by ecancer reporter Clare Sansom

About 15-20% of patients diagnosed with invasive breast cancer have tumours in which the gene human epidermal growth factor receptor 2 (HER2) is over-expressed.

Patients with these HER2 positive breast cancers have a poor prognosis without systemic therapy, although their prospects have been greatly improved by the introduction of the HER2 antibody trastuzumab (Herceptin).

Most patients treated with trastuzumab still do eventually develop progressive disease, and further options are still needed for treating them.

In particular, new options are needed for treating HER2 positive breast cancer patients whose disease has progressed despite several pre-treatments.

Trastuzumab emantasine is an antibody-drug conjugate in which the antibody acts not only as a therapeutic agent in its own right but also to deliver DM1 (Mertansine), a cytotoxic drug that affects microtubules, directly to the tumour cells.

Following positive results from the phase 3 EMILLIA trial, this drug has now been approved as a single-agent treatment for patients with advanced HER2 positive breast cancer who have previously received trastuzumab and a taxane.

Pre-treatment with lapatinib, a HER2 inhibitor, was an exclusion criteria for the EMILLIA trial, so trastuzumab emantasine has not been licensed for patients who have received lapatinib; no clear standard of care exists for these patients.

The open label phase 3 trial TH3RESA was designed to compare this agent against oncologists’ treatments of choice in patients who have previously received both trastuzumab and lapatinib.

The TH3RESA researchers, led by Ian Krop of the Dana-Farber Cancer Institute, Harvard University School of Medicine, Boston, Massachusetts, USA, have now published the final progression free survival analysis from the study.

Patients were eligible for inclusion in this study if they had HER2-positive advanced breast cancer that had progressed on two or more HER2-directed chemotherapy regimens including both trastuzumab and lapatinib.

A total of 602 eligible patients, recruited from 22 study centres on four continents, were randomised 2:1 to receive either trastuzumab emantasine or the treating physician’s choice of therapy; they were stratified by world region and by number and nature of previous treatments.

Patients randomised to the study drug initially received 3.6 mg/kg every 21 days, with two allowable dose reductions to 2.4 mg/kg before withdrawal from the study.

Treatments given to those randomised to receive their physician’s choice of agent included single-agent chemotherapy, single- or double-agent hormonal therapy and HER2-directed therapy.

All patients continued treatment until their disease progressed, they developed unmanageable toxicity or they died.

The primary endpoints for the study were progression-free survival (PFS) and overall survival; secondary endpoints included objective response, six-month and one-year survival, and safety.

About 324 PFS events were thought to be necessary before the primary PFS analysis could be performed; all patients also had to be fully enrolled into the study and have had at least one post-baseline tumour assessment.

The median follow-up period was 7.2 months in the trastuzumab emantasine group and 6.2 months in the control group.

There was a significant increase in progression free survival in the trastuzumab emantasine group, with a median PFS of 6.2 months (95% confidence interval 5.59-6.87 months) in that group compared to 3.3 months (95% CI 2.89-4.14 months) in the control group.

Similar results were obtained when the participants were divided into subgroups by age, hormone receptor status, presence or absence of brain metastases, previous treatment regimens and by the chosen treatment option in the control group.

There also seemed to be an increase in overall survival in the study group, although this did not reach statistical significance.

Severe (grade 3 or worse) adverse events were more common in the physician’s choice group than in the study group, with thrombocytopenia the only side effect that was more common in the study group.

A total of 44 of the 198 patients initially assigned to physician’s choice had crossed over to receive trastuzumab emantasine at the time of data cutoff.

Taken together, the results of this large Phase 3 trial suggest that trastuzumab emantasine is a relatively effective option for heavily pre-treated patients with HER2 positive breast cancer, and that it should be considered as a new “gold standard” treatment for these patients.

Reference

Krop, I.E., Kim, S-B., González-Martín, A., LoRusso, P.M., Ferrero, J-M., Smitt, M., Yu, R., Leung, A.C.F. and Wildiers, H., Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncology 15: 689–99.