Objective Response and Prolonged Disease Control of Advanced Adrenocortical Carcinoma with Cabozantinib

Abstract

Background: Objective response of advanced adrenocortical carcinoma (ACC) to mitotane and cytotoxic chemotherapy regimen is only ~20% and early tumor progression is frequent. Previous clinical trials with oral multikinase inhibitors were negative, which has been attributed in part to inadvertent drug interaction with mitotane. Cabozantinib (CABO) is an inhibitor of c-MET, vascular endothelial growth factor receptor 2, AXL, and RET and approved for advanced kidney cancer, liver carcinoma after previous sorafenib, and medullary thyroid carcinoma.

Objective: To investigate the clinical efficacy and safety of CABO monotherapy in ACC patients.

Design: Retrospective cohort study.

Setting: Three referral centers for ACC (Germany, United States).

Results: Sixteen patients (13 female) with progressive ACC received CABO after previous mitotane in 15/16 and 3 (median, range 0-8) further systemic treatments. Prior CABO therapy, mitotane was discontinued in all patients. Mitotane plasma concentration was <2 mg/L in 7/16 patients and discontinued >12 months in 6 additional patients before CABO use. In 4/5 cases with available plasma samples, CABO concentration was in the expected steady-state range. Adverse events of grade 1/2 and 3 were observed in 13 and 3 patients, respectively, and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 5, and progressive disease in 8 patients. Median progression-free and overall survival was 16 and 58 weeks, respectively.

Conclusion: CABO monotherapy appears to be safe and effective as a monotherapy in advanced ACC after failing prior treatments. Therefore, prospective investigation of CABO in ACC patients is warranted.

Keywords: ACC; adrenal cancer; cabozantinib; tyrosine kinase inhibitors.

© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

FDG-PET-CT of a 51-year-old patient with metastatic ACC (A) at baseline and (B) 3 months after treatment initiation with CABO shows evidence of pronounced metabolic response of the primary tumor and both lung and liver metastases. ACC, adrenocortical carcinoma; CABO, cabozantinib; FDG-PET-CT, fluorodeoxyglucose positron emission tomography computed tomography.

Figure 2.

Plasma concentrations of CABO in 4 patients with available samples. The shaded area is the expected 95% confidence interval of steady-state concentration in a mixed population of male and female patients with 60 mg CABO tablets (mean: straight line). Identification of individual patients given, in brackets: sex, mitotane plasma concentration prior CABO, best response. *Mitotane had been discontinued for 21 months and **93 months before CABO. CABO, cabozantinib.

Figure 3.

(A) Progression-free and (B) overall survival of patients treated with CABO. CABO, cabozantinib.