Exploratory Analysis of the Relationship Between Her2 Expression (BY QRT-PCR) and Efficacy with First-Line Trastuzumab Emtansine (T-DM1) Vs Trastuzumab Plus Docetaxel (HT) in a Randomized Phase 2 Study of Patients (PTS) with HER2-Positive MBC

ABSTRACT Background In TDM4450g (NCT00679341), 137 pts with HER2-positive MBC and no prior treatment for metastatic disease were randomized to T-DM1 or HT. Median progression-free survival (PFS) was 14.2 vs 9.2 mo, respectively (HR = 0.594); objective response rates (ORR) were 64.2% and 58.0%, respectively (Hurvitz 2011). In exploratory analyses of single-arm phase 2 MBC studies of T-DM1, greater expression of HER2 mRNA (assessed by qRT-PCR) was associated with greater ORR and longer PFS (Burris 2011; Krop 2012, in press). We now report a retrospective exploratory analysis of the relationship between qRT-PCR HER2 expression and efficacy outcomes in pts receiving T-DM1 or HT in TDM4450g. Table: 226P Median pre-treatment HER2 levels, concentration ratio units (range) HT T-DM1 (n = 61) 8.7 (0.5-105.0) (n = 55) 10.3 (0.4-103.0) Median PFS, months HER2 expression HT T-DM1 Hazard ratio relative to HT (95% CI) Low (n = 32) 9.8 (n = 26) 10.6 0.85 (0.44-1.67) High (n = 29) 8.8 (n = 29) Not reached 0.39 (0.18-0.85) ORR, % HER2 expression HT T-DM1 Odds ratio relative to HT (95% CI) Low (n = 31) 58.1 (n = 26) 53.8 0.84 (0.30-2.41) High (n = 29) 65.5 (n = 29) 72.4 1.58 (0.50-4.98) Methods Pts were randomized 1:1 to T-DM1 3.6 mg/kg q3w or H 6 mg/kg q3w (8 kg/mg in cycle 1) + T 75 or 100 mg/m2 q3w and treated until disease progression. HER2 expression was measured by qRT-PCR in archival tissue samples from all randomized pts. Efficacy outcomes included investigator-assessed PFS and ORR. The analysis results presented here are based on the clinical data with a median follow-up of ∼14 mo in each arm. Results In total, 122 tumor samples from 137 randomized pts were available for analysis of pre-treatment HER2 by qRT-PCR, resulting in a valid result for 116 pts (6 samples were below the limit of quantification). Efficacy outcomes by low ( Conclusions These results from an exploratory analysis suggest that the magnitude of efficacy from T-DM1 vs HT may correlate with HER2 expression levels (by qRT-PCR); this effect appears to be most pronounced for PFS. Analyses exploring the relationship between these findings and baseline characteristics are planned. Similar analyses are planned for ongoing phase 3 studies of T-DM1. Disclosure S. Hurvitz: SA Hurvitz has received support for study-related travel from Roche and research funding for her institution from Roche. L.C. Amler: Dr. Amler is employed by Genentech and has stock ownership in F. Hoffmann-La Roche. V. Ng: Dr. Ng is employed by Genentech and has stock ownership in F. Hoffmann-La Roche. E. Guardino: Dr. Guardino is employed by Genentech and has stock ownership in F. Hoffmann-La Roche. L. Gianni: L Gianni has had compensated consultant/advisory relationships with Genentech/Roche, GlaxoSmithKline and Pfizer. All other authors have declared no conflicts of interest.