FDA Approves Trastuzumab Deruxtecan for Unresectable or Metastatic HER2-Low Breast Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with unresectable or metastatic HER2-low breast cancer.

The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with unresectable or metastatic HER2-low breast cancer.1

The regulatory decision is based on data from the phase 3 DESTINY-Breast04 trial (NCT03734029), in which the antibody-drug conjugate (ADC) was found to significantly improve progression-free survival (PFS) and overall survival (OS) over physician's choice of chemotherapy in this patient population.2

Trastuzumab deruxtecan resulted in a median PFS of 10.1 months (95% CI, 9.5-11.5) vs 5.4 months (95% CI, 4.4-7.1) with chemotherapy (HR, 0.51; 95% CI, 0.40-0.64; P < .0001) in patients with hormone receptor–positive, HER2-low metastatic breast cancer. Moreover, the median OS was 23.9 months (95% CI, 20.8-24.8) with the ADC compared with 17.5 months (95% CI, 15.2-22.4) with chemotherapy (HR, 0.64; 95% CI, 0.40-0.86; P = .003).

“Today’s approval highlights the FDA’s commitment to be at the forefront of scientific advances, making targeted cancer treatment options available for more patients,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, stated in a press release. “Having therapies that are specially tailored to each patient’s cancer subtype is a priority to ensure access to safe and innovative treatments.”

For the study, 557 patients were randomly assigned 2:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Chemotherapy was comprised of capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).

Low expression of HER2 was defined as an immunohistochemistry (IHC) score of 1+ or 2+ with a negative in situ hybridization (ISH) test. Overall, 88.7% (n = 494) of patients were hormone receptor positive and 11.3% (n = 63) were negative.

Patient characteristics were noted to be well balanced between the arms. In the investigative arm, the median age of patients was 57.5 years (range, 31.5-80.2) and 99.5% were female. HER2-low was IHC 1+ for 57.6% of patients and IHC 2+ and ISH-negative for 42.4%.

ECOG performance status was split between 0 in 53.6% of patients and 1 in 46.4% of patients. The primary locations of metastases were the brain (6.4%), liver (71.3%), and lung (32.2%). Patients had received a median of 3 (range, 1-9) previous lines of therapy, which consisted of targeted or immunotherapy (74.8%), endocrine therapy (93.0%), and chemotherapy (100%).

Additional data presented during the 2022 ASCO Annual Meeting showed that among all patients who had been enrolled to DESTINY-Breast04, the median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan vs 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). The median OS was 23.4 months (95% CI, 20.0-24.8) in the investigative arm vs 16.8 months (95% CI, 14.5-20.0) in the control arm, translating to a 6.6-month improvement in survival with the ADC (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

In the cohort of patients with hormone receptor–negative disease, the median PFS with the ADC was 8.5 months (95% CI, 4.3-11.7) vs 2.9 months (95% CI, 1.4-5.1) with chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). In this group, the median OS was 18.2 months (95% CI, 13.6-not estimable) in those who received trastuzumab deruxtecan compared with 8.3 months (95% CI, 5.6-20.6) in those who were treated with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

In patients, trastuzumab deruxtecan elicited an overall response rate (ORR) of 52.3% (95% CI, 47.1%-57.4%) vs 16.3% (95% CI, 11.3%-22.5%) with chemotherapy. In the hormone receptor–negative cohort, the ORRs were 50.0% (95% CI, 33.8%-66.2%) and 16.7% (95% CI, 3.6%-41.4%) for trastuzumab deruxtecan (n = 40) and chemotherapy (n = 18), respectively.

In the cohort of patients with hormone receptor–positive disease, the ORR was 52.6% (95% CI, 47.0%-58.0%) with the ADC (n = 333) vs 16.3% (95% CI, 11.0%-22.8%) with chemotherapy (n = 166). Here, the median duration of response was 10.7 months with trastuzumab deruxtecan vs 6.8 months with physician's choice.

The most common toxicities experienced by patients who received trastuzumab deruxtecan in DESTINY-Breast04 included nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, musculoskeletal pain and diarrhea.

Moreover, the prescribing information includes a boxed warning to advise of the risk of interstitial lung disease and embryo-fetal toxicity.


  1. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed August 5, 2022. https://bit.ly/3d4X2JQ
  2. 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):abstr LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3