A phase 2 trial of dasatinib in patients with advanced HER2-positive and/or hormone receptor-positive breast cancer.

Abstract

PURPOSE:

SRC-family kinases (SFK) are involved in numerous oncogenic signaling pathways. A phase 2 trial of dasatinib, a potent oral tyrosine kinase inhibitor of SFKs, was carried out in patients with human epidermal growth factor receptor 2-positive (HER2+) and/or hormone receptor-positive (HR+) advanced breast cancer.

EXPERIMENTAL DESIGN:

Patients with measurable tumors and progression after chemotherapy and HER2 and/or HR-targeted agents in adjuvant or metastatic settings (maximum of two prior metastatic setting regimens) received twice daily dasatinib. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined response rate. Secondary endpoints included toxicity and limited pharmacokinetics.

RESULTS:

Seventy patients (55 years median age) were treated, 83% of HER2+ patients had received prior HER2-directed therapy, and 61% of HR+ patients had received prior endocrine therapy in the advanced setting. Dasatinib starting dose was reduced from 100 to 70 mg twice daily to limit toxicity. Median therapy duration was 1.8 months in both dose groups and most discontinuations were due to progression. Of 69 evaluable patients, three had confirmed partial responses and six had stable disease for 16 weeks or more (disease control rate = 13.0%); all nine of these tumors were HR+ (two were also HER2+). The most common drug-related toxicities were gastrointestinal complaints, headache, asthenia, and pleural effusion. Grade 3-4 toxicity occurred in 37% of patients and was comparable between doses; drug-related serious adverse events were less frequent with 70 mg twice daily than 100 mg twice daily.

CONCLUSION:

Limited single-agent activity was observed with dasatinib in patients with advanced HR+ breast cancer.

• Authors: Erica L Mayer, Jean-Francois Baurain, Joseph Sparano, Lewis Strauss, Mario Campone, Pierre Fumoleau, Hope Rugo, Ahmad Awada, Oumar Sy, Antonio Llombart-Cussac
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 21 Pg. 6897-904 (Nov 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21903773 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• Receptors, Estrogen
• Receptors, Progesterone
• Thiazoles
• Receptor, ErbB-2
• src-Family Kinases
• Dasatinib

Topics

• Administration, Oral
• Adult
• Aged
• Breast Neoplasms (drug therapy, metabolism)
• Dasatinib
• Female
• Humans
• Middle Aged
• Protein Kinase Inhibitors (adverse effects, therapeutic use)
• Pyrimidines (adverse effects, therapeutic use)
• Receptor, ErbB-2 (biosynthesis)
• Receptors, Estrogen (biosynthesis)
• Receptors, Progesterone (biosynthesis)
• Thiazoles (adverse effects, therapeutic use)
• src-Family Kinases (antagonists & inhibitors, metabolism)