Trastuzumab Deruxtecan Approved for Treatment of HER2-Low Breast Cancer

HER2 staining on breast cancer tissue.

The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhertu®, Daiichi Sankyo, Inc.) for adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)–low breast cancer. This treatment is indicated for patients who have previously undergone chemotherapy in the metastatic setting or who developed disease recurrence during or within six months of completing adjuvant chemotherapy.

“Currently available HER2-directed therapies have not improved clinical outcomes in patients with this subtype; therefore, HER2-low breast cancer is currently treated as HER2-negative, with patients stratified according to hormone receptor status,” wrote Shanu Modi, MD, Attending Physician and Medical Oncologist at Memorial Sloan Kettering Cancer Center, and colleagues, in their published results of the DESTINY-Breast04 trial (NCT03734029), on which the approval was based. “Overall, these patients have limited targeted treatment options after progression during primary therapy and most commonly receive single-agent palliative chemotherapy.” 

The safety and efficacy of trastuzumab deruxtecan was assessed in the phase 3, two-arm, open-label trial in which 557 patients were randomized 2:1 to receive either 5.4 mg/kg of trastuzumab deruxtecan intravenously every three weeks or the physician’s choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel. The primary end point was progression-free survival in patients with hormone receptor (HR)–positive assessed via blinded independent central review. Key secondary end points measured were progression-free survival in all patients, overall survival in HR-positive patients, and overall survival in all patients.

At a median follow-up of 18.4 months, median progression-free survival in the HR-positive cohort being treated with trastuzumab deruxtecan was 10.1 months compared with 5.4 months for those being treated with their physician’s choice. In the overall population, those being treated with trastuzumab deruxtecan continued to see significantly longer progression-free survival compared with those being treated with their physician’s choice (9.9 months versus 5.1 months). Overall survival in HR-positive patients also saw a significantly longer response in the trastuzumab deruxtecan arm compared with the physician’s choice arm (23.9 months versus 17.5 months). In the overall population, overall survival had similar results when comparing the trastuzumab deruxtecan arm and the physician’s choice arm (23.4 months versus 16.8 months). 

The most common adverse reactions seen in ≥20% of patients receiving trastuzumab deruxtecan were nausea, fatigue, alopecia, vomiting, anemia, constipation, decreased appetite, diarrhea, and musculoskeletal pain. Included in the boxed warning is an advisory for health professionals detailing the risk of interstitial lung disease and embryo-fetal toxicity with trastuzumab deruxtecan.

“This trial showed significantly longer progression-free survival and overall survival with trastuzumab deruxtecan than with the physician’s choice of chemotherapy among patients with HER2-low metastatic breast cancer, regardless of hormone receptor status,” concluded Dr. Modi and colleagues in their report. “These results have the potential to improve the treatment outcome for more than half of patients historically categorized as having HER2-negative breast cancer.”

The recommended dose of trastuzumab deruxtecan for breast cancer is 5.4 mg/kg intravenously once every three weeks, in a 21-day cycle, until disease progression or unacceptable toxicity.

For More Information

Modi S, Jacot W, Yamashita T, et al (2022). Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med, 387(1):9-20. DOI:10.1056/NEJMoa2203690 (2022). Trastuzumab deruxtecan (DS-8201a) versus investigator’s choice for HER2-low breast cancer that has spread or cannot be surgically removed [DESTINY-Breast04]. NLM identifier: NCT03734029.

Enhertu® (fam-trastuzumab deruxtecan-nxki) prescribing information (2022). Daiichi Sankyo, Inc. Available at:

US Food and Drug Administration (2022). FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. Available at:

Image credit: GenomeMe Lab Inc. Licensed under CC BY 4.0

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