The designation was based on results from the DESTINY-Breast06 trial, evaluating fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) compared with chemotherapy.
The FDA has accepted and granted priority review to the supplemental Biologics License Application (BLA) for fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) for the treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 ultralow (IHC 0 with membrane staining) breast cancer who have received at least 1 endocrine therapy in the metastatic setting.1
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“While endocrine therapies are widely used in the initial treatment of HR-positive metastatic breast cancer, most patients see limited benefit with additional lines of treatment, and subsequent chemotherapy is often associated with poor response rates and outcomes. The results from DESTINY-Breast06 show that Enhertu has the potential to evolve the current HR-positive treatment landscape and become the first targeted treatment for patients with HER2-low or HER2-ultralow expression following endocrine therapy,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, said in a news release.1
The designation was based on positive results from the DESTINY-Breast06 (NCT04494425) phase 3 trial, which evaluated the drug in comparison to chemotherapy. Investigators included individuals who had disease progression on at least 2 lines of prior endocrine therapy for metastatic disease or disease progression within 6 months of starting the first-line treatment for metastatic disease, specifically with endocrine therapy and a CDK4/6 inhibitor, according to the clinical trial information. Patients also have historically confirmed HR positive, either estrogen receptor and/or progesterone receptor positive, HER2-low, or HER2 IHC >0 <1+ expression confirmed by laboratory testing.2
The primary outcome included progression free survival (PFS) in the HR+, HER2-low population. Secondary end points included overall survival (OS) in the same population; PFS in the HER2-low and ultralow populations; OS in the HER2-low and ultralow populations; objective response rate (ORR) for the HR+, HER2-low population; duration of response (DOR) for the HR+, HER2-low population; and safety and tolerability.2
Trial Name: Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer (DB-06)
ClinicalTrials.gov ID: NCT04494425
Sponsor: AstraZeneca
Completion Date (Estimated): June 2026
From August 20, 2020, to March 18, 2024, investigators included a total of 866 individuals from 324 sites, with 436 in the fam-trastuzumab deruxtecan-nxki group and 430 in the chemotherapy group (59.8% received capecitabine, 24.4% nabpaclitaxel, and 15.8% paclitaxel). There were 713 in the HER2-low population and 153 in the ultralow population, according to the study authors.3
The median PFS for fam-trastuzumab deruxtecan-nxki was 13.2 months compared with 8.1 months with the chemotherapy group. For the intent-to-treat population, PFS was 13.2 months and 8.1 months, respectively. Investigators reported the PFS for the ultralow population was similar with 13.2 months and 8.3 months, respectively.3
For OS in the HER2-low population, investigators reported that the data were 38.9% mature in the fam-trastuzumab deruxtecan-nxki group and 41.2% mature in the chemotherapy group. The 12-month estimated OS rates were 87.6% and 81.7%, respectively. In the ultralow population, OS was similar.3
With regard to ORR, the HER2-low population rate was 56.2% with fam-trastuzumab deruxtecan-nxki compared with 32.3% with chemotherapy. Complete responses were reported in 2.5% and 0% of patients, respectively. For the ultralow population, the ORR was 61.8% and 26.3%, respectively. Further, in the intent-to-treat population, the DOR was 14.3 months and 8.6 months, respectively.3
As for safety, the incidence of adverse events (AEs) was similar in the 2 groups, at 98.8% in the fam-trastuzumab deruxtecan-nxki group and 95.2% in the chemotherapy group. The most common drug-related AEs included nausea, fatigue, and alopecia for fam-trastuzumab deruxtecan-nxki and fatigue, palmar-plantar erythrodysesthesia syndrome, and neutropenia in the chemotherapy group. As for grade 3 AEs, the rate reported in the fam-trastuzumab deruxtecan-nxki group was 52.8% and 44.4% in the chemotherapy group, with the most common being neutropenia, leukopenia, and anemia in both groups.3
Furthmore, serious AEs occurred in 20.3% and 16.1% of the fam-trastuzumab deruxtecan-nxki and chemotherapy groups, respectively, with 2.5% and 1.4%, respectively, being fatal.3
Fam-trastuzumab deruxtecan-nxki was previously granted breakthrough therapy designation by the FDA for this indication.1
