Antibody–Drug Conjugate Hits Elusive HER2⁺ Breast Tumors

HER2-positive breast tumors often develop resistance to trastuzumab (Herceptin; Genentech) treatment by collecting mutations that activate the phosphoinositide 3-kinase (PI3K) pathway, which helps control such processes as metabolism and cell division. The antibody–drug conjugate T-DM1 (Kadcyla; Genentech) works as well in women who have PIK3CA mutations as in those who don't, researchers reported at the American Association for Cancer Research Annual Meeting 2013 in Washington, DC, April 6–10.

Drug developers crafted T-DM1 as trastuzumab linked to the cytotoxic drug emtansine. “The idea is to use the antibody as a delivery system so that the drug gets absorbed and released only in cells that are HER2-positive,” says José Baselga, MD, PhD, physician-in-chief at the Memorial Sloan-Kettering Cancer Center in New York, NY.

T-DM1 gained U.S. Food and Drug Administration in February 2013 for treatment of patients with metastatic HER2-positive breast cancers who have received prior treatment with trastuzumab and a taxane chemotherapy. Baselga and colleagues wondered whether the drug would also help patients whose tumors resist trastuzumab because they harbor mutations in the PI3K pathway, which is downstream of HER2.

The researchers carried out a biomarker analysis of data from the EMILIA study, a phase III trial that compared T-DM1 to the standard drug duo of capecitabine and lapatinib for patients whose HER2-positive breast cancer had metastasized or was locally advanced.

As one part of the overall biomarker analysis, Baselga and colleagues sorted the subjects by the treatment they'd received and by whether they carried mutations in PIK3CA. This gene encodes the alpha isoform of PI3K's catalytic subunit and is often altered in HER2-positive breast cancers.

Women with PIK3CA mutations fared worse if they received the combination of capecitabine and lapatinib, with mean overall survival 10 months shorter than that of women who lacked these genetic changes. By contrast, women treated with T-DM1 who carried PIK3CA mutations lived about the same length of time as those who did not carry PIK3CA mutations.

For patients with altered PIK3CA, T-DM1 also extended mean progression-free survival over capecitabine and lapatinib, from 4.3 months to 10.9 months. Mean progression-free survival for all patients treated with T-DM1 was 9.6 months, compared with 5.4 months for patients treated with capecitabine and lapatinib.

These findings thus suggest that unlike the combination of capecitabine and lapatinib, T-DM1 works as well in patients who have PIK3CA mutations as in those who don't. Because individuals with PIK3CA mutations often don't respond well to traditional therapy for HER2-positive tumors, T-DM1 may provide an alternative treatment, the researchers conclude.

In addition to its findings about PIK3CA, the EMILIA biomarker analysis revealed that patients with tumors expressing higher levels of HER2 survived longer than patients with tumors expressing lower levels of HER2, with overall survival periods of 34.1 months versus 25.1 months, respectively.