Amount of HER2 Expression Associated With Response to T-DM1 in HER2-Positive Metastatic Breast Cancer

Oncology & Biotech News, June 2013, Volume 7, Issue 6

Women with the highest expression of HER2 had the most benefit from T-DM1, while the presence of PIK3CA mutations had no effect on response to T-DM1 but did interfere with response to capecitabine/lapatinib.

José Baselga, MD, PhD

The phase III EMILIA trial showed that trastuzumab emtansine (ado-trastuzumab emtansine; T-DM1; Kadcyla) improved progression-free survival (PFS) and overall survival (OS) in women with HER2-positive metastatic breast cancer previously treated with trastuzumab versus standard therapy with capecitabine/lapatinib. Based on the study, T-DM1 was approved by the FDA in February as a second-line therapy for HER2-positive metastatic breast cancer in this setting.

In an effort to understand whether certain groups derived preferential benefit from T-DM1, tumor tissue was collected prospectively for a biomarker analysis. Results of the biomarker analysis, presented at the 2013 AACR Annual Meeting demonstrated that all women in every subgroup had superior outcomes on T-DM1 versus capecitabine/lapatinib. However, women with the highest expression of HER2 had the most benefit from T-DM1, while the presence of phosphoinositide 3-kinase (PIK3CA) mutations had no effect on response to T-DM1 but did interfere with response to capecitabine/lapatinib.

The presence of PIK3CA mutations has been associated with resistance to trastuzumab in HER2-positive breast cancer. Lead author of the biomarker analysis José Baselga, MD, PhD, physician-in-chief at Memorial Sloan-Kettering Cancer Center in New York City, said, “Unlike other HER2-directed therapies, T-DM1 is PIK3CA mutation neutral.”

Baselga said that HER2-positive breast cancer is heterogeneous, and that he considers the findings of the biomarker study important. “These data will help us as we identify a panel of molecular features that we can use to make informed treatment decisions,” he noted.

The antibody-drug conjugate T-DM1 has a unique mechanism of action, linking trastuzumab to a highly toxic chemotherapy called emtansine. Once the trastuzumab portion of the compound binds to HER2, emtansine is released directly into the tumor cells, killing the tumor and sparing normal cells.

Tumor samples collected prospectively from patients enrolled in the EMILIA study were analyzed for the expression of EGFR, HER2 mRNA, and PIK3CA. PFS and then the amount of HER2 mRNA expression and PIK3CA mutation frequency were correlated with PFS and OS. Median HER2 mRNA concentration ratios and PIK3CA mutation frequencies were similar across all treatment arms.

T-DM1 achieved superior PFS and OS in all biomarker subgroups. However, tumors that expressed high HER2 mRNA levels had better outcomes compared with 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 led to worse outcomes in patients treated with capecitabine/lapatinib compared with wild-type PIK3CA. Those with mutations had shorter OS by a mean of 10 months versus wild-type PIK3CA. The presence of PIK3CA mutations had no effect on PFS or OS in the T-DM1 arm.

“Our results are not practice-changing at this point,” Baselga commented at an official press conference. “It is possible that patients with high HER2 expression may not need chemotherapy if treated with T-DM1, but that is speculation and would need to be studied.”

Compounds that target PIK3CA could be an option for HER2-positive patients with these mutations, but further study is needed, he said.

T-DM1 may find a role earlier in the course of breast cancer. Ongoing studies are evaluating the antibodydrug conjugate as adjuvant therapy and as first-line therapy for metastatic disease.

Other novel antibody-drug conjugates are being studied in solid tumors. Moderator of a press conference where these findings were presented, Louis M. Weiner, MD, director of the Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, said, “The lessons of T-DM1 are not unique to T-DM1, but to other antibody-drug conjugates as well. The therapeutic concept of antibody-drug conjugates makes sense. Target the antigen on the cell surface, and deliver powerful cytotoxic chemotherapy. The antibody delivers the potent drug that could not be given otherwise to exactly where it needs to go.”

Baselga J, Verma S, Jungsil R, et al. 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). Presented at: the AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. LB-63.