Trastuzumab Deruxtecan Improves PFS in Metastatic HR+/HER2-Low Breast Cancer After Endocrine Therapy

Treatment with fam-trastuzumab deruxtecan-nxki (Enhertu) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with standard-of-care (SOC) chemotherapy in patients with metastatic hormone receptor (HR)–positive, HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization [ISH]–) breast cancer after 1 or more lines of endocrine therapy, according to topline results from the phase 3 DESTINY-Breast06 trial (NCT04494425).¹

Furthermore, a statistically significant and clinically meaningful improvement in PFS was observed in the overall trial population, which included patients with HER2-low and HER2-ultralow disease (IHC 0 with membrane staining; IHC >0 <1+). Although overall survival (OS) data were not mature, a trend favoring trastuzumab deruxtecan was observed in both the overall and HR-positive, HER2-low populations.

No new safety signals were reported, and the safety profile of the antibody-drug conjugate was consistent with findings from previous clinical trials.

Full data from DESTINY-Breast06 will be presented at an upcoming medical meeting and shared with global health authorities.

“DESTINY-Breast06 shows that [trastuzumab deruxtecan] could become a new SOC for patients with HER2-low and HER2-ultralow metastatic breast cancer following 1 or more lines of endocrine therapy,” Susan Galbraith, executive vice president of Oncology R&D at AstraZeneca, stated in a news release. “These data underscore the potential for treatment with [trastuzumab deruxtecan] across the spectrum of HR-positive breast cancer, further redefining the treatment of metastatic breast cancer.”

In August 2022, the FDA approved trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. This approval was based on data from the phase 3 DESTINY-Breast04 trial (NCT03734029).²

DESTINY-Breast06 was a global, randomized, open-label trial that enrolled patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining; IHC >0 <1+) advanced or metastatic breast cancer. No prior chemotherapy for advanced or metastatic disease was permitted. Patients were required to have disease progression within 6 months of the initiation of first-line therapy consisting of endocrine therapy in combination with a CDK4/6 inhibitor, or they need to have at least 2 prior lines of endocrine therapy in the metastatic setting.¹

Investigators enrolled 866 patients with HER2-low (n = 713) or HER2-ultralow (n = 153) disease across sites in Asia, Europe, North America, and South America.

Patients were randomly assigned to receive trastuzumab deruxtecan or chemotherapy, which consisted of capecitabine (Xeloda), paclitaxel, or nab-paclitaxel (Abraxane).

PFS per blinded independent central review (BICR) in patients with HR-positive, HER2-low disease served as the trial’s primary end point. Secondary end points included OS in the HER2-low population; PFS per BICR and OS in the overall trial population; objective response rate; duration of response; time to first subsequent treatment or death; time to second subsequent treatment or death; and safety. Notably, analyses of the HER2-ultralow subgroup are not powered to demonstrate statistical significance.

“The topline results from DESTINY-Breast06 highlight the importance of continuing to challenge current treatment paradigms and established breast cancer classifications to evolve how we treat patients with HR-positive, HER2-expressing metastatic breast cancer,” Ken Takeshita, global head of R&D at Daiichi Sankyo, added in a news release. “Building on the practice-changing data seen in DESTINY-Breast04, these results reinforce the potential for use of [trastuzumab deruxtecan] earlier in the treatment landscape and in an even broader patient population.”

References

1. Enhertu demonstrated statistically significant and clinically meaningful improvement in progression-free survival in HR-positive, HER2-low metastatic breast cancer following one or more lines of endocrine therapy in DESTINY-Breast06 phase III trial. News release. AstraZeneca. April 29, 2024. Accessed April 29, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/enhertu-improved-pfs-in-her2-low-and-ultralow.html
2. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed April 29, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-her2-low-breast-cancer