Trastuzumab Deruxtecan Shows Improvement in PFS in Patients With HR+, HER2-Low Metastatic Breast Cancer

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The investigators note that additional research is needed to confirm positive overall survival trends in this patient population.

Results from the phase 3 trial, DESTINY-Breast06 (NCT04494425), demonstrated that trastuzumab deruxtecan (T-DXd, Enhertu; AstraZeneca and Daiichi Sankyo), compared with standard of care chemotherapy, showed both statistically significant and clinically meaningful improvement in progression-free survival (PFS) in patients with HR+, HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer following 1 or more lines of endocrine therapy. Additionally, improvement in PFS was also observed in the overall patient population.1

X-ray image of tumor in breast -- Image credit: Sebastian Kaulitzki | stock.adobe.com

Image credit: Sebastian Kaulitzki | stock.adobe.com

T-DXd is a HER2- directed antibody drug conjugate (ADC) that is made up by a HER2 monoclonal antibody attached to topoisomerase I inhibitor payloads by tetrapeptide-based cleavable linkers. Currently, T-DXd is approved for multiple indications in adult populations who have received prior lines of systemic or neoadjuvant therapy, including patients with some forms of breast cancer, gastric or gastroesophageal junction adenocarcinoma, non-small cell lung cancer, and other unresectable or metastatic HER2-positive (IHC 3+) solid tumors. Prior to its approval, there were no targeted therapies that were approved specifically for patients with an HER2-low expression.1

DESTINY-Breast06 is a global, randomized, open-label phase 3 that evaluated the efficacy and safety of T-DXd in patients with HR+, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow advanced or metastatic breast cancer compared with the investigator’s choice of standard of care chemotherapy (capecitabine, paclitaxel, or nab-paclitaxel). A total of 866 patients (HER2-low: n = 713; HER2-ultralow: n = 153) were enrolled in the trial. These patients had no prior chemotherapy for advanced or metastatic disease and either experienced disease progression within 6 months of initiating first line treatment with endocrine therapy with a CDK4/6 inhibitor, or received at least 2 prior lines of endocrine therapy in the metastatic setting.1,2

About the Trial

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 19, 2026

The trial’s primary end point is PFS in the HR+, HER2-low patient population until disease progression or death that is assessed up to approximately 60 months. The key secondary end point is overall survival (OS) in the HER2-low expression as well as patients in the overall population. Other secondary end points include objective response rate, duration of response, time to first subsequent treatment or death, time to second subsequent treatment or death, and safety, all of which were assessed up to approximately 60 months.1,2

The findings show that T-DXd demonstrated statistically significant and clinically meaningful improvement in PFS in both patients with HER-positive, HER2-low metastatic breast cancer and the overall trial population. Additionally, a prespecified subgroup analysis showed that improvement was consistent between patients with HER2-low and HER2-ultralow expressions. Further, the safety profile of T-DXd is consistent with prior clinical trials that evaluated its use as a treatment in breast cancer, and no new safety signals were observed.1

The investigators note that OS data was not mature at the time of analysis, though there were indications of a positive trend toward OS improvement in patients with HER2-low metastatic breast cancer and in the overall trial population. Further research is necessary to confirm these trends.1

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

A prior trial, DESTINY-Breast04 (NCT03734029), studied the efficacy of T-DXd compared with chemotherapy in patients with HR+ tumors. The results demonstrated that the median PFS was about 10.1 months in the T-DXd cohort compared with the chemotherapy cohort, which was 5.4 months. Similarly, the intent-to-treat (ITT) population had a median PFS of 9.9 months in the T-DXd group and 5.1 in the chemotherapy group. OS was also stronger in the T-DXd group compared with the chemotherapy group (23.9 vs 17.5 months).3

An exploratory analysis specifically in patients with triple-negative breast cancer (42 patients in the T-DXd arm) demonstrated PFS and OS results consistent with the HR+ and ITT populations, with a median PFS of 8.5 months and 2.9 months in the T-DXD and chemotherapy groups, respectively. The positive results from the DESTINY-Breast04 trial helped T-DXd get approved by the FDA for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who received prior lines of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.3

“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+, HER2-expressing metastatic breast cancer,” said Ken Takeshita, global head, R&D, Daiichi Sankyo, in the press release. “Building on the practice-changing data seen in DESTINY-Breast04, these results reinforce the potential for use of [T-DXd] earlier in the treatment landscape and in an even broader patient population.”1

References
1. AstraZeneca. Enhertu demonstrated statistically significant and clinically meaningful improvement in progression-free survival in HR+, HER2-low metastatic breast cancer following one or more lines of endocrine therapy in DESTINY-Breast06 Phase III trial. News release. April 29, 2024. Accessed April 30, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/enhertu-improved-pfs-in-her2-low-and-ultralow.html
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 identifier: NCT04494425. Updated April 12, 2024. Accessed April 30, 2024. https://clinicaltrials.gov/study/NCT04494425
3. Antrim, A. FDA Experts Review Data, Regulatory Insights for New Metastatic Breast Cancer Therapies. Pharmacy Times. https://www.pharmacytimes.com/view/fda-experts-review-data-regulatory-insights-for-new-metastatic-breast-cancer-therapies
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