Presentation Abstract

Abstract Number: LB-63
Presentation Title: Relationship between tumor biomarkers (BM) and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC)
Presentation Time: Sunday, Apr 07, 2013, 3:00 PM - 3:20 PM
Location: Ballroom A-B, Washington Convention Center
Author Block: José Baselga, Sunil Verma, Jungsil Ro, Jens Huober, Ellie Guardino, Liang Fang, Steven Olsen, Gail Lewis Phillips, Sanne De Haas, Mark Pegram. Mass. General Hospital Cancer Center Administration, Boston, MA, University of Toronto, Sunnybrook Odette Cancer Centre, Toronto, ON, Canada, Center for Breast Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, Korea, Republic of, University of Duesseldorf, Duesseldorf, Germany, Genentech, Inc and Stanford University, South San Francisco, CA, Genentech, South San Francisco, CA, F. Hoffmann-La Roche, Basel, Switzerland, Stanford University School of Medicine, Stanford, CA
Abstract Body: Background: The antibody-drug conjugate T-DM1 retains the mechanisms of action of trastuzumab, including HER2 targeting and interruption of HER2 signaling, and provides a means of delivering the cytotoxic agent DM1 directly to HER2-positive tumors. In the EMILIA study, T-DM1 demonstrated a statistically significant progression-free and overall survival (PFS, OS) benefit with less toxicity vs capecitabine plus lapatinib (XL) in patients (pts) with previously treated HER2-positive MBC. Activating mutations of PIK3CA may lead to resistance to currently available HER2-directed therapies. The relationship between treatment efficacy and tumor HER2 mRNA expression or PIK3CA mutation status was examined in pts from EMILIA.
Methods: Tumor tissue collected for HER2 testing was also used for HER2 mRNA analysis by qRT-PCR and for PIK3CA assessment (with additional consent), using a PIK3CA Mutation Detection Kit. PFS and OS were analyzed for each BM subgroup using the Kaplan-Meier method and a Cox regression model.
Results: Median mRNA concentration ratios and PIK3CA mutation frequency were similar across treatment arms and consistent with data previously reported. T-DM1 demonstrated superior PFS and OS vs XL in all BM subgroups. The hazard ratio of OS was less for pts with high (>median) vs low tumor HER2 mRNA levels. For XL-treated pts, PIK3CA mutations were associated with shorter median PFS and OS; PIK3CA mutations did not significantly affect T-DM1 treatment outcomes.
Table. Efficacy by BM Subgroup in EMILIA
T-DM1Hazard ratioa95% CI
nMedian PFS (months)nMedian PFS (months)
All patients4959.64966.40.66(0.56, 0.78)
HER2 mRNA concentration ratio
≤Median2308.22046.40.64(0.50, 0.82)
>Median19710.62356.90.65(0.50, 0.85)
PIK3CA mutation status
Mutated4010.9394.30.45(0.25, 0.82)
Wild type939.8876.40.74(0.50, 1.10)
T-DM1Hazard ratioa95% CI
nMedian OS (months)nMedian OS (months)
All patients49530.949625.10.70(0.56, 0.87)
HER2 mRNA concentration ratio
≤Median23026.520423.70.80(0.59, 1.09)
>Median19734.123524.80.53(0.37, 0.76)
PIK3CA mutation status
Mutated40NE3917.30.26(0.12, 0.57)
Wild type93NE8727.80.68(0.40, 1.15)
aHazard ratios are based on unstratified analyses.
CI, confidence interval; HER, human epidermal growth factor receptor; NE, not estimable; OS, overall survival; PIK3CA, phosphatidylinositide 3-kinase catalytic subunit α; PFS; progression-free survival; T-DM1, trastuzumab emtansine; XL, capecitabine + lapatinib

Conclusions: Pts in all BM subgroups analyzed to date had longer PFS and OS with T-DM1 vs XL. Pts with tumors expressing high HER2 mRNA levels derived even greater OS benefit from T-DM1. XL-treated pts with PIK3CA mutations had worse outcomes than those with wild type PIK3CA. T-DM1-treated pts with PIK3CA mutations had a similar treatment benefit as those without, suggesting that the unique mechanism of action of T-DM1 may overcome PIK3CA mutation resistance.