‘Enhertu sets new standard in breast cancer treatment’

Demonstrated efficacy in patients who failed endocrine therapy … rises as a new option for HR+/HER2- patients

Beyond low expression to ultra-low… shifting the HER2 treatment landscape

Enhertu is setting a new standard in HER2-positive breast cancer. With its treatment scope expanding beyond conventional HER2-positive and HER2-low populations to include ultra-low HER2 expression, the therapy is being viewed as a potential turning point in treatment strategy, particularly for HR+/HER2- low-expression metastatic breast cancer patients whose options were previously limited after endocrine therapy failure.

Professor Seok-Ah Im, Department of Hematology-Oncology, Seoul National University Hospital

On the 20th, Daiichi Sankyo Korea and AstraZeneca Korea held a press conference at The Plaza Hotel in Jung-gu, Seoul, to commemorate the indication expansion of the antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan).

The newly approved indication added last month is Enhertu as monotherapy for the treatment of adult patients with unresectable or metastatic breast cancer exhibiting HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 ultra-low expression (IHC 0 with membrane staining), who have previously received one or more endocrine therapies in the metastatic setting.

Enhertu is considered a therapy with broad potential across multiple solid tumors. While first-generation ADCs such as Roche’s Kadcyla (trastuzumab emtansine) remained largely confined to breast cancer indications, second-generation ADCs have successfully secured diverse indications. Enhertu, in particular, has demonstrated efficacy across various solid tumor types, including breast cancer, non-small cell lung cancer, and colorectal cancer.

ADCs are novel anticancer drugs created by linking an antibody that binds to a specific target antigen on the surface of cancer cells with a cytotoxic drug via a linker. The advantage of ADCs is that they leverage the antibody's selectivity for its target and the drug's cytotoxic activity to ensure the drug acts selectively only on cancer cells, thereby enhancing therapeutic efficacy while minimizing side effects.

Hormone receptor-positive (HR+) / HER2-negative (HER2-) breast cancer represents the most common subtype, accounting for approximately 70% of all breast cancers. Although generally associated with a more favorable prognosis relative to other subtypes, patients who are unsuitable for endocrine therapy or develop resistance often face limited treatment options, with chemotherapy remaining the primary alternative. The PFS achievable with first-line therapy is only about 6 months, indicating a high unmet clinical need.

The basis for the expanded indication is the Phase III DESTINY-Breast06 trial.

The trial enrolled 866 adult patients with metastatic HR-positive breast cancer who were HER2-low or HER2-ultra-low, had previously received endocrine therapy, and had no prior chemotherapy history in the advanced or metastatic setting.

In this study, HER2 ultra-low expression was defined as faint and incomplete HER2 staining on the cell membrane observed in 10% or fewer tumor cells (IHC 0 for membrane staining; in this study, IHC >0 and <1+).

Patients were randomized 1:1 to receive either Enhertu or the physician’s choice chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel).

Results demonstrated that Enhertu significantly extended median PFS to 13.2 months, compared with 8.1 months in the chemotherapy arm, based on blinded independent central review (BICR).

Enhertu also achieved an objective response rate (ORR) of 57.3%, nearly 1.8 times higher than the 31.2% observed in the control group. Complete responses (CR), absent in the chemotherapy cohort, were observed in approximately 3% of patients in the Enhertu group.

In terms of safety, adverse events were consistent with prior Enhertu studies. However, one Grade 5 interstitial lung disease (ILD) event associated with drug administration occurred..

Professor Seok-Ah Im, Department of Hematology-Oncology at Seoul National University Hospital, said, “Enhertu demonstrated a median progression-free survival exceeding 1 year while maintaining patient quality of life, suggesting a fundamental shift in treatment strategy. Following failure of endocrine therapy and CDK4/6 inhibitors, Enhertu has become the global standard of care.”

Clinical benefit extends from low to ultra-low expression… redefining HER2 treatment standards

Professor Gyeong Yeop Kong, Department of Pathology at Asan Medical Center

The subtype accounts for approximately 20–25% of breast cancer cases and tends to progress more rapidly and aggressively than other subtypes.

Prior to Enhertu’s introduction, HER2 classification relied primarily on immunohistochemistry (IHC), categorizing tumors as HER2-negative or HER2-positive.

IHC testing categorizes protein expression as 0, 1, 2, or 3, with 1 classified as HER2-negative and 3 as HER2-positive. Cases with a score of 2 are determined via in situ hybridization (ISH) analysis.

However, Enhertu demonstrates efficacy even in patients with low or ultra-low expression (IHC scores 0 or 1), establishing itself as a new standard treatment option across the entire HER2 expression spectrum.

Professor Gyeong Yeop Kong of the Department of Pathology at Asan Medical Center said, “The expansion of the HER2 expression spectrum to include not only low-expression but also ultra-low-expression cases provides clinical justification for considering a significant proportion of metastatic breast cancer patients as candidates for HER2-targeted therapy.”

He added, “Re-testing may be considered even for HR-positive patients initially diagnosed as HER2 IHC 0. Pathology reporting systems must evolve to enable accurate identification of ultra-low expression populations.”