A multi-centre phase II trial of pegylated liposomal doxorubicin and trastuzumab in HER-2 over-expressing metastatic breast cancer (MBC)

630 Background: Although combination therapy with conventional doxorubicin and trastuzumab (H) improves clinical outcome in HER-2 + MBC, a 27% cardiac dysfunction rate prevents clinical use of this combination. In a large phase III trial in MBC, pegylated liposomal doxorubicin (PLD:Caelyx®) was equally efficacious as conventional doxorubicin, but with significantly less cardiotoxicity. As well, the combination of PLD and H are synergistic in multiple breast cancer cell lines. With this rationale we performed a phase II trial of the combination of PLD and H as 1st line therapy in HER-2 + MBC, with cardiac safety as the primary end-point. Methods: Patients with measurable HER-2 + (IHC3+ or FISH positive) MBC were treated with PLD at 50 mg/m2 every 4 weeks and H at a 4 mg/kg loading then 2 mg/kg weekly. Left ventricular ejection fraction (LVEF) was assessed by MUGA at baseline and after every 2nd cycle. Prior adjuvant anthracycline exposure was allowed. Cardiac toxicity was defined as either a LVEF decline ≥ 15% regardless of absolute value; decline ≤ 10% with absolute LVEF < 45%; or symptomatic congestive heart failure (CHF). Results: 30 patients were enrolled from Aug 01 –Sept 03 from 4 Canadian centres. The median age was 59 years (31–75 years). 83% of the patients had visceral metastases, 64% had ER+ tumours and 41% had received prior adjuvant anthracyclines. A median of 5 cycles of PLD has been delivered so far (range 1–9). The mean LVEF at baseline, following cycles 2 and 4 were 63%, 59% and 60% respectively. A total of 3 patients experienced protocol-defined cardiotoxicity. No patient experienced symptomatic CHF. 27% of patients experienced grade 3 palmar-plantar erythrodysesthesia. The response rate (RR) for the evaluable cohort (n=29) was 55%. Within the 17 patients with no prior anthracycline exposure the RR was 65%. Median TTP and OS have not yet been reached. Conclusions: The combination of PLD and H is an active combination as 1st line therapy in HER-2 over-expressing MBC, with limited cardiotoxicity. This promising combination warrants further evaluation in the treatment of HER-2 over-expressing breast cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering Canada Schering Canada Schering Canada Hoffmann LaRoche; Schering-Plough

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