P3-14-28: ANZ 0502 NeoGem: A Phase II Trial Evaluating the Efficacy and Safety of Epirubicin and Cyclophosphamide Followed by Docetaxel with Gemcitabine (+ Trastuzumab If HER2 Positive) as Neoadjuvant Chemotherapy for Women with Large Operable or Locally Advanced Breast Carcinoma.
Authors: McCarthy N , Boyle F , Bull J , Leong E , Simpson A , Kannourakis G , Gebski V , Forbes JF , Wilcken N , Lindsay DF , Badger HD 
Published: June 2012

Abstract
Background
Neoadjuvant chemotherapy may provide an early indication of treatment effect and pathologic complete response (pCR) rate is a surrogate measure of disease-free and overall survival. Anthracyclines remain an important component of chemotherapy regimens for breast cancer (BC), adding a taxane conveys additional survival benefit. Gemcitabine (G) has established safety and efficacy in metastatic breast cancer (MBC) and combining G with docetaxel (D) shows preclinical synergy but not overlapping toxicities. In MBC, efficacy of trastuzumab (T) combined with single agent taxanes and G has been demonstrated for tumours that over-express human epidermal growth factor receptor 2 (HER2+). NeoGem aimed to evaluate the efficacy and safety of neoadjuvant epirubicin (E) and cyclophosphamide (C), followed by D and G +/− T (depending on HER2 status) in women with large operable or locally advanced BC.
Methods: Eligible patients (pts), ≥18 years, had unilateral, operable (at presentation) T2 (≥3cm), T3-4, N0-1, M0 primary BC, no prior chemotherapy or hormonal therapy and ECOG status 0–2. All pts received E (90mg/m2 i.v.) in combination with C (600mg/m2 i.v.) on day 1 q 21 for 4 cycles followed by D (75mg/m2 i.v.) on day 1 in combination with G (1000mg/m2 i.v.) on days 1 and 8 q 21 for 4 cycles. HER2+ pts received T (4mg/kg loading then 2mg/kg i.v.) concurrent with DG on days 1, 8 and 15 q 21 for 4 cycles. HER2+ pts received post-surgical T (6mg/kg) 3 weekly, for a total of one year of T therapy. Using a Simon's 2 stage trial design, the decision to proceed to stage 2 followed interim analysis of stage 1. Primary endpoint, pCR, was defined as no histologic evidence of invasive cancer in the breast. Secondary endpoint, pCRax, was defined as no histologic evidence of invasive cancer in the breast and axilla. EC followed by DG/DGT was expected to achieve a pCR rate of 35% in HER2 negative (HER2−) pts and 40% in HER2+, with the lowest limit of therapeutic efficacy being a pCR rate of 22% (HER2−) and 24% (HER2+). Hence 84 HER2− and 63 HER2+ pts were needed to detect significant differences in pCR rates (power 80%, 95% level of significance).
Results: Over 32 months 81 pts (63 HER2− and 18 HER2+) were enrolled, 78 (96% [61 HER2− and 17 HER2+]) proceeded to surgery. Of 78 pts, 21 (27%) achieved pCR and 19 (24%) achieved pCRax. Of the 61 HER2− pts, 12 (20% [95% CI: 12%-31%]) achieved pCR compared with 9 (53% [95%CI: 31%-74%]) of 17 HER2+ pts. Planned chemotherapy was completed by 67 pts (83%), 9 pts (11%) discontinued due to adverse events. Thirteen pts (16%) required DG dose reductions compared with 7 (8%) pts during EC; 57 (70%) pts had ≥ grade 3 neutropenia.
Conclusion: Efficacy in the HER2− cohort did not reach predetermined levels of significance (interim analysis); HER2+ recruitment proved too slow to continue. High haematological toxicity during DG, particularly neutropenia required use of supportive therapy (GCSF). Despite relatively small patient numbers, 53% pCR in the HER2+ cohort warrants further investigation.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-28.