Antibody-Drug Conjugates in HER2-Positive Breast Cancer
Antibody-drug conjugates (ADCs) represent a groundbreaking class of therapeutics that combine the high specificity of monoclonal antibodies with the potent anti-tumor activity of small molecular cytotoxic payloads. These innovative drugs have revolutionized the treatment landscape for human epidermal receptor 2 (HER2)-positive breast cancer, offering new hope for patients with this aggressive form of breast cancer. This article delves into the composition, mechanisms, clinical advancements, and adverse effects of ADCs, with a particular focus on trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (DS-8201a), the two ADCs approved for HER2-positive breast cancer.
Composition and Mechanism of ADCs
ADCs are complex molecules composed of three main components: a monoclonal antibody, a cytotoxic payload, and a linker that connects the two. Each component plays a critical role in the drug’s efficacy and safety profile.
Target Antigen and Monoclonal Antibody
The monoclonal antibody in an ADC is designed to target a specific antigen that is highly expressed on tumor cells but minimally expressed in normal tissues. For HER2-positive breast cancer, the target antigen is HER2, a receptor that is overexpressed in 15% to 20% of breast cancers. The monoclonal antibody used in both T-DM1 and DS-8201a is trastuzumab, a humanized immunoglobulin G1 (IgG1) antibody that binds to the extracellular domain IV of HER2. This binding inhibits HER2 homodimerization and blocks downstream signaling pathways, thereby exerting anti-tumor effects.
Linker
The linker is a crucial component that connects the monoclonal antibody to the cytotoxic payload. It must be stable in the bloodstream to prevent premature release of the payload, which could lead to off-target toxicity. Linkers can be classified as cleavable or non-cleavable. Cleavable linkers release the payload in the tumor microenvironment or within the target cell, while non-cleavable linkers require the ADC to be internalized and degraded in the lysosome to release the payload. T-DM1 uses a non-cleavable thioether linker, whereas DS-8201a employs a cleavable maleimide tetrapeptide linker.
Payload
The cytotoxic payload is the component responsible for the anti-tumor activity of the ADC. The payloads used in ADCs are typically highly potent, with low half-maximal inhibitory concentration (IC50) values to ensure effective tumor cell killing despite the limited number of antigens on the cell surface. T-DM1 carries DM1, a derivative of maytansine, which is a tubulin polymerization inhibitor. DS-8201a, on the other hand, carries DXd, a derivative of DX-8951, which is a topoisomerase I inhibitor. The drug-to-antibody ratio (DAR), which indicates the number of payload molecules conjugated to each antibody, is another critical parameter. T-DM1 has an average DAR of 3.5, while DS-8201a has a higher DAR of 8, allowing it to deliver more payload to the tumor cells.
Mechanism of Action
The anti-tumor mechanism of ADCs targeting HER2 involves multiple steps. First, the monoclonal antibody binds to HER2 on the surface of tumor cells, inhibiting HER2-mediated signaling pathways. The ADC is then internalized, and the payload is released either in the tumor microenvironment (for cleavable linkers) or within the lysosome (for non-cleavable linkers). The released payload can kill the target cell and, in the case of highly membrane-permeable payloads like DXd, can also kill adjacent HER2-negative tumor cells through a phenomenon known as the bystander effect. This effect is particularly beneficial in heterogeneous tumors where not all cells express HER2. Additionally, ADCs can induce tumor cell apoptosis through antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Comparison of T-DM1 and DS-8201a
T-DM1 and DS-8201a differ in several key aspects, including their payloads, linkers, and pharmacokinetic parameters. T-DM1 uses a non-cleavable linker and a tubulin polymerization inhibitor payload, while DS-8201a employs a cleavable linker and a topoisomerase I inhibitor payload. The higher DAR of DS-8201a allows it to deliver more payload to the tumor cells, potentially enhancing its efficacy. However, this also increases the risk of off-target toxicity. Both drugs have shown significant anti-tumor activity in clinical trials, but DS-8201a has demonstrated superior efficacy in some settings, particularly in patients with heavily pretreated HER2-positive breast cancer.
Clinical Advancements in HER2-Positive Breast Cancer
The introduction of ADCs has significantly improved the prognosis of patients with HER2-positive breast cancer. Both T-DM1 and DS-8201a have been approved for the treatment of HER2-positive metastatic breast cancer (mBC), and ongoing clinical trials are exploring their use in other settings, including adjuvant and neoadjuvant therapy.
