OP0001 Hypothyroidism as a potential biomarker of efficacy of famitinib, a novel VEGFR2 inhibitor in metastatic breast cancer

Abstract

<h3>Background</h3> Hypothyroidism is a common adverse event in patients treated with anti-VEGFR2 targeting agents and might be a valuable predictive factor of treatment efficacy. Famitinib malate is an inhibitor of multiple tyrosine kinases mainly targeting VEGFR2. The objectives of this study were to assess the efficacy and safety of famitinib in patients with heavily pretreated HER2-negative metastatic breast cancer (MBC), and to explore potential of famitinib-induced hypothyroidism and serum VEGF concentration for efficacy prediction. <h3>Methods</h3> This study enrolled patients pretreated with anthracycline, taxanes, and capecitabine, and who failed in the metastatic setting with at least one and at most two previous chemotherapy regimens. The primary endpoint was objective response rate (ORR). Famitinib was administered at 25mg per day in 4-week cycles. Thyroid function assessments including TSH, FT3, and FT4 were done at baseline and then every 4weeks. Plasma concentrations of VEGF were measured at baseline and two cycles after treatment. This trial is registered at ClinicalTrials.gov, NCT01653574. <h3>Findings</h3> 28 patients were enrolled. ORR was 14.3% and disease control rate was 46.4%. The most common grade 3 or 4 adverse events were hand-foot syndrome (25.0%), proteinuria (21.4%), and hypertension (17.9%). 64.0% of patients had raised TSH (>4.94mIU/L) at any time during the entire treatment period. Sixteen patients with a raised TSH had a significantly longer progression-free survival (PFS) than the nine patients with no TSH increase (107 versus 53days, respectively; <i>p</i>=0.002). TSH increase was also an independent prognostic factor for PFS in a Cox regression model. Plasma VEGF concentrations either at baseline or two cycles after treatment did not correlate significantly with clinical outcomes. <h3>Interpretation</h3> Famitinib showed substantial anti-tumour activity with a good safety profile in heavily pretreated patients with HER2-negative MBC. Famitinib-related TSH increase could be an early indicator of its efficacy. Serial monitoring of serum TSH might help to define VEGFR2-dependent or VEGFR2-independent drug resistance.