Antibody–Drug Conjugates in Breast Cancer: Evidence from Clinical Trials
- Fay
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Introduction
Antibody-drug conjugates (ADCs) represent a novel class of anticancer drugs that “bundle” targeted antibodies with potent chemotherapeutic agents, delivering them directly to cancer cells while minimizing damage to healthy cells. The first HER2-targeted ADC, trastuzumab deruxtecan (T-DM1), received U.S. Food and Drug Administration (FDA) approval in 2013 for treating HER2-positive metastatic breast cancer patients. It gained approval for adjuvant therapy in 2019, specifically for patients with residual disease following neoadjuvant chemotherapy. Since then, ADC drugs have rapidly advanced in breast cancer treatment.
As of February 2025, the FDA has approved over a dozen ADCs for multiple tumor types, including three for advanced breast cancer: trastuzumab deruxtecan (targeting HER2), sacituzumab govitecan (targeting TROP2), and datopotamab deruxtecan (targeting TROP2). All these drugs carry a potent chemotherapy agent called a topoisomerase I inhibitor. Clinical trials demonstrated that trastuzumab deruxtecan and sacituzumab govitecan significantly extended progression-free survival (PFS), overall survival (OS), and improved quality of life, while datopotamab deruxtecan also enhanced PFS.
Currently, these ADCs target distinct patient populations: Trastuzumab deruxtecan is indicated for HER2-high, HER2-low, and HER2-ultra-low advanced breast cancer patients; sacituzumab govitecan is approved for hormone receptor-positive (HR+), HER2-negative, and triple-negative breast cancer patients regardless of TROP2 expression levels; and datopotamab deruxtecan is indicated for HR+ HER2- advanced breast cancer patients. While all demonstrate efficacy in treating breast cancer, no direct comparative clinical trials exist. Real-world experience suggests sequential use may yield less benefit than anticipated, potentially due to their shared chemotherapeutic components.
Overall, despite significant advances in ADC development, numerous questions and unmet needs remain regarding optimal drug design, combination therapy strategies, the sequencing of different ADCs, and how biomarkers can predict efficacy. This article will introduce novel approaches for ADCs in breast cancer treatment and discuss key biomarker research that could enhance drug development.
ADCs by Target: Clinical Findings in Breast Cancer
HER2-Targeting Antibody-Drug Conjugates
Approximately 15–20% of breast cancer patients exhibit HER2 overexpression or amplification in their tumors. For these patients, chemotherapy combined with anti-HER2 therapy (such as trastuzumab and pertuzumab) has been the standard regimen. The earliest application of ADCs in solid tumors targeted HER2-positive breast cancer. Key clinical trials are listed in Table 1.
Trastuzumab-emtansine (T-DM1)
T-DM1 is the first anti-HER2 ADC, consisting of the humanized anti-HER2 antibody trastuzumab linked via a non-cleavable linker to the microtubule inhibitor DM1, with a drug-antibody ratio (DAR) of 3.5. In 2013, based on results from the EMILIA Phase III trial, T-DM1 was approved for advanced HER2-positive breast cancer patients who had previously received trastuzumab and taxane therapy. The trial demonstrated that T-DM1 achieved a median progression-free survival (PFS) of 9.6 months, significantly superior to the lapatinib-capecitabine group (6.4 months), with median overall survival (OS) of 30.9 months versus 25.1 months. Concurrently, the incidence of grade ≥3 adverse events was lower in the T-DM1 group (41% vs 57%), with the most common being thrombocytopenia (12.9%) and elevated AST (4.3%).
Subsequent studies demonstrated T-DM1 efficacy in second-line and beyond settings, patients with brain metastases, and neoadjuvant/adjuvant treatment. In the KATHERINE Phase III trial, T-DM1 significantly reduced the risk of invasive recurrence or death by 50% compared to trastuzumab in patients with early HER2-positive breast cancer who had residual disease after neoadjuvant therapy. Despite multiple attempts to use T-DM1 as a substitute for trastuzumab or in combination with chemotherapy in neoadjuvant/adjuvant settings, most trials failed to demonstrate a clear efficacy advantage. While T-DM1 showed favorable safety profiles, it has not fully replaced standard regimens.
Trastuzumab-deruxtecan (T-DXd)
T-DXd is a novel anti-HER2 ADC consisting of trastuzumab linked to the topoisomerase I inhibitor DXd. Compared to T-DM1, its cleavable tetrapeptide linker can be specifically cleaved by tumor-upregulated proteases, resulting in higher DXd concentrations within tumor cells while reducing systemic exposure. T-DXd exhibits a high drug-antidote ratio (DAR) of 8 and possesses a “bystander effect,” enabling it to act on tumors with heterogeneous HER2 expression.
In the Phase II DESTINY-Breast01 trial, T-DXd demonstrated significant efficacy in heavily pretreated patients with advanced HER2-positive breast cancer: median PFS of 19.4 months and ORR of 62%. However, interstitial lung disease (ILD) occurred in 15.8% of patients, with 2.7% fatalities. Subsequently, the DESTINY-Breast03 Phase III trial demonstrated that T-DXd further improved PFS (29.0 vs 7.2 months), OS (52.6 vs 42.7 months), and ORR (78.9% vs 36.9%) compared to T-DM1, establishing it as the preferred second-line treatment. T-DXd also overcomes T-DM1 resistance, with DESTINY-Breast02 demonstrating significant improvements in PFS and OS among patients who progressed on T-DM1.
