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Lancet (London, England) Jan 2023An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in... (Randomized Controlled Trial)
Randomized Controlled Trial
Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.
BACKGROUND
An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.
METHODS
This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110.
FINDINGS
Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group.
INTERPRETATION
Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration.
FUNDING
Daiichi Sankyo and AstraZeneca.
Topics: Humans; Female; Ado-Trastuzumab Emtansine; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36495879
DOI: 10.1016/S0140-6736(22)02420-5 -
Nature Reviews. Drug Discovery Feb 2023The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive... (Review)
Review
The long-sought discovery of HER2 as an actionable and highly sensitive therapeutic target was a major breakthrough for the treatment of highly aggressive HER2-positive breast cancer, leading to approval of the first HER2-targeted drug - the monoclonal antibody trastuzumab - almost 25 years ago. Since then, progress has been swift and the impressive clinical activity across multiple trials with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates that target HER2 has spawned extensive efforts to develop newer platforms and more targeted therapies. This Review discusses the current standards of care for HER2-positive breast cancer, mechanisms of resistance to HER2-targeted therapy and new therapeutic approaches and agents, including strategies to harness the immune system.
Topics: Humans; Female; Breast Neoplasms; Antineoplastic Agents; Receptor, ErbB-2; Trastuzumab; Antibodies, Monoclonal
PubMed: 36344672
DOI: 10.1038/s41573-022-00579-0 -
Drugs Apr 2020Trastuzumab deruxtecan (ENHERTU), a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate, is being developed for the treatment of HER2-expressing solid... (Review)
Review
Trastuzumab deruxtecan (ENHERTU), a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate, is being developed for the treatment of HER2-expressing solid tumours, including breast cancer, gastric cancer, colorectal cancer and non-small cell lung cancer by Daiichi Sankyo Company Ltd in collaboration with AstraZeneca. Based primarily on the results of the phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan was recently approved in the USA under accelerated approval for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. This article summarizes the milestones in the development of trastuzumab deruxtecan leading to this first approval.
Topics: Antineoplastic Agents; Camptothecin; DNA Topoisomerases, Type I; Drug Approval; Humans; Immunoconjugates; Neoplasms; Topoisomerase I Inhibitors; Trastuzumab
PubMed: 32144719
DOI: 10.1007/s40265-020-01281-4 -
Cancer Treatment Reviews Feb 2023A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional... (Review)
Review
A novel class of drugs, antibody-drug conjugates (ADCs), are now rapidly emerging as highly effective treatments for solid tumours. ADCs conjugate conventional chemotherapeutics with highly selective targeted monoclonal antibodies. Anti-HER2 therapies selectively target cancer cells expressing human epidermal growth factor receptor 2 (HER2), among them trastuzumab has been the first HER2-targeting monoclonal antibody to achieve successful results that made it the backbone of anti-HER2 therapies. Trastuzumab drug conjugates (T-DCs), use trastuzumab as a selective antibody to lead cytotoxic drugs inside cancer cells. Trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-Dxd) are the two approved T-DCs. T-Dxd along with other five T-DCs represents "second generation ADCs" that has been firstly tested in HER2 positive breast cancer (BC) and then in HER2-low BC and other cancers showing promising results thanks to extraordinary and innovative pharmacokinetic and pharmacodynamic characteristics. The evidence generated so far are establishing them as a completely new class of agents effective in solid cancer treatments but also warrants physicians against unconventional toxicity profiles. The role of T-DCs in HER2-positive BC has been largely reviewed, while in this review, we provided for the first time in literature an overview of trastuzumab drug conjugates (T-DCs) approved and/or in clinical development with a specific focus on their efficacy and safety profile in HER2-low BC and other solid tumours different from BC. We started by analysing T-DCs biological characteristics that underly the differences in T-DCs pharmacodynamics and safety profile, then presented the main evidence on the activity and efficacy of these emerging T-DCs in HER2-low BC and other HER2 overexpressing and/or mutated solid tumours and lastly, we provided an overview of the complex and still evolving scenario in which these compounds should be allocated. A specific focus on possible combination strategies with other drugs such as immunotherapy, chemotherapy and target therapy, to increase T-DCs activity and eventually overcome future upcoming resistance mechanisms, are here also critically reviewed.
