Several agents are currently being explored as frontline treatments for patients with HER2-positive metastatic breast cancer. The standard of care for these patients was disrupted in 2012, when the FDA approved a frontline regimen of pertuzumab, trastuzumab, and docetaxel.

This approval was based on findings from the phase III CLEOPATRA trial that randomized 808 women to trastuzumab, docetaxel, and pertuzumab or trastuzumab, docetaxel, and placebo. The addition of pertuzumab results in a dual blockade of the HER2 extracellular domain, which resulted in an impressive prolongation in both progression-free survival and overall survival, notes Andrew D. Seidman, MD. This three-drug regimen has become the standard of care in this setting, Seidman adds.

This switch in the standard of care complicates the interpretation of ongoing trial results, such as the phase III MARIANNE trial. In this trial, T-DM1 with or without pertuzumab is being compared to trastuzumab and a taxane. As a result, a cross trial comparison of the MARIANNE and CLEOPATRA trials will likely be necessary, Seidman notes. If these approaches are similar in terms of efficacy, their side effect profiles will be the deciding factor in how they are prescribed.

If they have similar efficacy, the frontline regimen utilized may also be impacted by the costs associated with treatment, Hope S. Rugo, MD believes. Moreover, she notes, there is a lack of data to support that T-DM1 is an effective treatment for brain metastases. Along these lines, local options are available for patients with brain metastases but, overall, there are few effective options for these patients, Joyce A. O'Shaughnessy, MD, adds.

A larger questions, believes Sara Hurvitz, MD, is the impact these trials and concerns will play on the overall sequencing of agents in the second- and third-line for patients with metastatic breast cancer.