Cabozantinib Yields Promising Intracranial Activity for Renal Cell Carcinoma Brain Metastases

Cabozantinib (Cometriq) demonstrated a tolerable safety profile and significant intercranial activity in patients with renal cell carcinoma (RCC) who have developed brain metastases, according to the results from a retrospective cohort study published in JAMA Oncology.

After a median follow-up of 17 months, those in cohort A—patients with progressing brain metastases without concomitant brain-directed local therapy—had an intercranial response rate of 55% (95% CI, 36%-73%) vs 47% (95% CI, 33%-61%) in cohort B—patients with stable or progressing brain metastases that have been concomitantly treated with local brain-directed therapy. The extracranial response rate in cohort A was 48% (95% CI, 31%-66%) with a median time to treatment failure of 8.9 months (95% CI, 5.9-12.3). Additionally, those in cohort A had a median overall survival (OS) of 15 months (95% CI, 9.0-30.0). Patients in cohort B had an extracranial response rate of 38% (95% CI, 25%-52%) with time to treatment failure of 9.7 months (95% CI, 6.0-13.2). Moreover, the median time to OS was 16 months (95% CI, 12.0-21.9).

“Leveraging the collective experience of 15 institutions, we characterized the intracranial and extracranial activity and safety profile of cabozantinib in patients with brain metastases from RCC in the largest cohort reported to our knowledge. Cabozantinib demonstrated high intracranial activity with a considerable response rate in heavily pretreated patients who had progressing intracranial disease without concomitant brain-directed local therapy,” investigators of the study said.

A total of 88 patients were treated with cabozantinib for advanced disease. Across the 15 institutions featured in this study, 38% of patients had radiological evidence of intracranial progression without concomitant brain directed local therapy at cabozantinib initiation and were a part of cohort A compared with 62% included in cohort B. Additionally, the median interval from prior brain-directed therapy to cabozantinib initiation in cohort A was 5 months. A total of 64% of patients in cohort B had intracranial progression with concomitant treatment of brain-directed local therapy, and 36% had stable intracranial disease at cabozantinib initiation.

The median time from metastatic RCC to diagnosis of brain metastases was 18 months. Investigators reported that at the time of analysis, 82% of patients discontinued treatment and 18% remained on therapy. Patients discontinued treatment due to disease progression (57%), toxic effects (11%), patient choice (4%), or for other reasons (10%).

Twenty-four percent of patients in cohort A had a single intracranial lesion, and the median number of lesions was 3. In cohort B, the median number of lesions was 2.

Investigators reported 3 complete responses (CRs) and 14 partial responses (PRs) in cohort A. A total of 10 patients experienced stable disease, and 4 patients experienced progressive disease. At 6 months, the intracranial progression rate was 25% (95% CI, 11%-41%). In cohort B, 1 patient had a CR and 24 had PRs. Six patients had a primary progressive intracranial disease as a best response, all of whom had previously received local brain-directed therapies. Patients receiving concomitant radiation had an overall response rate of 54%, and at 6 months intracranial progression was 15% (95% CI, 7%-25%) in cohort B.

Among intracranial responders, 11 patients in cohort A had an extracranial response and 6 had stable disease. Additionally, 21 patients in the cohort died. One patient experienced an extracranial CR in cohort B and 24 experienced PRs. A total of 14 patients had an extracranial response, 8 had extracranial stable disease, and 3 had progressive disease. Additionally, 36 patients died. Between both cohorts, 14% (n = 12) of patients who had intracranial progression died within 3 months.

The most common any grade adverse effects (AEs) included fatigue (77%), diarrhea (46%), palmar-plantar erythrodysesthesia (32%), and nausea (31%). A total of 15 patients had grade 3/4 AEs, with the most frequent being fatigue (7%) and mucositis (5%). No deaths were related to cabozantinib. Forty-eight patients required dose reductions and 10 patients had permeant discontinuations relating to toxic effects. No patients reported neurological toxic effects.

Reference

Hirsch L, Martinez Chanza N, Farah S, et al. Clinical activity and safety of cabozantinib for brain metastases in patients with renal cell carcinoma. JAMA Oncol. Published online October 21, 2021. doi:10.1001/jamaoncol.2021.4544