First-Line Option Clear in Sequencing of HER2-Positive Breast Cancer Treatments


As more treatment options become available for metastatic HER2-positive breast cancer, some questions regarding the optimal sequencing of therapies remain.

As more treatment options become available for metastatic HER2-positive breast cancer, some questions remain about the optimal sequencing of therapies in this patient population.

Mark D. Pegram, MD, director of the Breast Cancer Oncology Program and Stanford’s Women’s Cancer Center addressed some of these questions during his presentation “Contemporary Sequencing of Therapies in Advanced HER2-positive Breast Cancer” at the 32nd Annual Miami Breast Cancer Conference held February 26-28 in Miami Beach, Florida.

According to Pegram, mature survival data from the CLEOPATRA study, published recently in the New England Journal of Medicine, established pertuzumab/trastuzumab/docetaxel as the preferred first-line treatment in women with HER2-positive metastatic breast cancer.

The trial randomized patients who had not received prior chemotherapy or HER2-therapy to either pertuzumab/trastuzumab/docetaxel or placebo/trastuzumab/docetaxel. Median overall survival in the pertuzumab group was 56.5 months compared with 40.8 months in the group receiving the placebo combination (P < .001). In addition, patients assigned pertuzumab/trastuzumab/docetaxel had a median 6-month delay in progression compared with patients assigned the placebo combination.

The significance of these results was made more apparent when the manufacturer of ado-trastuzumab emtansine, or T-DM1, announced disappointing results of the phase III MARIANNE trial, which compared T-DM1 plus pertuzumab to trastuzumab plus a taxane. The trial failed to demonstrate that T-DM1 performed better in terms of progression-free survival compared with trastuzumab plus chemotherapy.

Based on the “compelling” data from CLEOPATRA, therefore, the regimen of  pertuzumab/trastuzumab/docetaxel has been established as the preferred first-line treatment in women with metastatic HER2-positive disease.

When considering therapies in women who have progressed after prior treatment with a taxane and trastuzumab, or those who have relapsed within 6 months of completion of adjuvant trastuzumab, clinicians should consider T-DM1. Results of the EMILIA study published in 2012 in the New England Journal of Medicine showed that in patients with HER2-positive disease previously treated with trastuzumab and a taxane, T-DM1 significantly improved progression-free and overall survival compared with lapatinib plus capecitabine, with less toxicity. 

When moving to the third-line in patients who have progressed with a pertuzumab-containing regimen and a T-DM1-containing regimen, most clinicians choose a lapatinib-containing regimen, either lapatinib/capecitabine or lapatinib/trastuzumab.

“There is level 1 evidence that lapatinib/capecitabine is an effective and safe regimen, and it has FDA approval,” Pegram told Cancer Network. “However, this is with the strong caveat that when these trials were done we did not have trastuzumab and T-DM1, and, consequently, there is no guarantee that lapatinib/capecitabine will look as good in patients who have already had these regimens compared to how it looked back in the day.”

Moving beyond third-line treatment, most clinicians are switching back to salvage chemotherapy plus trastuzumab in the last-line setting, Pegram said, combining the targeted therapy with various chemotherapy regimens. In addition, for many patients with HER2-positive disease, endocrine therapy may also still be an option.

Finally, Pegram encouraged clinicians to consider enrolling patients in clinical trials in salvage settings.

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