The antibody-drug conjugate T-DM1 (ado-trastuzumab emtansine; Kadcyla) has been explored across several settings as a treatment for patients with HER2-positive metastatic breast cancer. Many of these studies are ongoing or have been recently presented, notes moderator Adam M. Brufsky, MD, PhD.

The FDA approved T-DM1 in February 2013 for the treatment of patients with HER2-positive metastatic breast cancer following recurrence on trastuzumab and a taxane, either separately or in combination, explains Brufsky. The approval was based on results from the phase III EMILIA trial that compared T-DM1 to lapatinib plus capecitabine. In the trial, T-DM1 demonstrated superiority over the doublet by significantly extending progression-free survival (PFS) by 3.2 months and overall survival (OS) by 5.8 months. Moreover, treatment with T-DM1 was associated with fewer side effects.

The phase III TH3RESA study randomized 602 patients with advanced HER2-positive breast cancer previously treated with at least two HER2-directed therapies in a 2:1 ratio to receive T-DM1 or physician’s choice of treatment. Treatment with T-DM1 resulted in a median PFS of 6.2 months compared with 3.3 months in the control arm. Results from the TH3RESA and EMILIA trials have established T-DM1 as an important treatment for patients with HER2-positive metastatic breast cancer, believes Kimberly L. Blackwell, MD.

Building upon these results, the phase III MARIANNE trial is currently examining T-DM1 plus or minus pertuzumab compared to trastuzumab plus a taxane for untreated patients with HER2-positive metastatic breast cancer. Although results have not yet been presented, it is likely that this trial will establish T-DM1 as the first-line standard of care, states Brufsky. In addition to demonstrating the overall efficacy of T-DM1 in the frontline setting, the MARIANNE trial will establish whether the addition of pertuzumab to T-DM1 improves efficacy, notes Blackwell.

Adding to the data on these trials, Hope S. Rugo, MD, states that even following treatment with five different regimens patients with HER2-positive metastatic breast cancer still seem to respond to treatment with T-DM1. Moreover, some patients seem to experience a longer duration of response than others, including up to 4 years, Rugo notes.

At this point, outside of HER2 and possibly mutations in PIK3CA, there doesn’t seem to be a clear biomarker to predict which patients will respond better to treatment with T-DM1, notes Mark D. Pegram, MD. HER2 overexpression is essential to the efficacy of T-DM1, Blackwell notes. As a result, if a patient does not seem to respond well to a trastuzumab-based regimen there may be a need for HER2 retesting, in order to ensure T-DM1 is an appropriate treatment.

Obtaining a new tissue sample for testing in the metastatic setting represents a fresh set of challenges. In these situations, Blackwell recommends a biopsy of the most easily accessible metastatic lesions, which usually are located in the liver or the mediastinal lymph nodes. Additionally, bone metastases are reasonable target for biopsy. However, the results of these metastatic biopsies should be viewed in the context of clinical data, such as which therapies the patient has responded to in the past, Blackwell notes.

Outside of IHC and FISH, Pegram cautions against testing for HER2 gene amplification, since not all tumors fall within the intrinsic gene expression phenotype. Utilizing this method may result in misleading results that could be hazardous, Pegram states.