Dasatinib in advanced HER2/neu amplified and ER/PR-positive breast cancer: Phase II study CA180088

Abstract

1011 Background: SRC family kinases (SFKs) are involved in numerous signaling pathways including from ER and HER-2 receptors, as well as osteoclast function. Dasatinib is a potent oral inhibitor of SFKs. A phase II trial was performed in patients (pts) with ER+ and/or PR+ and/or HER-2-amplified progressive advanced breast cancer. Subsequent to study initiation, dasatinib demonstrated similar efficacy with a lower incidence of key side-effects at 100 mg once daily in CML and prostate cancer. Methods: Pts with measurable disease and progression after chemotherapy and other targeted agents were treated with dasatinib on a continuous twice-daily (BID) schedule; RECIST-defined response rate was primary endpoint. Results: Sixty-eight pts, 24 with HER-2-amplified and 44 with HER-2-normal, ER+ and/or PR+ disease, were treated. Original starting dose of 100 mg BID (23 pts) was reduced to 70 mg BID (45 pts) due to fluid retention, fatigue, or GI toxicity. Median age was 55 years; nearly all pts (93%) had prior therapy in advanced setting. 59 were radiographically-evaluable (8 discontinued for toxicity and 1 inevaluable). We observed 3 partial responses lasting 9, 9 and 8+ mos plus 6 stable disease ≥16 weeks (range 24–33 wks). All 9 controlled tumors were ER/PR+, 2 were also HER-2-amplified; thus, disease control rate was 19% in the 47 radiographically-evaluable pts with ER/PR+ disease. Median dose intensity was 136 mg/day at 70 mg BID and 175 mg/day at 100 mg BID; median duration of therapy was 1.8 mos in both dose groups. Most pts (75%) discontinued for disease progression. The most common drug-related AEs were diarrhea (49%), headache (34%), nausea (34%), asthenia (32%), pleural effusion (31%), musculoskeletal pain (25%), and vomiting (24%). Drug-related grade 3–4 AEs were reported in 37% of pts and comparable between doses, but related serious AEs were less frequent at 70 mg BID than 100 mg BID (16% vs 26%). Grade 3–4 laboratory abnormalities were uncommon. PK and biomarker analyses will be presented. Conclusions: Encouraging single-agent activity was observed with dasatinib in pts with advanced ER+ breast cancers. Future studies will address the combination of dasatinib with hormonal therapies using a better-tolerated once daily schedule. [Table: see text]