PD01-02: Randomized Phase II Study of Dasatinib vs Placebo in Addition to Exemestane in Advanced ER/PR-Positive Breast Cancer [BMS CA180-261 Study].
Authors: Llombart A , Ravaioli A , Strauss L , Sy O , Abrahao F , Geese WJ , Lortholary A , Rea D , Ro J-S , Sohn J , Kim S-B , Curigliano G 
Published: June 2012

Abstract
Background: Src-family kinases (SFKs) are involved in estrogen receptor (ER) and progesterone receptor (PgR) signaling pathways, in resistance to hormonal therapy, and in osteoclast function. Dasatinib is a potent oral inhibitor of SFKs and other kinases, but single-agent activity in advanced breast cancer (ABC) is limited. Biomarkers may identify patient subsets with increased benefit. In this Phase II study, the combination of dasatinib with exemestane was evaluated in patients (pts) with ER+ and/or PgR+ ABC resistant to a nonsteroidal aromatase inhibitor (NSAI).
Methods: In a randomized double-blind Phase II trial (CA180-261), 157 patients (pts) with ECOG performance status of 0–1, measurable or evaluable disease, and progression (PD) during, or within 1 year after adjuvant, treatment with an NSAI were stratified by symptomatic bone metastasis (SBM) and other factors, and assigned 1:1 to receive dasatinib (100 mg daily) or matched placebo in combination with exemestane (25 mg daily). Progression-free survival (PFS) was the primary endpoint and clinical benefit (CBR; partial response+stable disease ≥24 wks) the key secondary endpoint. The study was designed for 80% power to detect a hazard ratio (HR) of 0.67 between arms, corresponding to median PFS increase from 4 to 6 months using 1-sided α=0.1. Archival tumor samples for biomarker analysis were collected. Patient-reported pain score and a measure of bone lysis (urinary N-telopeptide, uNTX) were collected serially in pts with SBM.
Results: Planned analysis was performed after 119 events (PD or death) were recorded, at which time 129 pts had discontinued study treatment. Overall PFS comparison was non-significant (HR=0.86; 1-sided p=0.148), with median PFS of 16 weeks (95% CI 12, 18) in the placebo arm and 18 weeks (95% CI 15,24) in the dasatinib arm. Estimated free-from-progression rate at 24 weeks was 33% in placebo and 43% in the dasatinib arm. Pts with SBM, 40% of study population, had improved PFS on the dasatinib arm (HR=0.68, 1-sided p=0.094). Preliminary CBR at this analysis (31 of 38 censored pts continue on study) was higher in the dasatinib arm. Expected dasatinib-related toxicities were observed, including pleural effusion [23% (5% Gr≥3) in dasatinib vs 1% (0 Gr≥3) in placebo] and diarrhea [25% (1% Gr≥3) vs 1% (0 Gr≥3)]. Musculoskeletal adverse events (AEs) were comparable between arms, but fatigue or asthenia [37% (4% Gr≥3) vs 20% (0 Gr≥3)], skin AEs [28% (1% Gr≥3) vs 11% (0 Gr≥3)] and headache [22% (3% Gr≥3) vs 9% (0 Gr≥3)] were more common in dasatinib arm. Dose interruption or reduction was more frequent for dasatinib compared to placebo. Biomarker analyses are in progress.
Conclusion: PFS difference (HR=0.82) was not significant in overall study population, but higher CBR in the dasatinib arm and higher PFS in pts with SBM (HR=0.68) suggests that dasatinib has efficacy in a subset. The safety profile was consistent with dasatinib experience; AEs, including pleural effusion and diarrhea, were more common with dasatinib as compared with placebo. Updated efficacy and biomarker analyses will be presented.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-02.