FDA Approves Trastuzumab Deruxtecan for Unresectable or Metastatic HER2+ Breast Cancer


Fam-trastuzumab deruxtecan-nxki is now an FDA-approved regimen for the treatment of patients with unresectable or metastatic HER2-positive breast cancer.

The FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu) as a treatment option for adults with unresectable or metastatic HER2-positive breast cancer and have already received anti–HER2-based treatments in the metastatic, neoadjuvant or adjuvant settings, and have experienced disease recurrence during or within 6 months of therapy completion.1

Previously, in December 2019, the antibody-drug conjugate was granted an accelerated approval from the regulatory agency for use in adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.

The multicenter, open-label, DESTINY-Breast03 trial (NCT03529110) served as the confirmatory trial for the approval.2 To be eligible for enrollment, patients needed to have HER2-positive, unresectable or metastatic breast cancer that had progressed during or following treatment with trastuzumab (Herceptin) and a taxane in the context of advanced or metastatic disease or that had progressed within 6 months following neoadjuvant or adjuvant treatment involving trastuzumab or a taxane. Those with clinically stable, previously treated brain metastases were permitted.

If patients had brain metastases that were symptomatic or required treatment; if they previously received a HER2-targeted ADC, including trastuzumab emtansine (Kadcyla; T-DM1), for metastatic disease; or if they had a history of noninfectious ILD for which they had been given glucocorticoids, they were excluded.

A total of 524 study participants were randomized 1:1 to receive intravenous (IV) trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 261) vs IV T-DM1 at 3.6 mg/kg every 3 weeks (n = 263). Treatment was administered until disease progression or intolerable toxicity.

Stratification factors included hormone receptor status (positive vs negative), previous treatment with pertuzumab (Perjeta; yes vs no), and history of visceral disease (yes vs no).

The primary end point of the trial was progression-free survival (PFS) per blinded independent central review (BICR), and overall survival (OS) served as a key secondary end point. Other end points included overall response per BICR and investigator assessment, investigator-assessed PFS, and safety.

Demographic and baseline disease characteristics were found to be comparable between the 2 treatment arms, and were also determined to be largely representative of the overall population of patients with HER2-positive breast cancer.

Of note, 49.8% of those in the investigative arm and 46.8% of those in the control arm had received 1 prior line of therapy, not including endocrine therapy, for metastatic disease. Moreover, 62.1% of those in the trastuzumab deruxtecan arm vs 60.1% of those in the T-DM1 arm previously received pertuzumab. Stable brain metatases were noted in 23.8% and 19.8% of patients, respectively.

The median follow-up in the investigative arm was 16.2 months (range, 0-32.7) vs 15.3 months (range, 0-31.3) in the control arm. Trastuzumab deruxtecan significantly improved PFS vs T-DM1. Specifically, the median PFS was not yet reached (95% CI, 18.5–not estimable [NE]) in the investigative arm vs 6.8 months (95% CI, 5.6-8.2) in the control arm (HR, 0.28; 95% CI, 0.22-0.37; <.0001).

Moreover, at 12 months, 75.8% (95% CI, 69.8%-80.7%) of patients who received trastuzumab deruxtecan were still alive and free of disease progression vs 34.1% (95% CI, 27.7%-40.5%) of those who were given T-DM1.

Per investigator assessment, the median PFS in the investigative arm was 25.1 months (95% CI, 22.1-NE) vs 7.2 months (95% CI, 6.8-8.3) in the control arm (HR, 0.26; 95% CI, 0.20-0.35; <.001).

Notably, the PFS benefit achieved with trastuzumab deruxtecan over T-DM1 was noted across all subsets of patients examined, irrespective of prior lines of therapy received.

At the data cutoff of May 21, 2021 for the interim analysis, 94.1% (95% CI, 90.3%-96.4%) of patients in the investigative arm will still alive at 12 months vs 85.9% (95% CI, 80.9%-89.7%) of those in the control arm (HR, 0.55; 95% CI, 0.36-0.86; =.007). The difference between the treatment arms was not found to be statistically significant, although the data are immature.

Moreover, the objective response rate based on the patients with measurable disease assessed by BICR at baseline was 82.7% (95% CI, 77.4%-87.2%) with trastuzumab deruxtecan vs 36.1% (95% CI, 30.0%-42.5%) with T-DM1.

Regarding safety, the most frequent toxicities experienced by patients who received trastuzumab deruxtecan were nausea, fatigue, vomiting, alopecia, constipation, anemia, and musculoskeletal pain.

Serious effects that were reported in more than 1% of patients who received the ADC included vomiting, ILD, pneumonia, pyrexia, and urinary tract infection.

The FDA stated that prescribing information for trastuzumab deruxtecan includes a Boxed Warning to advise of the risk of ILD and embryo-fetal toxicity.


  1. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed May 4, 2022. https://bit.ly/3ybhZLL
  2. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022

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