The emergence of targeted therapy for HER2-low triple-negative breast cancer: a review of fam-trastuzumab deruxtecan

ABSTRACTIntroduction Metastatic triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer. Despite recent advances, metastatic TNBC remains difficult to treat with limited targeted treatment options. Fam-trastuzumab deruxtecan (T-DXd), is a novel antibody-drug conjugate (ADC) targeting human epidermal growth factor receptor 2 (HER2) and is composed of a unique linker bound to the topoisomerase I inhibitor DXd. T-DXd has significant anti-tumor activity in patients with HER2-low TNBC.Areas Covered This review reports on the mechanism, pre-clinical/clinical studies, efficacy, and tolerability of T-DXd. A literature search was conducted via PubMed using keywords such as 'fam-trastuzumab deruxtecan,' 'Enhertu,' and 'HER2-low cancers.'Expert Opinion The Phase III Destiny-Breast04 Trial showed benefit in progression-free and overall survival in patients with HER2-low metastatic breast cancers treated with T-DXd compared to treatment of physician's choice chemotherapy. T-DXd is the first pharmaceutical to effectively target a HER2-low population with clinically meaningful efficacy in patients with HER2-low TNBC. Compared to chemotherapy, T-DXd has a similar safety profile, with the additional need for close monitoring for interstitial lung disease. Given the clinical activity of T-DXd in TNBC, it is likely there will be continued efforts to refine HER2-low diagnostics and to develop additional ADCs with other protein targets.KEYWORDS: Antibody-drug conjugate (ADC)fam-trastuzumab deruxtecan (T-DXd)human epidermal growth factor receptor 2 (HER2)-lowtriple-negative breast cancer (TNBC)topoisomerase I Article highlights Triple-negative breast cancer (TNBC) lacks the expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) amplification.Immunotherapy, poly (ADP-ribose) polymerase (PARP) inhibitors, and the antibody-drug conjugate (ADC) sacituzumab govitecan represent recent advances in the treatment of metastatic TNBC. Despite these advances, survival remains inferior compared to other breast cancer subtypes and there is a continued need for novel effective therapies.Fam-trastuzumab deruxtecan (T-DXd) is an ADC, targeting HER2, composed of a novel peptide linker and a payload derived from the topoisomerase I inhibitor, DX-8951 (DXd).In preclinical studies, T-DXd was found to have anti-tumor activity in HER2-low cancer cells, in addition to HER2-positive models.In a Phase I, two-part study, T-DXd showed anti-tumor activity in a heavily pre-treated HER2-low metastatic or advanced breast cancer population.In the Phase III Destiny-Breast04 trial, patients with advanced or metastatic HER2-low breast cancer, had superior progression-free survival (PFS) and overall survival (OS) when treated with T-DXd compared to treatment of physician's choice (TPC) chemotherapy. This benefit was observed in both the hormone receptor (HR)-positive and TNBC populations.In the Destiny-Breast04 trial, side effects were similar in patients treated with T-DXd or TPC. Notably, more cases of pneumonitis or interstitial lung disease occurred in the T-DXd group. Physicians should be diligent in monitoring patients treated with T-DXd for pneumonitis and promptly initiate glucocorticosteroid treatment and stop T-DXd if this toxicity is observed.The success of T-DXd in HER2-low breast cancer will likely spur the development of newer therapeutics and impact how HER2-low breast cancers are treated.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresA reviewer on this paper has received research funding from Pfizer, Roche, has served on the advisory boards of Seagen, AstraZeneca, Pfizer, Roche, has received speakers fees from Seagen, AstraZeneca, Pfizer, Roche, Gilead, Lilly, Esai and has received conference support from AstraZeneca, Lilly, Roche.Additional informationFundingThis paper received no funding.