A Randomized Phase II Study of Eribulin/Cyclophosphamide or Docetaxel/Cyclophosphamide as Neoadjuvant Therapy in Operable HER2-negative Breast Cancer.

BACKGROUND: Eribulin mesylate is a non-taxane microtubule inhibitor effective in the treatment of metastatic breast cancer refractory to anthracyclines and taxanes. In preclinical studies, additional mechanisms of eribulin included reversal of epithelial mesenchymal transition and tumor vascular remodeling. The present study compared the safety and efficacy of eribulin plus cyclophosphamide (ErC) to docetaxel plus cyclophosphamide (TC) as neoadjuvant therapy for operable HER2- breast cancer. PATIENTS AND METHODS: Women with invasive HER2- breast adenocarcinoma with no distant metastases were eligible. After a 10-patient safety lead-in, the patients were randomized 2:1 to receive either ErC (eribulin 1.4 mg/m2 on days 1 and 8 plus cyclophosphamide 600 mg/m2 on day 1) or TC (docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1) administered every 21 days for 6 cycles, followed by surgery. The pathologic complete response (pCR) rate was the primary endpoint. Tumor samples collected at baseline and at surgery were assayed for select epithelial mesenchymal transition and vascular density markers: E-cadherin, vimentin, and CD31 expression. RESULTS: A total of 76 patients were enrolled. Of the 76 patients, 10 received ErC in the lead-in phase and 66 were randomized to ErC (n = 44) or TC (n = 22). The pCR rates with ErC and TC were 13% and 9%, respectively. Both regimens produced frequent neutropenia and peripheral neuropathy. Both regimens increased vascular density as measured by CD31 staining. CONCLUSION: The neoadjuvant regimens of ErC and TC resulted in relatively low pCR rates in this patient population. No unexpected toxicities were observed. Our results also provided no suggestion that ErC is a neoadjuvant treatment with greater efficacy than that of standard regimens.

Cabazitaxel Plus Lapatinib as Therapy for HER2+ Metastatic Breast Cancer With Intracranial Metastases: Results of a Dose-finding Study.

BACKGROUND: Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood-brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood-brain barrier. The present phase II study (ClinicalTrials.gov identifier, NCT01934894) evaluated the combination of these agents to treat HER2+ MBC patients with CNS metastases. MATERIALS AND METHODS: Patients with HER2+ MBC and ≥ 1 untreated or progressive, measurable CNS metastasis were eligible. Using a 3+3 dose escalation design, patients were treated with escalating doses of intravenous cabazitaxel every 21 days and oral lapatinib daily in 21-day treatment cycles. Intracranial disease restaging was performed every 2 cycles for the first 8 cycles and then every 3 cycles until progression or unacceptable toxicity. RESULTS: Eleven patients were treated at 2 dose levels. Six patients were treated at dose level 1 (intravenous cabazitaxel 20 mg/m2 plus oral lapatinib 1000 mg daily), and five were treated at dose level 2 (intravenous cabazitaxel 25 mg/m2 plus oral lapatinib 1000 mg daily). The most common treatment-related adverse events were myelosuppression, diarrhea, fatigue, and skin toxicity. A total of 5 dose-limiting toxicity events occurred. No intra- or extracranial objective responses were observed. CONCLUSION: The combination of cabazitaxel plus lapatinib was not feasible because of toxicity and because no objective CNS activity was seen in the 5 evaluable patients. The role of cabazitaxel to treat breast cancer patients with CNS metastases remains undefined.