SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence.
It is estimated that approximately 60% of metastatic breast cancers categorized as HER2-negative express low levels of HER2, defined as a score of 1+ on ImmunoHistoChemical (IHC) analysis or as an IHC score of 2+ and negative results on In Situ Hybridization (ISH). These HER2-low breast cancer tumors are treated as HER2-negative, as currently available HER2-directed therapies have resulted in poor outcomes. These patients have limited targeted treatment options and are often treated with single agent palliative chemotherapy following progression on first line chemotherapy.
ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to Trastuzumab, a cleavable tetrapeptide-based linker, and a potent cytotoxic Topoisomerase I inhibitor as the cytotoxic drug (payload). ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life , thus minimizing systemic exposure. The potential activity of ENHERTU® in HER2-low breast cancer tumors is driven by the bystander antitumor effect, offered by the optimized ADC technology. Previously published Phase I and II trials have shown that ENHERTU® in heavily pretreated patients with HER2-low metastatic breast cancer resulted in an Overall Response Rate of 37%, and median Progression Free Survival ranging from 6.3 to 11.1 months.
DESTINY-Breast04 is a multicenter, randomized, open-label, Phase III trial, conducted to evaluate the efficacy and safety of ENHERTU® as compared with the physician’s choice of chemotherapy, in patients with HER2-low metastatic breast cancer. In this study, patients were randomly assigned in a 2:1 ratio to receive ENHERTU® 5.4 mg/kg IV every 3 weeks (N=373) or the physician’s choice of Capecitabine, Eribulin, Gemcitabine, Paclitaxel, or Nab-paclitaxel (N=184). Low expression of HER2 was defined as a score of 1+ on ImmunoHistoChemical (IHC) analysis or as an IHC score of 2+ and negative results on In Situ Hybridization (ISH). Randomization was stratified according to HER2-low status (IHC 1+ versus IHC 2+ and ISH-negative), the number of previous lines of chemotherapy for metastatic disease (one versus two), and Hormone Receptor (HR) status (positive versus negative) and if positive, previous CDK4/6 inhibitor therapy versus no CDK4/6 inhibitor therapy. IHC scores for HER2 expression were determined through central testing with the use of VENTANA HER2/neu investigational assay system, according to an algorithm adapted from the 2018 ASCO/CAP testing guidelines. Eligible patients must have received chemotherapy for metastatic disease or have had disease recurrence during or within 6 months after completing adjuvant chemotherapy. Patients with Hormone Receptor positive (HR-positive) disease must have received at least one line of endocrine therapy. Patients with treated, stable brain metastases were eligible. Patients were ineligible if they had a history of noninfectious interstitial lung disease treated with steroids or had suspected interstitial lung disease on imaging at screening. Both treatment groups were well balanced and approximately 89% in the ENHERTU® group and 90% in the chemotherapy group were HR-positive. The Primary end point was Progression Free Survival (PFS) among patients with HR-positive disease. Secondary end points included PFS among all patients, Overall Survival (OS) in the HR-positive cohort and among all patients, Objective Response Rate (ORR), Duration of Response, and efficacy in the HR-negative cohort. The median duration of follow up for survival was 18.4 months.
At the time of the primary efficacy analysis, the median PFS in the HR-positive cohort was 10.1 months in the ENHERTU® group and 5.4 months in the physician’s choice group (HR for disease progression or death=0.51; P<0.001). This benefit with ENHERTU® was seen consistently across all analyzed subgroups which included HER2 IHC 1+, HER2 IHC 2+ and ISH-negative, as well as those who had received previous treatment with CDK4/6 inhibitors. The median PFS among all patients was 9.9 months in the ENHERTU® group and 5.1 months in the physician’s choice group (HR for disease progression or death=0.50; P<0.001). The median PFS in the HR-negative cohort was 8.5 months in the ENHERTU® group and 2.9 months in the physician’s choice group (HR=0.46).
The median OS in the HR-positive cohort was 23.9 months in the ENHERTU® group and 17.5 months in the physician’s choice group (HR for death=0.64; P=0.003). The median OS among all patients was 23.4 months in the ENHERTU® group and 16.8 months in the physician’s choice group HR=0.64; P=0.001). The median OS in the HR-negative cohort was 18.2 months in the ENHERTU® group and 8.3 months in the physician’s choice group (HR=0.48).
The ORR in the HR-positive group was 52.6% in the ENHERTU® group and 16.3% in the physician’s choice group, and the median duration of response was 10.7 months in the ENHERTU® group and 6.8 months in the physician’s choice group. The ORR among all patients was 52.3% in the ENHERTU® group and 16.3% in the physician’s choice group. Among HR-negative cohort, the ORRs were 50% and 16.7% respectively.
Grade 3 or higher adverse events occurred in 53% of the patients who received ENHERTU® and 67.4% of those who received the physician’s choice of chemotherapy. Adjudicated, drug-related Interstitial Lung Disease or pneumonitis occurred in 12.1% of the patients who received ENHERTU®.
The authors concluded that this is the first Phase III, practice-changing trial of a HER2-directed therapy in patients with HER2-low metastatic breast cancer, to show a statistically significant and clinically meaningful benefit in PFS and OS, compared to standard chemotherapy, regardless of Hormone Receptor status, with a generally manageable safety profile. The authors added that the strong efficacy of ENHERTU® in this HER2-low patient population, with approximately 50% lower risk of disease progression and 36% lower risk of death with ENHERTU® compared to standard chemotherapy, supports the need to reclassify HER2-low as a new targetable category of metastatic breast cancer.
Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. Modi S, Jacot W, Yamashita T, et al. for the DESTINY-Breast04 Trial Investigators. N Engl J Med 2022; 387:9-20.
