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 (HER2þ) and/or hormone receptor-positive (HRþ) 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 HER2þ patients had received prior HER2-directed therapy, and 61% of HRþ 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 ¼ 13.0%); all nine of these tumors were HRþ (two were also HER2þ). 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 HRþ breast cancer. Clin Cancer Res; 17(21); 6897-904. Ó2011 AACR.

Phase II Trial of Dasatinib in Patients with Metastatic Breast Cancer Using Real-Time Pharmacodynamic Tissue Biomarkers of Src Inhibition to Escalate Dosing

“…These results are in contrast to 2 recent phase II studies that also evaluated single-agent dasatinib for advanced breast cancer (19,20). In the first study, Finn and colleagues treated 44 patients with triple-negative MBC, 66% of whom had received prior therapy for advanced disease, and showed a clinical benefit rate (defined as partial response or stable disease lasting at least 16 weeks) of 9.3% (19).…”

“…In the first study, Finn and colleagues treated 44 patients with triple-negative MBC, 66% of whom had received prior therapy for advanced disease, and showed a clinical benefit rate (defined as partial response or stable disease lasting at least 16 weeks) of 9.3% (19). In the second study, Mayer and colleagues treated 68 patients with HER2-amplified and/or HR-positive MBC, 93% of whom had received prior therapy for metastases, and showed a clinical benefit rate of 19%; interestingly, all patients who achieved some degree of disease control were HR-positive (20). Both studies showed that tolerability of dasatinib was better when the dose was reduced from 100 mg twice daily to 70 mg twice daily.…”

Gene Signature–Guided Dasatinib Therapy in Metastatic Breast Cancer

“…For specimens that passed QC, the median time from biopsy procedure to prediction results was 7 days (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Among the 30 patients who tested positive for at least one gene signature, 7 were positive for two different signatures (5 were double-positive for the DTI plus the cell line-derived sensitivity signature and 1 patient each for DTI plus SRC pathway and SRC pathway plus cell line-derived sensitivity signature).…”

“…One study included patients with triple-negative disease and the other, patients with hormone receptor or Her-2-positive cancers. Both studies showed limited antitumor activity, with objective response rates of 4.7% and 5.6%, respectively (6,7).…”

A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy

“…This may have resulted in decreased physiologic reserve as shown by the 44% frequency of ECOG PS of 0 compared with 60% of ECOG 0 patients in the aforementioned study [14]. Similar toxicities and short treatment times were observed in patients with advanced breast cancer treated with dasatinib following previous chemotherapy [18,19]. Recently reported results of the READY trial showed that the addition of dasatinib to docetaxel failed to prolong overall survival in patients with metastatic CRPC [20].…”