May 19, 2016
May 2013, Vol 2, No 3
Higher HER2 Expression Leads to Better Outcomes With T-DM1 in HER2-Positive Metastatic Breast Cancer
UncategorizedAmong women with HER2-positive metastatic breast cancer, those with the highest expression of HER2 had the best outcomes on treatment with T-DM1, according to a biomarker analysis of the phase 3 EMILIA trial presented at the American Association for Cancer Research 2013 Annual Meeting. Further, the analysis found that T-DM1 achieved superior outcomes in all patients enrolled in the trial versus capecitabine/lapatinib. The presence of PI3 kinase mutations (PIK3CA) had no effect on treatment with T-DM1, while these mutations compromised the effectiveness of capecitabine/lapatinib and are known to interfere with the effectiveness of trastuzumab.
“HER2-positive breast cancer is the same in all patients. The data of our biomarker analysis will help personalize therapy for individuals with HER2-positive breast cancer and make informed treatment decisions,†stated José Baselga, MD, PhD, Physician in Chief at Memorial Sloan-Kettering Cancer Center in New York City.
T-DM1 is the first antibody-drug conjugate to be approved by the FDA. The drug links the antibody trastuzumab to a highly potent toxic chemotherapy called emtansine. Trastuzumab attaches to the HER2 protein expressed in HER2-positive breast cancers and triggers the release of emtansine into the tumors, thereby killing tumor cells. Emtansine could not otherwise be administered to patients because it is so toxic, Baselga noted.
EMILIA was designed to compare the effectiveness of T-DM1 versus capecitabine/lapatinib in patients with metastatic HER2-positive breast cancer previously treated with trastuzumab plus taxane chemotherapy. T-DM1 significantly improved both progression-free survival (PFS) and overall survival (OS) compared with capecitabine/lapatinib.
Tumor samples were collected prospectively to study biomarkers. PFS and OS were correlated with biomarkers such as EGFR, HER2 mRNA, and PIK3CA. Median HER2 mRNA concentration ratios and PIK3CA mutation frequencies were similar across all treatment arms at baseline.
T-DM1 achieved superior PFS and OS in all biomarker subgroups. However, high expressors of HER2 mRNA levels derived even more benefit from T-DM1 than those with lower levels of expression. In the high expressors, median PFS was 34.1 months with T-DM1 versus 24.8 months with capecitabine/lapatinib.
The presence of PIK3CA mutations had no effect on PFS or OS in patients treated with T-DM1, but in the capecitabine/lapatinib arm, the presence of PIK3CA mutations led to worse outcomes than with wild-type PIK3CA.
“T-DM1 is PIK3CA mutation neutral,†Baselga told listeners.
At present, the working hypothesis is that tumors with high HER2 overexpression are hypersensitive to anti-HER2 therapies and may not need additional chemotherapy. “But this is speculation at this point,†he explained.
T-DM1 is currently being studied earlier in the course of disease as adjuvant therapy, and also as first-line therapy for metastatic disease.
Novel antibody-drug conjugates are in development for other types of cancer, he noted.
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