Trastuzumab Deruxtecan Receives Priority Review for Select Patients With HER2+ Metastatic Breast Cancer


A supplemental biologics license application has been granted to trastuzumab deruxtecan-nxki for the treatment of adult patients with select HER2-positive breast cancer.

Fam-trastuzumab deruxtecan-nxki (Enhertu) has been granted a priority review as a therapy for adults with unresectable or metastatic HER2-positive breast cancer who have been pretreated with another anti–HER2-based regimen.1

The decision is based on findings from the phase 3 DESTINY-Breast03 trial (NCT03529110), in which the blinded independent central review (BICR)–assessed median progression-free survival (PFS) with trastuzumab deruxtecan (n = 261) had not yet been reached (95% CI, 18.5–not evaluable [NE]) vs 6.8 months (95% CI, 5.6-8.2) with trastuzumab emtansine (Kadcyla; T-DM1; n = 263), translating to a 72% reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10-22).2 The 12-month PFS rates in the investigative and control arms were 75.8% (95% CI, 69.8%-80.7%) and 34.1% (95% CI, 27.7%-40.5%), respectively.

The median overall survival (OS) was NE in both treatment arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). the 12-month OS rate with trastuzumab deruxtecan was 94.1% (95% CI, 90.3%-96.4%) vs 85.9% (95% CI, 80.9%-89.7%) with T-DM1.

“This regulatory review of [trastuzumab deruxtecan] in the United States marks the first time this medicine is participating in both the Real-Time Oncology Review and Project Orbis programs,” Ken Takeshita, MD, global head of R&D at Daiichi Sankyo, stated in a press release. “The FDA’s prioritization of our application underscores the potential of this medicine and the continued need to expedite the availability of new treatment options, while making it possible to potentially receive approvals in several countries concurrently.”

The open-label, multicenter DESTINY-Breast03 trial enrolled patients with unresectable or metastatic HER2-positive breast cancer who received prior treatment with trastuzumab (Herceptin) and a taxane in the advanced or metastatic setting. Notably, patients with clinically stable, treated brain metastases were permitted.

Study participants were randomized 1:1 to receive either trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks or T-DM1 at 3.6 mg/kg every 3 weeks. Stratification factors comprised hormone receptor status, previous treatment with pertuzumab (Perjeta), and history of visceral disease.

The primary end point of the trial was PFS per BICR assessment and a key secondary end point was OS. Other secondary end points included objective response rate (ORR) per BICR and investigator, duration of response (DOR) per BICR, investigator-assessed PFS, and safety.

The most common grade 3 or higher treatment-related, treatment-emergent adverse effects reported with trastuzumab deruxtecan included neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in alanine aminotransferase (1.6%), decreased appetite (1.2%), increase in aspartate aminotransferase (0.8%), diarrhea (0.4%), and alopecia (0.4%).

Moreover, 10.5% of patients experienced interstitial lung disease (ILD) or pneumonitis associated with treatment, as determined by an independent adjudication committee. Most of these events (9.7%), were grade 1 (2.7%) or grade 2 (7.0%), although 2 grade 3 effects (0.8%) were reported. Notably, no grade 4 or 5 ILD or pneumonitis was observed.

In addition, manufacturers urge providers to assess left ventricular ejection fraction (LVEF) in patients prior to treatment with trastuzumab deruxtecan, and to continue to assess periodically throughout treatment. If LVEF reaches 40-45% and there has been a decrease between 10-20% since baseline, treatment should be put on hold and LVEF should be reassessed in 3 weeks. If LVEF has not returned to within 10% of baseline, treatment should be discontinued.

Complete blood counts should be monitored to assess potential neutropenia—as severe neutropenia was found to occur in a high volume of patients. If absolute neutrophil counts reach grade 3 (<1.0 to 0.5 x 109/L), treatment should be interrupted until counts return to grade 2 or less.

In the event of grade 3 thrombocytopenia a (platelets <50 to 25 x 109/L), treatment should be stopped until grade 1 or less is reached, then dose may be maintained. If AE reaches grade 4 (<25 x 109/L), treatment should be stopped until grade 1 or less. Treatment dose should then be reduced by 1 level.

“The review across geographies and the priority review in the United States as part of Project Orbis is so important because it speaks to the transformative potential of [trastuzumab deruxtecan] based on the unprecedented PFS benefit in this setting,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a press release.3 “The news reinforces the importance of bringing this potential new option to patients as quickly as possible.”

In October 2021, the FDA granted a breakthrough therapy designation to trastuzumab deruxtecan for use in adult patients with unresectable or metastatic HER2-positive breast cancer who previously received 1 or more anti–HER2-based regimens.4 The designation was based on data from DESTINY-Breast03.


  1. ENHERTU granted priority review in the US for patients with HER2 positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. Daiichi Sankyo Company, Limited; January 17, 2022. Accessed January 17, 2022.
  2. Cortés J, Kim S-B, Chung W-P, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: results of the randomized, phase 3 study DESTINY-Breast03. Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
  3. Enhertu granted priority review in the US for patients with HER2-positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. AstraZeneca; January 17, 2022. Accessed January 17, 2022.
  4. Enhertu granted breakthrough therapy designation in US for patients with HER2-positive metastatic breast cancer treated with one or more prior anti-HER2-based regimens. News release. AstraZeneca; October 4, 2021. Accessed January 17, 2022.

This article was originally published on OncLive as “FDA Grants Priority Review to Trastuzumab Deruxtecan for Select HER2+ Metastatic Breast Cancer”

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