Dr Toni Choueiri
The tyrosine kinase inhibitor cabozantinib has shown promising activity against brain metastases in patients with renal cell carcinoma (RCC), achieving a 50% response rate, according to US researchers.
A retrospective cohort study involving 88 patients with metastatic RCC and brain metastases treated in 15 international institutions showed that cabozantinib could potentially pass through the blood-brain barrier to reach the metastases, the authors said.
In a report published in JAMA Oncology, they said cabozantinib has been approved to treat advanced RCC, but it has undergone very little testing in patients with brain metastases who are are typically excluded from clinical trials out of concern for poor life expectancy and poor treatment tolerability.
Clinicians at the Dana-Farber Institute, Boston, therefore analysed outcomes for two cohorts of patients treated with the drug: cohort A comprised 33 patients with progressing brain metastases without concomitant brain-directed local therapy, and cohort B comprised 55 patients with stable or progressing brain metastases concomitantly treated by brain-directed local therapy
With a median follow-up of 17 months, the intracranial response rate was 55% (95% CI, 36%-73%) and 47% (95% CI, 33%-61%) in cohorts A and B, respectively.
In cohort A, the extracranial response rate was 48% (95% CI, 31%-66%), median time to treatment failure was 8.9 months (95% CI, 5.9-12.3 months), and median overall survival was 15 months (95% CI, 9.0-30.0 months).
In cohort B, the extracranial response rate was 38% (95% CI, 25%-52%), time to treatment failure was 9.7 months (95% CI, 6.0-13.2 months), and median overall survival was 16 months (95% CI, 12.0-21.9 months).
Cabozantinib was well tolerated, with no unexpected toxic effects or neurological adverse events reported. No treatment-related deaths were observed.
Senior author Dr Toni Choueiri, director of the Lank Center for Genitourinary Oncology at the Institute, said the promising findings supported prospective studies of the drug in this patient group, whose poor prognosis had created a significant unmet need.
Dr Choueiri said brain metastases occurred in 10% to 15% of patients with metastatic renal cell carcinoma and were usually treated with surgery and/or radiation. Systemic treatment with targeted drugs like sunitinib had proven relatively ineffective, and immunotherapy drugs had not shown much benefit either.
“A lot of drugs that work well outside the brain don’t work well for brain metastases,” he noted.
Dr Choueiri said the study had been prompted by previous case reports of cabozantinib in renal cancer patients with brain metastases suggesting potential benefit.
“Given the sparse literature and high clinical need, we sought to assess the activity and safety of cabozantinib in patients with brain metastases from renal cell cancer, leveraging an international multicenter collaboration,” the researchers explained.
However, while the response rate that was higher than what would usually be expected, he cautioned, some of the responses were not durable and the tumours became resistant after several months.
A prospective phase II trial of cabozantinib is now under way in France, “and hopefully this will be definitive,” he said.