Enhertu (Fam-trastuzumab-deruxtecan-nxki) – Revolutionizing treatment paradigm for HER2-Low breast cancer

Siddiqui, Tasmiyah; Rani, Payal; Ashraf, Tayyaba; Ellahi, Aayat

doi:10.1016/j.amsu.2022.104665

Cited by 7 publications

(3 citation statements)

References 7 publications

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“…Particularly, in vitro assays proved that the HER2 hCAR-T with the co-stimulatory domain 41BBζ exhibited high levels of specific cytotoxicity directed at multiple tumor targets that express high and low antigen levels, like the HER2-low breast cancer cell line MDA-MB-231. In addition, based on the fact that novel anti-HER2 drugs like T-DXd are being used against HER2-low breast tumors and are being successful [ 105 , 319 , 320 , 321 ], in the near future CAR-T cells against TNBC patients may be tested in HER2-low subjects. Examples of TNBC targets included in CAR-T cells are: EGFR, ICAM1, MUC1, Mesothelin, CD133, CD44v6, CD70, TROP2, folate receptor α, and NKG2D, among others, and are extensively reviewed elsewhere [ 322 ].…”

Section: Cell Therapiesmentioning

confidence: 99%

Emerging Targeted Therapies for HER2-Positive Breast Cancer

Mercogliano

Bruni

Mauro

et al. 2023

Cancers

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Breast cancer is the most common cancer in women and the leading cause of death. HER2 overexpression is found in approximately 20% of breast cancers and is associated with a poor prognosis and a shorter overall survival. Tratuzumab, a monoclonal antibody directed against the HER2 receptor, is the standard of care treatment. However, a third of the patients do not respond to therapy. Given the high rate of resistance, other HER2-targeted strategies have been developed, including monoclonal antibodies such as pertuzumab and margetuximab, trastuzumab-based antibody drug conjugates such as trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), and tyrosine kinase inhibitors like lapatinib and tucatinib, among others. Moreover, T-DXd has proven to be of use in the HER2-low subtype, which suggests that other HER2-targeted therapies could be successful in this recently defined new breast cancer subclassification. When patients progress to multiple strategies, there are several HER2-targeted therapies available; however, treatment options are limited, and the potential combination with other drugs, immune checkpoint inhibitors, CAR-T cells, CAR-NK, CAR-M, and vaccines is an interesting and appealing field that is still in development. In this review, we will discuss the highlights and pitfalls of the different HER2-targeted therapies and potential combinations to overcome metastatic disease and resistance to therapy.

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Section: Cell Therapiesmentioning

confidence: 99%

Emerging Targeted Therapies for HER2-Positive Breast Cancer

Mercogliano

Bruni

Mauro

et al. 2023

Cancers

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“…Upregulation of human epidermal growth factor receptor 2 (HER2) is very common in breast cancer, which makes it an important target for systemic treatment ( 1 ). In the last decade, HER2-targeted antibody-drug conjugates (ADCs) have been emerging agents for HER2-positive breast cancer ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Combination therapy with antibody‑drug conjugate RC48 (disitamab vedotin) and zimberelimab (PD‑1 inhibitor) successfully controlled recurrent HER2‑positive breast cancer resistant to trastuzumab emtansine: A case report

Fan

Sang

2023

Oncol Lett

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Options for later-line therapy are limited for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who have exhibited resistance to several systemic treatments. Antibody drug conjugates (ADCs) and immune checkpoint inhibitors are novel approaches for HER2-positive breast cancer, but few reports have been published regarding the efficacy of their combinations, particularly in patients with prior ADC failure. The present report describes a case of recurrent metastatic HER2-positive breast cancer, which responded poorly to several perioperative systemic therapies, including chemotherapies, HER2-targeted antibodies, small molecule inhibitors and trastuzumab emtansine (an ADC), along with post-surgical radiotherapy. Following failure of front-line therapies for recurrent cancer located in the chest wall, combination treatment with another HER2-targeted ADC, disitamab vedotin (120 mg), and zimberelimab (240 mg), a fully humanized anti-programmed cell death protein-1 (PD-1) antibody, administered intravenously every 2 weeks, was initiated. The tumor lesions improved slightly after two cycles of treatment and shrunk markedly, and almost disappeared at the end of the sixth cycle of therapy. The patient is still in remission at present. The present findings suggest the potential efficacy of HER2-targeted ADCs combined with PD-1 inhibitors for patients with HER2-positive breast cancer, including those resistant to prior HER2-targeted ADCs.

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“…As shown in Figure1, an antibody with dual functionalization linker Cys-cappings[27,28], e.g., maleimide derivatives containing orthogonal alkyne and ketone handles, can be produced for further conjugation with dual drug payloads. Approved ADCs with a homogeneous DAR8 hydrophilic linkerpayloads like Enhertu® show encouraging efficacy in low TAAexpressing breast cancer and other indications[29], but a DAR of 8 is not suitable for many linker-payloads. Having drug payloads with different mechanisms of action within a single ADC molecule can be a way to overcome the drug-resistance and heterogeneity of cancer cells.…”

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confidence: 99%

A Surprising Benefit of Cysteine Capping for Antibody Drug Conjugates

2022

J Cancer Immunol

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With a burst of nine FDA approvals granted since 2017, ADCs are riding a significant market boom and gathering optimism as a promising therapeutic approach [2][3][4][5][6][7][8]. With >80 investigational candidates and around 150 active clinical trials [9], ADCs are among the fastest-growing drug classes in cancer therapeutics targeting both solid tumor indications and hematological malignancies. ADCs are complex molecules composed of three key components: a tumor-associated-antigen (TAA)-targeting monoclonal antibody, a cytotoxic drug payload, and a cleavable or noncleavable linker. Conjugation technology is another important aspect of ADCs, by which payloads and linkers are covalently attached to the antibodies. Conventional drug conjugation methods are either through less precise interchain disulfide Cys or random lysine residue in the antibody components, resulting in a huge product heterogeneity with limited control over the conjugation locations. Next-generation site-specific conjugation technologies (Summarized in Table 1; reviewed by [10][11][12]) define precise and proper drug attachments, which determine drug potency and exposure, allow for an optimized and tunable structure-activity relationship, as well as better characterized and monitored homogeneous drug products. Manufacturing Challenges of Site-specific ADCsHowever, manufacturing high-quality site-specific ADCs for clinical confirmation often encounters significant technical hurdles. For the most established Cys-based site-specific conjugation, it requires a complicated full reduction and reoxidation conjugation process [13], due to a disulfide capping on the engineered unpaired Cys residues (Figure 1, [13][14][15]). This so-called Cys-capping modification is a type of posttranslational modifications (PTMs) that are the disulfides typically with either Cys or glutathione (Figure 1). It is also detectable in endogenous membrane-bound or secreted proteins with solvent-exposed unpaired Cys residues [16][17][18].

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Enhertu (Fam-trastuzumab-deruxtecan-nxki) – Revolutionizing treatment paradigm for HER2-Low breast cancer

Cited by 7 publications

References 7 publications

Emerging Targeted Therapies for HER2-Positive Breast Cancer

Emerging Targeted Therapies for HER2-Positive Breast Cancer

Combination therapy with antibody‑drug conjugate RC48 (disitamab vedotin) and zimberelimab (PD‑1 inhibitor) successfully controlled recurrent HER2‑positive breast cancer resistant to trastuzumab emtansine: A case report

A Surprising Benefit of Cysteine Capping for Antibody Drug Conjugates

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