Phase II trial of dasatinib in triple-negative breast cancer: results of study CA180059.

Abstract

Abstract Abstract #3118 Background: Dasatinib (SprycelR; BMS-354825) is a potent orally-available inhibitor of Src-family kinases and other kinases with anti-proliferative, anti-osteoclastic and anti-metastatic activity demonstrated pre-clinically. Expression profiling suggested that basal-like cancers may be preferentially sensitive to dasatinib. Methods: A Phase II single-agent trial of dasatinib, using a continuous schedule, was performed in patients with advanced triple-negative (as proxy for basal-like) breast cancers. Subjects were required to have measurable locally-advanced or metastatic triple-negative (ER/PR-negative, Her2-normal) disease and prior anthracycline and/or taxane therapy. A 2-stage Gehan design was adopted, with RECIST-defined response as primary endpoint; subjects discontinued for toxicity were considered non-responders. The original dasatinib dose of 100 mg BID (n=21) was reduced to 70 mg BID (n=23) to improve tolerability. Biomarkers were analyzed in tumor and plasma samples obtained for PK analysis. Results: From 12/06 through 12/07, 44 subjects were treated at 14 institutions: median age 55 yrs, median time from diagnosis 30 mo, prior therapy for advanced disease in 29 (66%). Of 43 response-evaluable subjects, 7 discontinued for toxicity prior to on-study assessment. Of 36 subjects with radiographic assessment, there were 2 confirmed PR [1 continues >1 year + 1 discontinued for intolerance at week 16] plus 2 SD lasting >16 weeks. Four additional subjects had transient clinical benefit reflected by improvement in bone pain (anecdotal) or short-term tumor shrinkage (reductions of 11 - 29%). Tolerability was improved at a dose of 70 mg compared with 100 mg BID. In preliminary analysis, fewer subjects experienced any serious adverse event (13% at 70 mg BID vs 48% at 100 mg BID), fewer reported Grade 3 toxicity, including gastrointestinal (10% vs 26%), pleural effusion (4% vs 9%), generalized edema (0% vs 9%) or pericardial effusion (0% vs 9%), and fewer had dasatinib dose reduction (24% vs 61%). Fatigue, myalgia/arthralgia and headache were comparable at the two doses. No Grade 4 drug-related events occurred. Grade 3-4 abnormal laboratory values were uncommon. Biomarker and PK data will be presented. Conclusions: Modest but encouraging single-agent activity was observed with dasatinib in patients with advanced triple-negative breast cancers, with clinical benefit rate of 9.3% (4/43). Future studies are warranted to address optimal dose and schedule of dasatinib in combination with chemotherapy for this challenging tumor type. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3118.