Novel HER2–targeted therapies for HER2–positive metastatic breast cancer

Kunte, Siddharth; Abraham, Jame; Montero, Alberto J.

doi:10.1002/cncr.33102

Cited by 142 publications

(112 citation statements)

References 48 publications

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“…Lately, several more anti-ERBB2 agents have been approved for breast cancer, including pertuzumab, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, as well as pan-ERBB small-molecule inhibitors lapatinib or afatinib. [36][37][38] Additionally, ERBB2 amplification and activating mutations were also seen in other solid tumor types such as NSCLC and CRC albeit at a lower frequency. Approximately 5% of CRCs harbor ERBB2 alterations, including amplifications and mutations; among them, 2% to 3% are amplifications (Table 1).…”

Section: Human Epidermal Growth Factor Receptor 2 Amplification and Mutationsmentioning

confidence: 99%

A Brief Overview and Update on Major Molecular Genomic Alterations in Solid, Bone and Soft Tissue Tumors, and Hematopoietic As Well As Lymphoid Malignancies

Zhang

Yao

Zhong

et al. 2021

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Recent advances in comprehensive genomic profiling by next-generation sequencing have uncovered the genomic alterations at the molecular level for many types of tumors; as such, numerous small specific molecules that target these alterations have been developed and widely used in the management of these cancers. Objective.— To provide a concise molecular genomic update in solid, bone and soft tissue tumors, hematopoietic as well as lymphoid malignancies; discuss its clinical applications; and familiarize practicing pathologists with the emerging cancer biomarkers and their diagnostic utilities. Data Sources.— This review is based on the National Comprehensive Cancer Network guidelines and peer-reviewed English literature. Conclusions.— Tumor-specific biomarkers and molecular/genomic alterations, including pan-cancer markers, have been significantly expanded in the past decade thanks to large-scale high-throughput technologies and will continue to emerge in the future. These biomarkers can be of great value in diagnosis, prognosis, and/or targeted therapy/treatment. Familiarization with these emerging and ever-changing tumor biomarkers will undoubtedly aid pathologists in making accurate and state-of-the-art diagnoses and enable them to be more actively involved in the care of cancer patients.

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Section: Human Epidermal Growth Factor Receptor 2 Amplification and Mutationsmentioning

confidence: 99%

A Brief Overview and Update on Major Molecular Genomic Alterations in Solid, Bone and Soft Tissue Tumors, and Hematopoietic As Well As Lymphoid Malignancies

Zhang

Yao

Zhong

et al. 2021

Archives of Pathology &Amp; Laboratory Medicine

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“…44 T-DXd (DS-8201a, Enhertu®) is composed of an anti-HER2 immunoglobulin G1 antibody and a topoisomerase I inhibitor payload, coupled by a cleavable tetrapeptide-based linker. 43,45 It has a high drug-to-antibody ratio of 8 and a potent bystander effect. 18 In December 2019, T-DXd gained accelerated FDA approval for adult patients with unresectable or metastatic HER2þ BC who have received two or more prior anti-HER2-based regimens in the metastatic setting.…”

Section: Trastuzumab Deruxtecanmentioning

confidence: 99%

Sacituzumab govitecan and trastuzumab deruxtecan: two new antibody–drug conjugates in the breast cancer treatment landscape

et al. 2021

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Background: Two new antibodyedrug conjugates (ADCs) containing a topoisomerase I inhibitor payload have recently emerged in the breast cancer (BC) treatment landscape. Sacituzumab govitecan-hziy (SG) is a first-in-class antitrophoblast cell-surface antigen 2 ADC approved for pretreated metastatic triple-negative breast cancer (mTNBC) and trastuzumab deruxtecan (T-DXd) gained approval for human epidermal growth factor receptor-2 (HER2)-positive advanced BC (aBC). We aim to provide a contemporary review and the current clinical trial landscape of SG and T-DXd in BC. Materials and methods: We conducted a literature search from Medline database through PubMed, major conference proceedings [abstracts from European Society for Medical Oncology (Breast) Congress, American Society of Clinical Oncology annual meeting, San Antonio Breast Cancer Symposium] and ClinicalTrials.gov with search terms 'sacituzumab govitecan', 'IMMU-132', 'trastuzumab deruxtecan' and 'DS-8201a' up to 21 March 2021. Results: We assessed 293 records for eligibility, of which 153 were included in this review after screening and exclusion. For SG, efficacy and safety data are available from a phase III trial in pretreated mTNBC and from a phase I/II basket study in mTNBC and hormone receptor-positive/HER2-negative aBC. Thirteen trials with pending primary analysis are ongoing with SG as single agent or in combination, of which 11 are enrolling (2/11 in the early setting). For T-DXd, efficacy/safety data are available as single agent in pretreated HER2-positive (phase Ib and phase II) and in HER2low aBC (phase Ib), and in combination with nivolumab in HER2-low/positive aBC (phase Ib). Of 23 ongoing trials with T-DXd, 12 are open for enrollment and 3 phase III trials have completed recruitment. The distinct safety profiles of both drugs and their management are discussed. Conclusion: Given their robust single-agent activity, SG and T-DXd are expected to substantially impact treatment standards, both in and far beyond the currently approved indications. Several trials are investigating new treatment settings for both drugs, including a transition to earlier lines and combinations with other anticancer treatments such as immune checkpoint inhibitors.

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“…Both agents are irreversible pan-HER inhibitors and consequently, like neratinib, are laden with higher rates of EGFR-mediated toxicities. 101 , 102 Their role so far is unclear as they are yet to be examined in patients who have all received trastuzumab, pertuzumab and T-DM1, making it difficult to extrapolate this data to the global population for consideration in the third-line setting.…”

Section: Scope Of This Reviewmentioning

confidence: 99%

Treating Advanced Unresectable or Metastatic HER2-Positive Breast Cancer: A Spotlight on Tucatinib

Ulrich

Okines

2021

BCTT

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The management of HER2 positive breast cancer has been transformed by the development of targeted therapies. Dual blockade with the monoclonal antibodies, trastuzumab and pertuzumab, added to first-line taxane chemotherapy and second-line therapy with the antibody-drug conjugate, T-DM1, are internationally agreed standards of care for advanced HER2 positive breast cancer, where available. However, until recently, options for patients for third-line therapy and beyond were of modest efficacy or limited by toxicity. In 2019, the results of trials of two exciting new agents for this space were presented. A third-generation HER2 tyrosine kinase inhibitor, tucatinib, combines the efficacy of the second-generation drug, neratinib, with a more manageable toxicity profile and has become a new standard of care after T-DM1, in combination with capecitabine and trastuzumab. The antibody-drug conjugate, trastuzumab deruxtecan, demonstrated remarkable efficacy in heavily pre-treated patients and received accelerated approval in the United States, whilst confirmatory Phase 3 trials are completed. This review will discuss the available data for the post-T-DM1 setting, focusing on tyrosine kinase inhibitors including tucatinib.

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Novel HER2–targeted therapies for HER2–positive metastatic breast cancer

Cited by 142 publications

References 48 publications

A Brief Overview and Update on Major Molecular Genomic Alterations in Solid, Bone and Soft Tissue Tumors, and Hematopoietic As Well As Lymphoid Malignancies

A Brief Overview and Update on Major Molecular Genomic Alterations in Solid, Bone and Soft Tissue Tumors, and Hematopoietic As Well As Lymphoid Malignancies

Sacituzumab govitecan and trastuzumab deruxtecan: two new antibody–drug conjugates in the breast cancer treatment landscape

Treating Advanced Unresectable or Metastatic HER2-Positive Breast Cancer: A Spotlight on Tucatinib

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