cohort study of 88 patients with RCC brain metastases, the intracranial response rate with cabozantinib was 55% (95% CI 36-73%) in those with progressing brain metastases without concomitant brain-directed local therapy (cohort A), and 47% (95% CI 33-61%) in patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy (cohort B).

In addition, extracranial response rates were 48% (95% CI 31-66%) and 38% (95% CI 25-52%) in cohorts A and B, respectively, while median overall survival (OS) was 15 months (95% CI 9.0-30.0) and 16 months (95% CI 12.0-21.9), in the two groups, according to Toni Choueiri, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

"In the absence of consensus guidelines and prospective data, this international retrospective experience provides evidence that cabozantinib generally can be administered safely and is active in this relatively large population with poor prognosis, as reflected in the poor OS despite cabozantinib intracranial activity," the researchers wrote in .

In addition, they noted, cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events (AEs), and no treatment-related deaths.

The investigators explained that while results from the and trials have established a role for cabozantinib in patients with advanced RCC, neither of those studies included patients with progressive brain metastases.

However, case reports, as well as a , have suggested that cabozantinib can cross the blood-brain barrier and treat brain metastases, the team added.

The new multicenter international study included patients (78% of whom were male, median age 61) treated with cabozantinib from January 2014 to October 2020 in 15 international institutions. Cohort A included 33 patients while cohort B included 55 patients.

The median interval from prior brain-directed therapy to the initiation of treatment with cabozantinib was 5 months, the researchers said. Cabozantinib was administered as a second-line treatment in 27% of patients, and as third-line or beyond in 68%, with previous treatments including VEGFR TKIs in 77% of patients and single-agent PD-1 checkpoint inhibitor therapy in 55%.

At a median follow-up of 17 months, the team reported the following for cohorts A and B, respectively:

• Complete responses: 10% and 2%
• Partial responses: 45% in each cohort
• Stable disease: 32% and 42%
• Progressive disease: 13% and 11%

Of the 17 patients in cohort A with an intracranial response, 11 had an extracranial response and six had extracranial stable disease. Of the 25 patients in cohort B with intracranial response, 14 had extracranial responses, eight had extracranial stable disease, and three had extracranial progressive disease as the best response.

Median time to treatment failure was 8.9 months (95% CI 5.9-12.3) in cohort A, and 9.7 months (95% CI 6.0-13.2) in cohort B.

The most common treatment-related AEs of any grade were fatigue (77% of patients), diarrhea (46%), palmar-plantar erythrodysesthesia (32%), and nausea (31%), while grade 3/4 treatment-related AEs were reported in 15 patients -- most frequently fatigue (7%) and mucositis (5%). There were no cabozantinib-related deaths.

Dose reductions were required in 48 patients, with 10 permanent discontinuations owing to toxic effects, and there were no neurological AEs, the researchers reported.

"Further investigations are needed to confirm the present findings and to extend evaluation to more symptomatic or aggressive cases not included in this study," Choueiri and co-authors wrote, adding that the French prospective phase II trial is evaluating cabozantinib in patients with brain metastases from metastatic RCC.

Study limitations, the researchers said, included the retrospective nature; the lack of central radiological review for all cases, which might have affected assessment of tumor responses; and the lack of information about concomitant use of systemic corticosteroids with cabozantinib, which could have influenced the neurological and radiological assessments.

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