Abstract PD07-01: Phase 2 Study of Ixabepilone Versus Paclitaxel as Neoadjuvant Therapy for Early Stage Breast Cancer with Comparative Biomarker Analysis

Abstract

Abstract Background: Anthracyclines (A) and taxanes (T) are standard neoadjuvant treatments for breast cancer (BC), achieving pathologic complete response (pCR) rates of 20-30% in unselected patient (pt) populations. Ixabepilone (ixa) is approved for treatment of metastatic BC: plus capecitabine (Cap) in pts progressing after A and T or as monotherapy after progression on A, T and Cap. Prior data suggest that overexpression of βIII tubulin is associated with resistance to paclitaxel (P) while activity of ixa was unaffected. We present the first randomized comparison of neoadjuvant ixa and P in early stage BC. Primary objectives were to estimate pathologic complete response rate (pCR) in the overall population and in biomarker-defined populations. Methods Pts with early stage BC were biopsied for immunohistochemical (IHC) and mRNA biomarker analyses prior to chemotherapy. Following 4 cycles of doxorubicin/cyclophosphamide (AC), pts were randomized to either every 3 week ixa (40mg/m2:4 cycles) or weekly P (80mg/m2:12 doses). Post-therapy surgery and pathological reports were used to assess pCR. Baseline βIII expression was assessed via a standardized IHC assay (Dako, CA) and predefined single gene mRNA markers (including TUBB3, CAPG, TACC3) were assessed via Affymetrix gene expression profilling. The pCR rate and cutoff for biomarker positivity were estimated using a cross-validation method. Secondary endpoints in the study included clinical objective response rate and safety. Results Pts (N=384) were enrolled in 15 countries: 313 pts were treated with AC. 295 pts were randomized; 289 were treated with either ixa or P. Of these, 247 (123, ixa; 124, P) had βIII IHC data and 231 (114, ixa; 117, P) had both pathologic and βIII IHC data. Baseline characteristics were balanced between arms, including triple negative pts (TN, 49%). The pCR rate in all randomized pts was 24.3% (90% CI: 18.6-30.8) with ixa and 25.2% (90% CI: 19.4-31.7) with P. pCR rates were similar regardless of sub-group. Table 1. pCR rates No significant interaction was observed between βIII expression and treatment arms (logistic regression analysis). Secondary efficacy measures were consistent with the pCR results. No clinically meaningful differences in efficacy endpoints were noted between ixa and P with mRNA markers (TUBB3, CAPG and TACC3; analyses are ongoing with others). The safety profiles of ixa and P were similar, including incidence of peripheral neuropathy (Grade 3/4: ixa 4.1% vs P 3.5%). An exception was greater neutropenia with ixa (Grade 3/4; 41.3% versus 8.4% with P) although there was no difference in the rate of febrile neutropenia (0.7%). Summary Overall, the results indicated that ixa had similar efficacy to P when measured by pCR in the neoadjuvant BC setting. No clinically meaningful differences were noted in the efficacy profile of ixa compared to P across the subsets analyzed. Ixa or P following AC was well tolerated with similar safety profiles. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-01.