New data from researchers at Memorial Sloan Kettering Cancer Center (MSK) featured in the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting press program and simultaneously published in The New England Journal of Medicine (NEJM) today highlights a novel antibody-drug conjugate for individuals with human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer, a newly defined targetable subset of breast cancer. The phase 3 international DESTINY-Breast04 trial found that trastuzumab deruxtecan (T-DXd) doubled progression-free survival (PFS) for patients with HER2-low metastatic breast cancer and significantly improved overall survival (OS) regardless of hormone receptor status, when compared with standard chemotherapy. Trial findings will be presented in the meeting’s press and plenary sessions on June 5, 2022, by Shanu Modi, MD, medical oncologist in the Breast Medicine Service at MSK.
“The results of DESTINY-Breast04 are practice-changing and redefine how a large population of metastatic patients will be treated,” said Dr. Modi. “Historically, HER2 status has been defined as positive versus negative, but we know that a large proportion of cancers within the HER2-negative classification also express low levels of HER2 – which we commonly refer to as HER2-low breast cancers – and this low level of HER2 may still be targetable. While our currently available HER2-targeted therapies unfortunately have not been effective for patients with HER2-low breast cancer, the efficacy of T-DXd has opened a novel treatment option for this newly defined patient population.”
The phase 3 DESTINY-Breast04 trial included 557 patients with HER2-low (as defined as immunohistochemistry [IHC] grade 1+ or IHC2+/in situ hybridization [ISH]-negative) metastatic breast cancer, previously treated with one to two prior lines of chemotherapy for metastatic disease. Participants were randomly assigned, on a two-to-one basis, either to treatment with T-DXd or the physician’s choice of several standard chemotherapy drugs. Dr. Modi and colleagues found that for patients with HER2-low and hormone receptor-positive (HR+) cancer who received T-DXd versus standard chemotherapy, PFS nearly doubled (10.1 months versus 5.4 months) and significantly improved OS (23.9 months versus 17.5 months).
“Approximately 60% of HER2-negative metastatic breast cancers express low levels of HER2, yet these have always been defined and treated as HER2-negative breast cancers, where treatment choice is guided by the hormone receptor status,” explained Dr. Modi. “Once there is resistance to the initial therapies, patients with HER2-low breast cancers have limited late-line targeted options and ultimately are offered palliative single agent chemotherapy. The results with T-Dxd shown today have the potential to significantly improve treatment outcomes for this large population of patients.”
Used in this trial, the novel antibody-drug conjugate (ADC), T-DXd, links trastuzumab, a HER2 monoclonal antibody, to deruxtecan, a topoisomerase I inhibitor that interrupts DNA replication in cancer cells. The combination of trastuzumab plus deruxtecan as an ADC is a breakthrough for this new subset of patients.
Dr. Modi’s initial research, published in NEJM in December 2019, led to the approval of T-DXd by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior anti-HER2-based treatment. In April 2022, the FDA granted Breakthrough Therapy Designation for T-DXd in HER2-low metastatic breast cancer. T-DXd is also being studied in multiple other HER2-targetable cancers, including gastric, lung, and colorectal cancers.