Abstract
HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in non-small cell lung cancer (NSCLC) and colorectal cancer, however, to date, there are no approved HER2-targeted therapies with these indications. Trastuzumab deruxtecan (T-DXd) is a novel HER2-directed antibody drug conjugate showing significant anti-tumor activity in heavily pre-treated HER2-positive breast and gastric cancer patients. Preliminary data have shown promising objective response rates in patients with HER2-positive NSCLC and colorectal cancer. T-DXd has an acceptable safety profile, however with concerns regarding potentially serious treatment-emergent adverse events. In this review we focus on the pharmacologic characteristics and toxicity profile of T-Dxd, and provide an update on the most recent results of clinical trials of T-DXd in solid tumors. The referenced papers were selected through a PubMed search performed on 16 March 2021 with the following searching terms: T-DXd and breast cancer, or gastric cancer, or non-small cell lung cancer (NSCLC), or colorectal cancer. Oral presentation, abstracts, and posters presented at the American Society of Clinical Oncology (ASCO, Alexandria, VA, USA) 2020 and the European Society for Medical Oncology (ESMO, Lugano, Switzerland) 2020 annual meetings were retrieved for data on T-DXd. We also overview ongoing research and data of combination therapies currently under investigation, which will impact on future therapeutic strategies. Clinicaltrials.gov was searched to identify ongoing clinical trials of T-DXd alone or in combination in solid tumors.
Highlights
HER2 targeted therapies have dramatically improved the prognosis of HER2-positive breast cancer patients in the adjuvant and neoadjuvant settings and in metastatic disease [1], and of patients with HER2-positive metastatic gastric cancer [2]
Several anti-HER2 drugs have been approved for the treatment of breast cancer: dual blockade with trastuzumab and pertuzumab, both anti-HER2 humanized monoclonal antibodies, in combination with chemotherapy is approved as first line treatment for metastatic disease [3]; the antibody–drug conjugate (ADC) trastuzumab emtansine (T-DM1) and the
In this review we focus on the molecular and pharmacologic characteristics, and toxicity profile of this novel anti-HER2 compound, and provide an update on the most recent results of ongoing clinical trials of T-DXd in solid tumors
Summary
HER2 targeted therapies have dramatically improved the prognosis of HER2-positive breast cancer patients in the adjuvant and neoadjuvant settings and in metastatic disease [1], and of patients with HER2-positive metastatic gastric cancer [2]. Several anti-HER2 drugs have been approved for the treatment of breast cancer: dual blockade with trastuzumab and pertuzumab, both anti-HER2 humanized monoclonal antibodies (mAb), in combination with chemotherapy is approved as first line treatment for metastatic disease [3]; the antibody–drug conjugate (ADC) trastuzumab emtansine (T-DM1) and the HER2 kinase inhibitor lapatinib are currently approved for further lines of treatment [4,5]. T-DXd has shown significant anti-tumor activity in patients with heavily pre-treated HER2-positive metastatic breast cancer [10], leading to an accelerated Food and Drug Administration (FDA, Silver Spring, MD, USA) approval in 2019 [11]. In this review we focus on the molecular and pharmacologic characteristics, and toxicity profile of this novel anti-HER2 compound, and provide an update on the most recent results of ongoing clinical trials of T-DXd in solid tumors. We overview ongoing clinical research in this field and provide data of combination therapies currently under investigation, which will impact on future therapeutic strategies
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