The FDA approved T-DM1 (ado-trastuzumab emtansine) in February 2013 as a treatment for patients with HER2-positive metastatic breast cancer following progression on trastuzumab with a taxane, based on impressive findings from the phase III EMILIA study. Clinical trials are now assessing the efficacy of T-DM1 in earlier lines of treatment.

In a phase II 137-patient randomized study, frontline T-DM1 was compared with docetaxel plus trastuzumab. The progression-free survival with T-DM1 was 14.2 month versus approximately 9 months with trastuzumab plus docetaxel, explains lead investigator Sara Hurvitz, MD. The rate of grade 3/4 adverse events with trastuzumab and docetaxel was approximately 90% compared with nearly 40% with T-DM1, representing a substantial improvement in toxicity.

These data serve as a precursor to the large 3-arm phase III MARIANNE trial that is looking trastuzumab plus a taxane compared with T-DM1 plus pertuzumab and T-DM1 with placebo, Hurvitz notes. However, this study was designed prior to the reporting of data from the CLEOPATRA trial, and does not contain a trastuzumab, pertuzumab, and docetaxel arm.

In CLEOPATRA, pertuzumab, trastuzumab, and docetaxel showed an impressive 15.7-month improvement in overall survival compared with trastuzumab and docetaxel in women with HER2-positive breast cancer in the first-line setting. The median OS with the pertuzumab combination was 56.5 months compared with 40.8 months with trastuzumab and a taxane.

Preliminary, an optimal treatment approach might utilize trastuzumab, pertuzumab, and chemotherapy in the neoadjuvant setting followed by T-DM1 at the time of recurrence, suggests Eleftherios Mamounas, MD. The neoadjuvant administration of pertuzumab gained FDA approval in September 2013. In order to ensure access to all patients, the NCCN guideline recommends utilizing the agent in the neoadjuvant and adjuvant setting, notes Hope S. Rugo, MD. However, this recommendation was created despite evidence of benefit, suggests Adam Brufsky, MD, PhD.