How is HER2-positive metastatic breast cancer treated?

Updated: Jul 16, 2020
  • Author: Maurie Markman, MD, MS; Chief Editor: Karl S Roth, MD  more...
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In the metastatic setting, a pivotal phase III trial compared first-line chemotherapy (doxorubicin/epirubicin and cyclophosphamide or paclitaxel) plus trastuzumab versus chemotherapy alone in HER2-positive patients. Trastuzumab plus chemotherapy was associated with a significant improvement in time to disease progression (7.4 mo vs 4.6 mo), objective response rate (50% vs 32%), and 1-year survival (25.1 mo vs 20.3 mo) compared with chemotherapy alone. [19]

Additionally, there is evidence suggesting that up-front use of trastuzumab with chemotherapy, in women with advanced HER2-positive breast cancer, prolongs life as compared with sequential administration, with trastuzumab reserved for the time of disease progression on an initial chemotherapy regimen. Based on these results, the FDA approved trastuzumab for first-line therapy in HER2-positive metastatic breast cancer. However, the question of optimal duration of trastuzumab therapy remains unresolved.

Clinical evidence to support continued trastuzumab treatment after initial progression has emerged. Retrospective studies have described a response to trastuzumab in multiple lines of therapy, and patients treated with more than 2 trastuzumab-containing regimens appear to have advantageous overall survival and time to progression.

Results from a prospective, randomized study of 112 patients with HER2-positive metastatic breast cancer initially progressing on a trastuzumab-based therapy (GBG-26/BIG 3-05 study) showed that trastuzumab/capecitabine resulted in a longer progression-free survival (PFS)(8.2 mo vs 5.6 mo) and overall survival (25.5 mo vs 20.4 mo) as compared with the capecitabine-only arm. [20] Objective response rates were also significantly improved in the combination arm (48.1%) versus capecitabine alone (27%). Larger trials are currently ongoing to assess the activity of trastuzumab in multiple lines of treatment.

Another agent used in the treatment of HER2-positive metastatic breast cancer is lapatinib, a tyrosine kinase inhibitor (TKI). Lapatinib was approved in 2007 for the treatment of metastatic breast cancer in HER2-positive patients after progression on trastuzumab. This small molecule is known to block multiple epidermal growth factor receptors (EGFRs), EGFR (HER-1) and HER2, and is generally well tolerated, with the main toxicities being diarrhea, skin rash, fatigue, and nausea.

An analysis of cardiac toxicity found that 1.6% of patients exposed to lapatinib experienced a decline in left ventricular ejection fraction (LVEF), with 0.2% being symptomatic, lower than the comparable incidence observed with trastuzumab. [21] Preclinical data have indicated synergistic activity between lapatinib and trastuzumab, leading to a randomized study of this combination.

A phase III trial involving 296 heavily pretreated, trastuzumab-refractory metastatic breast cancer patients randomized to treatment with lapatinib alone or lapatinib with trastuzumab reported combination therapy significantly improved PFS (8.4 wks vs 12 wks) compared with lapatinib alone. [22] There was a nonsignificant trend toward improved median overall survival. Diarrhea and rash were the most common adverse effects. An asymptomatic decline in LVEF was seen in 5% of patients in the combination arm, compared with 2% in the lapatinib-alone arm.

In one study, 991 patients with HER2-positive advanced breast cancer previously treated with trastuzumab and taxane were randomized to treatment with the antibody-drug conjugate trastuzumab emtansine or lapatinib plus capecitabine. Trastuzumab emtansine was shown to significantly prolong PFS (9.6 months vs. 6.4 months) and overall survival (30.9 months vs. 25.1 months) compared with lapatinib plus capecitabine, and was associated with a better toxicity profile. [23]

Trastuzumab deruxtecan is an antibody-drug conjugate which contains the humanized anti-HER2 IgG1, trastuzumab, covalently linked to the topoisomerase I inhibitor, deruxtecan. In the open-label, phase 2 DESTINY-Breast01 study (n = 184), patients who had received a median of 6 previous treatments were given trastuzumab deruxtecan every 3 weeks. The overall response rate was 60.3%, complete responses were observed in 4.3%, and partial responses in 56%. Median duration of response was 14.8 months. Median PFS was 16 months. [24, 25]

In April 2020, tucatinib was approved by the FDA. It is an orally bioavailable, small molecule tyrosine kinase inhibitor (TKI) that is highly selective for HER2. This drug is indicated in combination with trastuzumab and capecitabine for treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting.

Approval was based on the HER2CLIMB trial (n=612). The international multicenter study randomized patients to receive trastuzumab and capecitabine plus either tucatinib or placebo. The median PFS in the tucatinib-treated group was 7.8 months, compared with 5.6 months in the control arm. The median overall survival in the tucatinib-treated arm was 21.9 months, versus 17.4 months in the control arm. The median PFS for patients with baseline brain metastases in the tucatinib-treated arm was 7.6 months, compared with 5.4 months for patients in the control arm. [26]

Baselga et al reported that adding pertuzumab to traditional therapy with trastuzumab and docetaxel improved disease-free survival time in patients with HER2-positive metatstatic breast cancer. [16] For more information, see Novel HER2 Receptor Agents, below.

See Breast Cancer Treatment Protocols for summarized information.

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