Topics: Humans; Female; Breast Neoplasms; Antibodies, Monoclonal, Humanized; Trastuzumab; Ado-Trastuzumab Emtansine; Receptor, ErbB-2; Antineoplastic Agents; Antibodies, Monoclonal; Immunoconjugates
PubMed: 36587473
DOI: 10.1016/j.ctrv.2022.102500 -
Cancer Discovery May 2020HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted...
HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or -mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8-11.1] months. In -mutant non-small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1-14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and -mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. SIGNIFICANCE: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or -mutant solid tumors, especially -mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs...
Topics: Adult; Aged; Aged, 80 and over; Camptothecin; Female; Humans; Immunoconjugates; Middle Aged; Neoplasms; Receptor, ErbB-2; Trastuzumab; Young Adult
PubMed: 32213540
DOI: 10.1158/2159-8290.CD-19-1014 -
Future Oncology (London, England) Jan 2022Trastuzumab deruxtecan (T-DXd, DS-8201), an anti-HER2 antibody-drug conjugate, has shown significant clinical benefits in HER2+ metastatic breast cancer patients. In the... (Review)
Review
Trastuzumab deruxtecan (T-DXd, DS-8201), an anti-HER2 antibody-drug conjugate, has shown significant clinical benefits in HER2+ metastatic breast cancer patients. In the phase 2 DESTINY-Breast01 trial, T-DXd demonstrated an objective response of 60.9% and median progression-free survival of 16.4 months, laying the foundation for accelerated approval in HER2+ metastatic breast cancer patients who have received two or more prior anti-HER2-based regimens in the metastatic setting. Moreover, T-DXd exhibited promising antitumor efficacy against HER2-low-expressing metastatic breast cancer. Its distinctive side effect was pneumonitis, with a 13.6% incidence. It is approved in the US with boxed warnings for interstitial lung disease and embryo-fetal toxicity. This review focuses on preclinical, pharmacokinetic and pharmacodynamic data on T-DXd and clinical evidence of its antitumor activity (both as monotherapy and in combination) and tolerability in metastatic breast cancer.
Topics: Breast Neoplasms; Camptothecin; Clinical Trials as Topic; Female; Humans; Immunoconjugates; Receptor, ErbB-2; Trastuzumab
PubMed: 34823373
DOI: 10.2217/fon-2021-0550 -
Cancer Communications (London, England) Aug 2023Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer. However, the inevitable occurrence of acquired...
BACKGROUND
Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer. However, the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit, and there is currently no effective reversal measure. Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves, while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking. This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.
METHODS
Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing. Bioinformatics were used to analyze cell subtypes, metabolic pathways, and molecular signaling pathways. Changes in microenvironmental indicators (such as macrophage, angiogenesis, and metabolism) were verified by immunofluorescence (IF) and immunohistochemical (IHC) analyses. Finally, a multi-scale agent-based model (ABM) was constructed. The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.
RESULTS
Based on transcriptome sequencing, molecular biology, and in vivo experiments, we found that the level of glutamine metabolism in trastuzumab-resistant HER2-positive cells was increased, and glutaminase 1 (GLS1) was significantly overexpressed. Meanwhile, tumor-derived GLS1 microvesicles drove M2 macrophage polarization. Furthermore, angiogenesis promoted trastuzumab resistance. IHC showed high glutamine metabolism, M2 macrophage polarization, and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nude mice. Mechanistically, the cell division cycle 42 (CDC42) promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B (NF-κB) p65 and drove GLS1 microvesicle secretion through IQ motif-containing GTPase-activating protein 1 (IQGAP1). Based on the ABM and in vivo experiments, we confirmed that the combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer.
CONCLUSIONS
This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism, M2 macrophage polarization, and pro-angiogenic function of macrophages, leading to acquired trastuzumab resistance in HER2-positive gastric cancer. A combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.
