- Recently published in The New England Journal of Medicine, results from the phase 3, multicenter DESTINY-06 clinical trial show that treatment with the antibody drug conjugate trastuzumab deruxtecan (T-DXd) significantly improved progression-free survival compared with chemotherapy in patients with hormone receptor-positive (HR+) metastatic breast cancer with low or ultralow levels of HER2 whose disease had already failed prior endocrine-based therapy.
- Trastuzumab deruxtecan is approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for patients with HR+ HER2-low metastatic breast cancer whose disease has progressed after one or more lines of endocrine therapy and chemotherapy. This antibody drug conjugate recently received reimbursement authorization from the Spanish Agency of Medicines and Medical Devices (AEMPS) and Spanish Ministry of Health.
- Results from this phase 3 study suggest that T-DXd is effective in earlier lines of therapy, even when patients have not been exposed to conventional chemotherapy.
Results from the phase 3, mutlicenter, open-label DESTINY-Breast06 trial, recently published online ahead of print in The New England Journal of Medicine1, show that the antibody drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) improved progression-free survival versus conventional chemotherapy in patients with hormone receptor-positive (HR+) metastatic breast cancer with low or ultralow levels of HER2 expression, who had received one or more lines of prior endocrine-based therapy but no chemotherapy for metastatic disease.
Low or ultralow levels of the HER2 protein
Female breast cancer is the second leading cause of global cancer incidence in 2022, with an estimated 2.3 million new cases, comprising 11.6% of all cancer cases. Among women, breast cancer is the most commonly diagnosed cancer, and it is the leading cause of cancer deaths globally2. Approximately 70% of all breast cancers are classified as being HR+.
“Advanced breast tumors with low HER2 expression levels were typically categorized as being HER2-negative because HER2 targeted therapies do not generally show efficacy in this setting. As we develop more effective treatment strategies and discover more about these tumors, the spectrum of HER2 expression and therapeutic status has expanded to include the HER2-low and ultra-low subcategories.” said Cristina Saura, Head of the Vall d’Hebron University Hospital’s Breast Cancer Unit and the Vall d’Hebron Institute of Oncology’s (VHIO) Breast Cancer Group.
Data from the DESTINY-Breast04 randomized clinical trial, presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting—also published in The New England Journal of Medicine3 and co-authored by Cristina Saura—led to the approval of T-DXd in the USA and Europe for the treatment of patients with HR+ HER2-low metastatic breast cancer whose disease had already failed endocrine therapy and one or more lines of chemotherapy. The Spanish Agency of Medicines and Medical Devices (AEMPS) and Spanish Ministry of Health recently approved the reimbursement of T-DXd for this indication in Spain.
T-DXd in earlier lines of treatment
Based on these successes, the investigators hypothesized that T-DXd could also be effective in earlier lines of treatment, even when patients have not been exposed to conventional chemotherapy.
“DESTINIY-06 was designed to evaluate the efficacy and safety of trastuzumab deruxtecan compared with the treating physician’s choice of chemotherapy in patients with HR+ HER2-low or ultralow metastatic breast cancer who had already received one or more lines of endocrine therapy, but no prior chemotherapy for metastatic disease,” explained Saura, a co-author of this present study.
A total of 866 patients who had HR+ tumors which expressed either low or ultralow levels of HER2 were randomly assigned (1:1 ratio) to receive either T-DXd or physician’s choice chemotherapy. A 38% reduction in risk of disease progression was observed in patients with HER2-low disease in the T-DXd group compared with the chemotherapy group. Progression-free survival was 13.2 months in those patients who received T-DXd versus 8.1 months in those who received chemotherapy. These results were consistent in the subgroup of 153 patients with HER2-ultralow disease.
“These results are especially relevant since they suggest that treatment with this antibody drug conjugate, even at low HER2 expression levels, could be more effective in earlier lines of therapy compared with conventional chemotherapy, thus extending the potential benefits of HER2-directed therapy to an increasing number of patients,” concluded Cristina Saura.
While this new therapeutic indication has not yet been approved by the regulatory authorities, results from this present study could pave the way for new treatment options in metastatic breast cancer for this patient population.
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References
- Bardia A, Hu X, Dent R, Yonemori K, Barrios CH, O’Shaughnessy JA, Wildiers H, Pierga JY, Zhang Q, Saura C, Biganzoli L, Sohn J, Im SA, Lévy C, Jacot W, Begbie N, Ke J, Patel G, Curigliano G; DESTINY-Breast06 Trial Investigators. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024 Sep 15. doi: 10.1056/NEJMoa2407086. Epub ahead of print.
- Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263.
