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Enhertu Shows Significant Survival Benefit Over Chemotherapy in HR-Positive, HER2-Low Metastatic Breast Cancer

Image credit: Sebastian Kaulitzki |

Treatment with Enhertu (trastuzumab deruxtecan) produced improved progression-free survival (PFS) compared with standard-of-care chemotherapy in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or 2+/ISH-) metastatic breast cancer (MBC) following one or more prior lines of endocrine therapy, according to data from the Phase III DESTINY-Breast06 trial.1 Enhertu, a HER2-directed antibody-drug conjugate jointly developed and commercialized by AstraZeneca and Daiichi Sankyo, has approved indications in breast cancer, non-small cell lung cancer, and gastroesophageal junction adenocarcinoma.

“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,” said Ken Takeshita, global head, R&D, Daiichi Sankyo, in a press release. “Building on the practice-changing data seen in DESTINY-Breast04, these results reinforce the potential for use of Enhertu earlier in the treatment landscape and in an even broader patient population.”1

The mechanism of action of Enhertu involves the humanized anti-HER2 IgG1 antibody trastuzumab attaching by a cleavable linker to the small molecule DXd, which then links to HER2 on tumor cells to halt growth and causes the antibody to be internalized as lysosomal enzymes cleave off DXd. DXd subsequently causes DNA damage as it replicates and apoptotic cell death as a topoisomerase I inhibitor.2,3

The global, randomized, open-label, DESTINY-Breast06 trial analyzed Enhertu’s efficacy and safety at a dose of 5.4 mg/kg compared with investigator’s choice of chemotherapy with capecitabine, paclitaxel, or nab-paclitaxel in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (defined as IHC 0 with membrane staining; IHC >0<1+) advanced or metastatic breast cancer. Investigators enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) who had not previously received chemotherapy for advanced or metastatic disease and who either experienced disease progression within six months of starting first-line combination treatment with an endocrine therapy plus a CDK4/6 inhibitor or who were previously administered at least two lines of endocrine therapies in the metastatic setting.

The trial’s primary endpoint was PFS in the HR-positive, HER2-low patient population as determined by blinded independent central review (BICR). Key secondary endpoints included overall survival (OS) in patients with HER2-low expression, PFS by BICR and OS in the overall trial population, as well as objective response rate, duration of response, time to first subsequent treatment or death, time to second subsequent treatment or death, and safety.

Investigators noted a statistically significant and clinically meaningful improvement in PFS among the primary trial population of patients with HR-positive, HER2-low MBC administered Enhertu vs. those administered chemotherapy. Further, they also observed statistically significant and clinically meaningful improvements in PFS in the overall trial population of patients with HER2-low and HER2-ultralow MBC. The clinically meaningful survival improvement was found to be consistent between patients with HER2-low and HER2-ultralow expression as part of a prespecified subgroup analysis.

OS data were immature at the time of the evaluation but showed an early trend in OS improvement in patients administered Enhertu compared with chemotherapy in patients with HER2-low MBC, as well as in the overall trial population. The trial is ongoing to further evaluate OS and additional secondary endpoints. In a press release, AstraZeneca stated that it will share the data at an upcoming medical meeting and with global regulatory authorities.

“DESTINY-Breast06 shows that Enhertu could become a new standard of care for patients with HER2-low and HER2-ultralow metastatic breast cancer following one or more lines of endocrine therapy,” said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in a press release. “These data underscore the potential for treatment with Enhertu across the spectrum of HR-positive breast cancer, further redefining the treatment of metastatic breast cancer.”1


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.

2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. U.S. Food and Drug Administration. Accessed April 29, 2024.

3. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed April 29, 2024.