ADCs in Advanced HER2-Positive Breast Cancer
T-DM1 was the first ADC approved for HER2-positive mBC, based on the results of the phase III EMILIA trial. In this study, T-DM1 significantly improved both median progression-free survival (PFS) and overall survival (OS) compared to capecitabine plus lapatinib. The median PFS was 9.6 months for T-DM1 versus 6.4 months for the control group, and the median OS was 30.9 months versus 25.1 months, respectively. These results led to the approval of T-DM1 in 2013 for patients with HER2-positive mBC who had previously received trastuzumab and a taxane.
DS-8201a, on the other hand, was approved in 2019 based on the results of the DESTINY-Breast01 trial. This study evaluated the safety and efficacy of DS-8201a in patients with HER2-positive mBC who had previously received T-DM1. The results were striking, with an objective response rate (ORR) of 60.9%, including 6.0% complete responses and 54.9% partial responses. The median PFS was 16.4 months, and the median OS was not reached at the time of analysis. These results demonstrated the superior efficacy of DS-8201a in a heavily pretreated patient population.
ADCs in Adjuvant and Neoadjuvant Therapy
The KATHERINE study evaluated the use of T-DM1 in the adjuvant setting for patients with residual invasive disease after neoadjuvant therapy. The results showed that T-DM1 significantly improved invasive disease-free survival (iDFS) compared to trastuzumab alone, with a 3-year iDFS rate of 88.3% versus 77.0%. This study established T-DM1 as a standard of care for patients with residual disease after neoadjuvant therapy.
In the neoadjuvant setting, the KRISTINE study evaluated the combination of T-DM1 and pertuzumab. While the study did not meet its primary endpoint, it provided valuable insights into the potential use of ADCs in this setting. Ongoing clinical trials are exploring the use of DS-8201a in adjuvant and neoadjuvant therapy, although caution is warranted due to the higher incidence of serious adverse events associated with this drug.
ADCs in HER2 Low-Expressing Breast Cancer
HER2 low-expressing breast cancer, defined as immunohistochemistry (IHC) 1+ or IHC 2+/fluorescence in situ hybridization (FISH) negative, represents a significant proportion of breast cancer cases. Traditional HER2-targeted therapies, such as trastuzumab, are not effective in this population. However, DS-8201a has shown promising activity in HER2 low-expressing mBC. In a phase Ib study, the ORR was 37%, and the median PFS was 11.1 months. These results suggest that DS-8201a could be a valuable treatment option for patients with HER2 low-expressing breast cancer.
ADCs in HER2-Positive Breast Cancer with Brain Metastases
Brain metastases (BMs) are a common complication of HER2-positive breast cancer and are associated with a poor prognosis. T-DM1 has shown efficacy in patients with BMs, with a median OS of 26.8 months in the EMILIA study, compared to 12.9 months for lapatinib plus capecitabine. The KAMILLA study further confirmed the efficacy of T-DM1 in patients with BMs, with a clinical benefit rate of 43% and a median PFS of 18.1 months. DS-8201a has also shown activity in patients with BMs, with a median PFS of 18.1 months in the DESTINY-Breast01 study.
ADCs Combined with Other Treatments
Combining ADCs with other therapies is an area of active investigation. The NSABP FB-10 study explored the combination of T-DM1 and lenvatinib in patients with HER2-positive mBC, with an ORR of 63%. Additionally, the combination of T-DM1 with immunotherapy has shown promise, particularly in patients with PD-L1-positive tumors. The KATE2 study compared T-DM1 plus atezolizumab to T-DM1 alone and found that the combination improved median PFS and 1-year OS in the PD-L1 positive subgroup.
Adverse Events of ADCs
The toxicity profile of ADCs is influenced by multiple factors, including the monoclonal antibody, payload, and linker. Common adverse events (AEs) associated with T-DM1 and DS-8201a include nausea, fatigue, alopecia, and thrombocytopenia. Grade 3–5 AEs with T-DM1 include thrombocytopenia, anemia, and elevated liver enzymes, while DS-8201a is associated with hematologic toxicity, such as neutropenia, anemia, and leukopenia. Notably, DS-8201a has a higher incidence of serious AEs, including pneumonitis and interstitial lung disease, which can lead to treatment discontinuation.
Conclusion
ADCs have transformed the treatment landscape for HER2-positive breast cancer, offering new therapeutic options for patients with this aggressive disease. T-DM1 and DS-8201a have demonstrated significant efficacy in clinical trials, leading to their approval for the treatment of HER2-positive mBC. Ongoing research is exploring the use of ADCs in other settings, including adjuvant and neoadjuvant therapy, HER2 low-expressing breast cancer, and breast cancer with brain metastases. While ADCs are associated with a unique set of adverse events, their benefits in terms of improved survival and disease control outweigh the risks for many patients. As the field of ADCs continues to evolve, these drugs are likely to play an increasingly important role in the treatment of breast cancer and other malignancies.
doi.org/10.1097/CM9.0000000000001932
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