Anti-HER2 Therapy for Metastatic Breast Cancer

Experience with anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, and the antibody-drug conjugate, trastuzumab emtansine (T-DM1), has shown that blocking the HER2 protein results in significant clinical benefit, states Ian E. Krop, MD. In the phase III CLEOPATRA trial, patients with HER2-positive metastatic breast cancer were randomized to frontline therapy with docetaxel and trastuzumab with or without pertuzumab. The median overall survival (OS) with the triplet was 56.5 months compared with 40.8 months in the placebo arm, representing an overall difference of 15.7 months.

In the second-line setting, T-DM1 has shown significant improvements in progression-free survival (PFS) and OS compared with capecitabine and lapatinib, says Krop. In the pivotal phase III EMILIA trial, the median OS was 30.9 versus 25.1 months with T-DM1 and lapatinib plus capecitabine, respectively. Median PFS was 9.6 months with T-DM1 compared with 6.4 months for lapatinib plus capecitabine.

Given the effectiveness of this agent in the second-line setting and as a single agent, the phase III MARIANNE trial evaluated T-DM1 with or without pertuzumab for untreated patients with HER2-positive metastatic breast cancer. In the study, patients were randomized to receive T-DM1, T-DM1 plus pertuzumab, or a taxane (docetaxel or paclitaxel) plus trastuzumab. Results showed that neither regimens containing T-DM1 were superior to the control arm.

The MARIANNE data will not change the standard of care, which is trastuzumab plus pertuzumab in the first-line setting, comments Krop. T-DM1 remains the second-line standard of care. T-DM1 remains under investigation for patients with HER2-positive breast cancer, specifically those with low-risk stage I disease, says Hope S. Rugo, MD.

The phase III ExteNET trial evaluated neratinib, an oral tyrosine kinase inhibitor that blocks HER2, in patients with HER2-positive breast cancer. The 2-year invasive disease-free survival rate was 93.9% in the neratinib arm versus 91.6% with placebo, representing a 33% reduction in the risk of recurrence (HR = 0.67; P = .009). However, 95.4% of patients treated with neratinib experienced all-grade diarrhea (39.9% were grade 3/4), points out Rugo.

The rates of diarrhea seen in the ExteNET study could be related to an initial lack of antidiarrheal therapy, which caused immediate diarrhea in the majority of patients. The management of diarrhea is now better understood, and the current standard includes routine prophylaxis, says Rugo. Studies continue to assess neratininb, and there is interest in combining neratinib with trastuzumab and pertuzumab, adds Rugo.