FDA Grants Priority Review to Trastuzumab Deruxtecan for HER2-low, HER2 Ultralow Breast Cancer

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

“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

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

REFERENCES

1. Enhertu (fam-trastuzumab deruxtecan-nxki) granted priority review in the US for patients with HER2-low or HER2-ultralow metastatic breast cancer who have received at least one line of endocrine therapy. News release. AstraZeneca. October 1, 2024. Accessed October 2, 2024. https://www.businesswire.com/news/home/20241001863203/en/ENHERTU%C2%AE-fam-trastuzumab-deruxtecan-nxki-granted-Priority-Review-in-the-US-for-patients-with-HER2-low-or-HER2-ultralow-metastatic-breast-cancer-who-have-received-at-least-one-line-of-endocrine-therapy

2. Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator's Choice Chemotherapy in HER2-low, Hormone Receptor Positive, Metastatic Breast Cancer (DB-06). ClinicalTrials.gov identification: NCT04494425. July 12, 2024. Accessed October 2, 2024. https://clinicaltrials.gov/study/NCT04494425

3. Bardia A, Hu X, Dent R, et al. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. Published online September 15, 2024. doi:10.1056/NEJMoa2407086