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Adrenal (Excluding Mineralocorticoids)

ORF37-03 - Cabozantinib in Advanced Adrenocortical Carcinoma after standard therapy: final phase 2 trial results and the relevance of prior mitotane use

Sunday, June 14, 2026
3:30 PM - 4:15 PM CT


Background: First line treatment of advanced adrenocortical carcinoma (ACC) with mitotane and cytotoxic chemotherapy has limited efficacy. The tyrosine kinase inhibitor (TKI) cabozantinib (cabo) may be effective in second line. Mitotane induces hepatic enzymes and accelerates the clearance of drugs including TKI.

Objective: To prospectively determine the clinical activity of Cabo in patients with unresectable or metastatic ACC after failure of standard therapy. To evaluate the impact of prior mitotane exposure on cabozantinib pharmacokinetics.
Study

Design: Prospective, open-label, multicenter, single-arm phase II study (NCT03612232) with Simon two-stage accrual design. Cabo was administered orally at 60 mg daily. Radiological tumor assessment was performed every eight weeks. The protocol excluded patients with mitotane plasma levels >5 mg/L.
Primary Outcome: Proportion of progression free patients at four months (PFS4).

Results: Thirty-seven patients were enrolled; 36 underwent at least one follow-up imaging. All but three had received prior mitotane, 28 had received three or more lines of prior systemic therapy. Cabo was discontinued in two patients due to treatment-related toxicity before primary endpoint assessment despite stable disease. Among 34 evaluable patients, 14 (41%) met the primary endpoint. The probability for PFS4 was 42.5% (95%-CI 29.1-62.1). Median duration of treatment was 22 weeks. Best overall response was partial remission in two patients. Five patients achieved disease control >40 weeks. No new safety signals were observed.
At the standard dose of 60 mg, the steady-state median AUCτ,ss for cabo was 12,837 ng*h/mL (5,913–24,733) in patients with detectable plasma mitotane at baseline, which was significantly lower than in patients without prior mitotane (33,814; 30,210–35,477; p=0.0096) or with prior mitotane but undetectable baseline plasma concentration (19,945 ;10,570–37,842; p = 0.010). Higher cabo exposure was associated with a trend towards improved response at 4 months (n.s.).

Conclusion: This investigator-initiated study, the largest prospective trial of cabozantinib in ACC to date, has met its primary endpoint supporting the clinical activity of Cabo in advanced ACC. Prior mitotane in the majority of patients likely contributed to less favorable outcomes compared with a previous phase II study (NCT03370718, Campbell et al. 2025). Clinical investigation of cabo in mitotane naïve patients is needed to determine the actual efficacy of Cabo in advanced ACC.

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