Phase II Study of Sorafenib with Anastrozole To Overcome Resistance to Aromatase Inhibitors (AIs) in Patients with Hormone Receptor Positive (ER/PR+) AI Resistant Metastatic Breast Cancer (MBC).

Abstract

Abstract Background: Studies are focusing on agents which may overcome endocrine therapy resistance in patients with hormone receptor positive (ER/PR+) MBC. Activation of the Ras-Raf-MAPK pathway has been proposed as a mechanism of resistance to AIs. Thus, we are evaluating the use of sorafenib (SOR), a multi (Raf)-kinase inhibitor targeting both tumor cells and the tumor vasculature in patients with AI-resistant MBC.Methods: We are conducting a phase I/II study of SOR in combination with anastrozole 1 mg po daily (ANT) in MBC patients utilizing an optimal 2-stage design. Eligible patients include post-menopausal women with ER/PR+ MBC with disease recurrence or progression on an AI. Participants may not have received > 2 prior chemotherapies for MBC. Primary objectives are to determine the recommended dose and clinical benefit rate (CBR) (CR, PR and SD ≥ 24 weeks) of SOR with ANT. Secondary objectives are to determine toxicity, enumerate circulating endothelial cells (CECs) as an angiogenesis biomarker, and analyze the effect of treatment on CYP3A4-metabolized steroids.Results: 0/3 patients in cohort 1 (200mg BID) and 0/3 in cohort 2 (400mg BID) had dose-limiting toxicities in cycle 1. Thus, our recommended Phase II dose of SOR was 400 mg BID. Interim analysis of the first 12 patients showed >30% CBR, allowing for continued accrual to planned 35 patients. All patients had ECOG PS of 0-2. The median age was 55 years. Among 35 enrolled patients, 5 had stable disease for > 24 weeks, 2 had durable PR > 6 months, and 19 had progressive disease before 6 months. 8 patients were not response-evaluable. 1 patient on active therapy is too early to evaluate response. Clinical benefit rate is 20%. Adverse events (AEs) were generally Grade 1/2. The most common AEs (all; Grade 3/4) were fatigue (66%; 14%), diarrhea (54%; 6%), nausea/vomiting (60%; 9%), and skin rash of any kind (66%; 43%) including hand-foot syndrome (57%; 34%). G3/4 hypertension occurred in 11%. Preliminary analysis suggests that decrease in CECs from baseline to 1 week after treatment predicts for a response. Correlative science analyses are ongoing.Conclusions: The combination of SOR and ANT in patients with ER/PR+ AI-resistant MBC demonstrated an encouraging 20% CBR and is worthy of further study. A decrease in CECs appears to predict response. Toxicity with 400 mg po bid SOR occurred frequently but was manageable with dose reductions. Given the negligible activity of single-agent SOR in MBC, we believe that the benefit may be attributable to the restoration of sensitivity to AIs through inhibition of the Ras-Raf-MAPK pathway. Supported Patient for Progress Award 3 P30CA051008-15S3 and Sorafenib provided by CTEP-NCI. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3090.