Notably, T-DXd is effective not only in HER2-high patients but also in those with HER2-low (IHC 1+ or 2+ and ISH-negative) or extremely low expression (IHC 0 but membrane-positive) breast cancer. The DESTINY-Breast04 and DESTINY-Breast06 trials demonstrated that T-DXd significantly prolongs PFS and OS in HER2-low/ultra-low breast cancer, leading to its corresponding approval for these patient populations.
For patients with brain metastases, T-DXd also demonstrated significant intracranial activity. In the DESTINY-Breast03 and TUXEDO-1 trials, intracranial ORR reached 67.5% and 73.3%, respectively, indicating the potential of ADCs in brain metastases, although whether they cross the blood-brain barrier remains unclear.
TROP2-Targeting ADCs
Triple-negative breast cancer (TNBC) accounts for approximately 15–20% of breast cancers. It is highly malignant, prone to metastasis, and associated with poor prognosis. TROP2, a tumor surface glycoprotein, is highly expressed in various tumors including TNBC and served as one of the early targets in ADC research.
Sacituzumab Govitecan (SG)
SG is the first TROP2-targeting ADC, consisting of a humanized IgG1 anti-TROP2 antibody linked via a cleavable linker to the topoisomerase I inhibitor SN-38, with a high DAR of 7.6.
The ASCENT Phase III trial demonstrated that SG significantly improved ORR (35% vs 5%), PFS (5.6 vs 1.7 months), and OS (12.1 vs 6.7 months) in patients with TNBC who had received multiple prior therapies. For HR+/HER2- patients, the TROPiCS-02 Phase III trial demonstrated SG improved PFS (5.5 vs 4.0 months) and OS (14.4 vs 11.2 months), with efficacy independent of TROP2 expression levels. Adverse events for SG primarily included bone marrow suppression and diarrhea, but discontinuation rates were low, indicating manageable safety. SG is also being explored in early-stage breast cancer. The NeoSTAR Phase II trial showed that neoadjuvant monotherapy with SG achieved a pCR rate of 30% and an ORR of 64% in early-stage TNBC, with manageable safety.
Datopotamab deruxtecan (Dato-DXd)
Dato-DXd is a TROP2-targeted antibody-drug conjugate (ADC) carrying the topoisomerase I inhibitor DXd, with a drug-antibody ratio (DAR) of 4. The TROPION-Breast01 Phase III trial demonstrated improved PFS (6.9 vs 4.9 months) and ORR (36.4% vs 22.9%) in HR+/HER2- breast cancer, with fewer adverse events than the control group. The BEGONIA study demonstrated that Dato-DXd combined with the PD-L1 inhibitor durvalumab achieved an ORR of 79% and PFS of 13.8 months in first-line treatment of TNBC, with manageable safety. The I-SPY 2.2 neoadjuvant trial showed that Dato-DXd had a low pCR rate (6%) in HR+/HER2- patients, but achieved 30–54% pCR in TNBC and specific immune-sensitive subtypes.
SKB264
SKB264 also targets TROP2 but employs a different drug conjugate (KL610023) with a DAR of 7.4. Early studies showed an ORR of 40% and PFS of 5.7 months in advanced TNBC; in HR+/HER2- breast cancer, ORR was 36.8% with PFS of 11.1 months. The Phase III OptiTROP-Breast01 trial demonstrated that SKB264 extended PFS compared to chemotherapy (5.7 vs 2.3 months), with an ORR of 43.8% vs 12.8%. It was approved in 2024 for use in Chinese patients with advanced TNBC.
Conclusion
In summary, HER2- and TROP2-targeting ADCs have substantially transformed the therapeutic landscape of breast cancer. HER2-directed ADCs, such as T-DM1 and T-DXd, have demonstrated robust efficacy across advanced and early-stage HER2-positive disease, including patients with brain metastases, with T-DXd showing superior response rates, progression-free survival, and overall survival compared with T-DM1. Notably, T-DXd has also expanded the treatment options for HER2-low and ultralow breast cancers, highlighting the potential of ADCs in tumors with heterogeneous antigen expression. Similarly, TROP2-directed ADCs, including sacituzumab govitecan, datopotamab deruxtecan, and SKB264, have improved outcomes in triple-negative and HR+/HER2- breast cancers, where conventional therapies are limited, with promising efficacy observed in both heavily pre-treated metastatic and early-stage settings. Across these ADCs, common toxicities such as myelosuppression, diarrhea, and interstitial lung disease are generally manageable, underscoring the favorable therapeutic index of modern ADCs. Overall, these advances illustrate how ADCs can effectively combine targeted delivery with potent cytotoxicity, offering new opportunities for personalized treatment and addressing unmet needs in heterogeneous breast cancer populations.
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