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DESTINY-Breast06 Trial Data Show Enhertu Improves Survival in Patients with HR-Positive, HER2-Low and HER2-Ultralow Metastatic Breast Cancer

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Trial data presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting show the potential of Enhertu (trastuzumab deruxtecan; AstraZeneca and Daiichi Sankyo) in the treatment of HR-positive, HER2-low and HER2-ultralow metastatic breast cancer (MBC). In the Phase III DESTINY-Breast06 trial (NCT04494425), Enhertu demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS) vs. standard-of-care chemotherapy among the patient population with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) MBC and in the overall trial population, including patients with HR-positive, HER2-low and HER2-ultralow breast cancer who were previously administered one or more lines of endocrine therapy.1

“DESTINY-Breast06 represents another potential paradigm shift in how we treat patients across the spectrum of HR-positive metastatic breast cancer,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, said in a press release. “The results reinforce the potential for Enhertu to improve outcomes earlier in the treatment landscape and in a broader population of patients with HER2-expressing breast cancer who have never before been eligible for a HER2-directed therapy.”1

A specifically engineered HER2-directed DXd antibody drug conjugate, Enhertu’s mechanism of action involves the humanized anti-HER2 IgG1 antibody trastuzumab attaching by a cleavable linker to the small molecule DXd. Trastuzumab then attaches to HER2 on tumor cells to inhibit growth, which causes the antibody to be internalized as lysosomal enzymes cleave off DXd. Subsequently, DXd causes DNA damage as it replicates and apoptotic cell death as a topoisomerase I inhibitor.2,3

In April, the FDA granted accelerated approval to Enhertu for adults with unresectable or metastatic HER2-positive, IHC 3+ solid tumors who were previously administered systemic therapy and who have no satisfactory alternative treatment options. The approval was based on findings from the Phase II DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials.4

The global, randomized, open-label, DESTINY-Breast06 trial enrolled 866 patients to compare Enhertu at a dose of 5.4 mg/kg vs. investigator’s choice of chemotherapy with capecitabine, paclitaxel, or nab-paclitaxel. The trial’s primary endpoint is PFS among patients with HR-positive, HER2-low MBC as measured by blinded independent central review (BICR), with key secondary endpoints that include PFS by BICR in the overall patient population, OS in the HER2-low patient population, and OS in the overall trial population.

The results show that Enhertu lowered the risk of disease progression or death by 38% per BICR compared with chemotherapy in patients with HER2-low expression (hazard ratio [HR] 0.62; 95% confidence interval [CI]: 0.51-0.74; p<0.0001). In the Enhertu cohort, median PFS was 13.2 months vs. 8.1 months in the chemotherapy cohort. In the overall patient population, Enhertu lowered the risk of disease progression or death by 37% compared with chemotherapy(HR 0.63; 95% CI: 0.53-0.75; p<0.0001).

“Enhertu continues to deliver pioneering results for a HER2-directed medicine across many different types of cancer,” said Ken Takeshita, global head, R&D, Daiichi Sankyo, in the release. “These latest results from DESTINY-Breast06 demonstrate clinically meaningful results with Enhertu even in tumours with very low levels of HER2 expression, suggesting that it may have an important role in treating a wide range of HER2-expressing metastatic breast cancer.”1

A prespecified exploratory analysis showed that among patients with HER2-ultralow expression, Enhertu lowered the risk of disease progression or death by 22% vs. chemotherapy, translating to a median PFS of 13.2 months compared with 8.3 months in the chemotherapy cohort (HR 0.78; 95% CI: 0.50-1.21).

“Endocrine therapies are widely used early in the treatment of HR-positive metastatic breast cancer, but following one or more lines of treatment, patients often derive limited efficacy from further endocrine-based therapy,” principal trial investigator Giuseppe Curigliano, MD, PhD, professor of Medical Oncology at the University of Milan and head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, Italy, said in the release. “With a median [PFS] of more than a year, the results from DESTINY-Breast06 show that Enhertu could become a new standard of care for patients with HER2-low- and HER2-ultralow-expressing tumors following endocrine therapy in the metastatic setting.”1

References
1. Enhertu demonstrated a median progression-free survival of 13.2 months in HR-positive, HER2-low and HER2-ultralow metastatic breast cancer following one or more lines of endocrine therapy. News release. AstraZeneca. June 2, 2024. Accessed June 6, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/Enhertu-demonstrated-median-progression-free-survival-thirteen-months.html#!
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. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-option-patients-her2-positive-breast-cancer-who-have-progressed-available. Accessed June 6, 2024.
3. Enhertu. Prescribing information. Daiichi Sankyo, Inc.; 2022. Accessed June 6, 2024.
4. ENHERTU Approved in the U.S. as First Tumor Agnostic HER2 Directed Therapy for Previously Treated Patients with Metastatic HER2 Positive Solid Tumors. News Release. Tokyo: Daiichi Sankyo; April 5, 2024. Accessed June 6, 2024. https://daiichisankyo.us/press-releases/-/article/enhertu-approved-in-the-u-s-as-first-tumor-agnostic-her2-directed-therapy-for-previously-treated-patients-with-metastatic-her2-positive-solid-tumors