Trastuzumab Deruxtecan Undergoes Priority Review for HER2-Low Metastatic Breast Cancer


Based on data from the DESTINY-Breast04 trial, the FDA has granted a priority review designation for the supplemental biologics license application for fam-trastuzumab deruxtecan-nxki.

Based on data from the DESTINY-Breast04 trial (NCT03734029), the FDA has granted a priority review designation for the supplemental biologics license application for fam-trastuzumab deruxtecan-nxki (Enhertu). The agency is expected to decide on the submission for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received 1 prior therapy in the metastatic setting in the fourth quarter of 2022.1

HER2-low status is defined as disease classified as immunohistochemistry [IHC] 1+ or IHC 2+ and in-situ hybridization [ISH]–negative. Investigators hypothesized that by targeting a lower range of HER2 expression, treatments could delay disease progression in patients with metastatic disease.2

DESTINY-Breast04, a randomized, open-label pivotal trial, randomly assigned patients to receive the antibody-drug conjugate at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice chemotherapy physician’s choice of chemotherapy at locally approved dosing (n = 184). The treatment options included capecitabine (Xeloda), eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane).3,4

The primary end point was progression-free survival (PFS) in patients with hormone receptor–positive disease. The median PFS in the primary end point population was 10.1 months (95% CI, 9.5-11.5) with trastuzumab deruxtecan vs 5.4 months (95% CI, 4.4-7.1) with standard of care in patients with hormone receptor–positive, HER2-low metastatic breast cancer (HR, 0.51; 95% CI, 0.40-0.64; P < .0001). The median overall survival (OS) was 23.9 months (95% CI, 20.8-24.8) vs 17.5 months (95% CI, 15.2-22.4), respectively (HR, 0.64; 95% CI, 0.48-0.86; P = .003).3,4

“The data from DESTINY-Breast04 represent the first time a HER2-targeted therapy has shown a survival benefit in patients with HER2-low metastatic breast cancer,” Susan Galbraith, MBBChir, PhD, said in a news release.1 “For more than 2 decades, only patients with HER2-positive breast cancer have been able to benefit from HER2-targeted therapies. If approved, [trastuzumab deruxtecan] will redefine how we classify and treat metastatic breast cancer, enabling patients whose tumors have lower levels of HER2 expression the opportunity to benefit from a HER2-directed therapy.” Galbraith is the executive vice president, oncology research and development at AstraZeneca.

Among all randomized patients the risk of disease progression or death was reduced by 50% with trastuzumab deruxtecan (HR, 0.50; 95% CI, 0.40-0.63). Specifically, the median PFS was 9.9 months (95% CI, 9.0-11.3) vs 5.1 months (95% CI, 4.2-6.8) with chemotherapy, and the median OS was 23.4 months (95% CI, 20.0-24.8) vs 16.8 months (95% CI, 14.5-20.0), respectively (HR, 0.64; 95% CI, 0.49-0.84; P = .001).3,4

The benefit extended to patients with hormone receptor–negative disease. The median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan vs 2.9 months (95% CI, 1.4-5.1) with chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). The median OS in this population was 18.2 months (95% CI, 13.6–not estimable) vs 8.3 months (95% CI, 5.6-20.6), respectively (HR, 0.48; 95% CI, 0.24-0.95).

“The results seen in the DESTINY-Breast04 trial represent a significant advance and reinforce the potential for trastuzumab deruxtecan to become a new standard of care for patients with previously treated HER2-low metastatic breast cancer,” Ken Takeshita, MD, global head of research and development at Daiichi Sankyo, said in a news release.1 He added that the priority review designation highlights the importance of these data. “We look forward to working with the FDA to potentially bring [trastuzumab deruxtecan] to patients with HER2-low metastatic breast cancer as quickly as possible.”

The most common all-grade treatment-related adverse effects for trastuzumab deruxtecan vs chemotherapy were nausea (73% vs 23.8%, respectively), fatigue (47.7% vs 42.4%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%).

In terms of interstitial lung disease, 12.1% of patients (n = 45) experienced an event—5 patients had a grade 3 event, and 3 patients had a grade 5 event. Further, 14 drug-related deaths occurred with trastuzumab deruxtecan (3.8%) vs 5 for physician’s choice of therapy (2.9%).


  1. Enhertu granted priority review in the U.S. for patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo. July 25, 2022. Accessed July 26,
  2. Eiger D, Agostinetto E, Saúde-Conde R, de Azambuja E. The exciting new field of HER2-low breast cancer treatment. Cancers (Basel). 2021;13(5):1015. doi:10.3390/cancers13051015
  3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40(suppl 17):LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3
  4. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
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