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Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial.

CONTEXT
Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib.


OBJECTIVE
The objective of the study was to determine the antitumor effects of sunitinib in refractory ACC.


DESIGN
This was a phase II, open-label trial using a two-stage accrual design.


SETTING
The study was conducted at two tertiary referral centers.


PATIENTS
Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study.


INTERVENTION
The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off).


MAIN OUTCOME MEASURE
Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation).


RESULTS
Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction.


CONCLUSION
Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.