Topics: Animals; Mice; Humans; Trastuzumab; Mice, Nude; Glutamine; Stomach Neoplasms; Drug Resistance, Neoplasm; Macrophages; Tumor Microenvironment
PubMed: 37434399
DOI: 10.1002/cac2.12459 -
Xenobiotica; the Fate of Foreign... Oct 2020Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7-8 with the topoisomerase I...
Trastuzumab deruxtecan (T-DXd, DS-8201a) is an antibody-drug conjugate (ADC), comprising an anti-HER2 antibody (Ab) at a drug-to-Ab ratio of 7-8 with the topoisomerase I inhibitor DXd. In this study, we investigated the pharmacokinetics (PK), biodistribution, catabolism, and excretion profiles of T-DXd in HER2-positive tumour-bearing mice.Following intravenous (iv) administration of T-DXd, the PK profiles of T-DXd and total Ab (the sum of conjugated and unconjugated Ab) were almost similar, indicating that the linker is stable during circulation. Biodistribution studies using radiolabelled T-DXd demonstrated tumour-specific distribution and long-term retention. DXd was the main catabolite released from T-DXd in tumours, with exposure levels at least five times higher than those in normal tissues and seven times higher than those achieved by non-targeted control ADC. Following iv administration of DXd, it was rapidly cleared from the circulation (; 1.35 h) and excreted mainly through faeces as its intact form.The PK profiles reveal that T-DXd effectively delivers the expected payload, DXd, to tumours, while minimising payload exposure to the systemic circulation and normal tissues. The released DXd is rapidly cleared from systemic circulation, presumably via the bile with negligible metabolism, and excreted through the faeces.
Topics: Ado-Trastuzumab Emtansine; Animals; Camptothecin; Cell Line, Tumor; Immunoconjugates; Mice; Topoisomerase I Inhibitors; Trastuzumab
PubMed: 32306807
DOI: 10.1080/00498254.2020.1755909 -
International Journal of Molecular... Apr 2021HER2 targeted therapies have significantly improved prognosis of HER2-positive breast and gastric cancer. HER2 overexpression and mutation is the pathogenic driver in... (Review)
Review
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.
Topics: Animals; Antineoplastic Agents, Immunological; Camptothecin; Clinical Trials as Topic; Humans; Immunoconjugates; Neoplasms; Receptor, ErbB-2; Trastuzumab
PubMed: 33946310
DOI: 10.3390/ijms22094774 -
European Journal of Medicinal Chemistry Dec 2019Targeted drug delivery has improved cancer treatment significantly in recent years, although it is difficult to achieve. Different approaches have been developed to... (Review)
Review
Targeted drug delivery has improved cancer treatment significantly in recent years, although it is difficult to achieve. Different approaches have been developed to apply targeted drug delivery. Among which, antibody-drug conjugate (ADC) provides a potentially ideal solution to such a challenge. ADC is an innovative drug treatment model with three key components: payload, monoclonal antibody, and linker. The monoclonal antibody targets the antigen-expressing tumor cells and internalizes the payload linked by the linker to the target cells to reduce the side effects of the traditional chemotherapy drugs. The off-target effect has an excellent therapeutic prospect. Among them, ado-trastuzumab emtansine (T-DM1) is a successful example of targeting human epidermal growth factor receptor-2 (HER2). Its antibody (trastuzumab) is derived from Herceptin with annual sales of more than $6 billion. It has excellent targeting and specific anti-tumor activity against HER2. Its linker is not cleavable and releases the Lys-linker-payload to kill the cells. The two ADCs described here use the same antibody as T-DM1, but the cleavable linker and the more toxic payload allow them to have the not only targeting of T-DM1, but also the reduce T-DM1 resistance and improve efficacy in heterogeneous tumors. This paper describes the mechanism of action and the biochemical characteristics of different parts and preclinical and clinical progress of trastuzumab deruxtecan(DS-8201a) and (vic-)trastuzumab duocarmazine (SYD985).
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Breast Neoplasms; Camptothecin; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Drug Resistance, Neoplasm; Female; Humans; Immunoconjugates; Lung Neoplasms; Receptor, ErbB-2; Stomach Neoplasms; Trastuzumab
PubMed: 31563805
DOI: 10.1016/j.ejmech.2019.111682