Trastuzumab deruxtecan is a treatment option for pre-treated HER2-low metastatic breast cancer

1. Median overall survival is longer for HER2-low breast cancer patients receiving trastuzumab deruxtecan compared with other chemotherapy treatment options.

2. Trastuzumab deruxtecan is associated with increased risk of interstitial lung disease and pneumonitis

Evidence Rating Level: 1 (Excellent)

Study Rundown: Treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer includes targeted treatment with trastuzumab, an anti-HER2 monoclonal antibody. An antibody-drug conjugate, trastuzumab deruxtecan, combines the monoclonal antibody with a topoisomerase I inhibitor and has been shown to be effective in highly expressed HER2 breast cancers. Because more than half of the HER2-negative breast cancers do express some amount of HER2, there is a possible therapeutic effect of this treatment in this heterogeneous group of patients. This study aimed to determine the outcome on progression-free survival (PFS), overall survival (OS), and safety of trastuzumab deruxtecan as compared with other standard chemotherapy treatment options as selected by a physician in patients with HER2-low metastatic breast cancer. The median PFS for all patients receiving trastuzumab deruxtecan was 9.9 months as compared to 5.1 months for patients on other chemotherapy. The median OS for all patients on trastuzumab deruxtecan was 23.4 months compared to 16.8 months in those receiving other chemotherapy. The majority of patients in the trastuzumab deruxtecan and the physician-chosen chemotherapy group experienced adverse effects (AEs) and roughly a quarter of AEs were serious. The most common drug-related AEs in the trastuzumab group were nausea, fatigue, and alopecia which occurred more frequently than in the physician-chosen chemotherapy group. Each group had AEs that were associated with death (14 in the trastuzumab group and 5 in the chemotherapy group), but there were no drug-related deaths in the chemotherapy group, while there were 3 drug-related deaths in the trastuzumab group. Limitations to this study include the applicability of this treatment to the specific groups that were ineligible to join the trial, for example, those with history of glucocorticoid treatment for noninfectious interstitial lung disease or who were suspected of having interstitial lung disease. Overall, treatment with trastuzumab deruxtecan will change practice as it defines a new category of HER2 expressing breast cancers that would benefit from this treatment over standard chemotherapy.

Click to read the study in The New England Journal of Medicine

Relevant Reading: The latest research and development into the antibody-drug conjugate, [fam-] trastuzumab deruxtecan (DS-8201a), for HER2 cancer therapy

In-Depth [randomized controlled trial]: This open-label, two group, phase 3 study enrolled a total of 557 patients with HER2-low metastatic breast cancer who were randomly assigned in a 2:1 ratio to receive either trastuzumab deruxtecan (n = 373) or another chemotherapy treatment option (n = 184). For all patients receiving trastuzumab deruxtecan the median PFS was 9.9 months (95% CI, 9.0 to 11.3 months) versus 5.1 months (95% CI, 4.2 to 6.8 months) for patients on other chemotherapy (HR, 0.50; 95% CI, 0.40 to 0.63). For all patients on trastuzumab deruxtecan the median OS was 23.4 months (95% CI, 20.0 to 24.8 months) versus 16.8 months (95% CI, 14.5 to 20.0 months) in the group receiving other chemotherapy treatment (HR, 0.64; 95% CI, 0.49 to 0.84). 99.5% of patients receiving trastuzumab deruxtecan and 98.3% of patients receiving other chemotherapy experienced AEs; the most common AEs were nausea (73% vs. 23.8%), fatigue (47.7% vs. 42.4%), and alopecia (37.7% vs. 32.6%). 12% of patients developed treatment related interstitial lung disease/pneumonitis.14 patients in the trastuzumab group had AEs associated with death, while 5 did in the other chemotherapy group.

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