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Clinical Breast Cancer Dec 2023Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug-conjugate (ADC), primarily used in the treatment of HER2-positive breast cancer. This study aimed to conduct a... (Meta-Analysis)
Meta-Analysis Review
Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug-conjugate (ADC), primarily used in the treatment of HER2-positive breast cancer. This study aimed to conduct a systematic review to evaluate the efficacy and safety of T-DXd in treating breast cancer, based on clinical trials. A systematic search of the literature was conducted to identify clinical trials investigating the efficacy and safety of T-DXd in breast cancer. Clinical trials of any phase were included. Outcome measures were any adverse events and survival. Meta-analysis was conducted where possible. Pooled prevalence for each adverse event of any grade and grade 3 or greater were estimated. Progression-free survival (PFS), overall survival (OS) and objective response rates (ORRs) were also reported to evaluate the efficacy of T-DXd in breast cancer. A total of 1593 patients from 6 clinical trials were included. Common adverse events of any grade were nausea, anemia, neutropenia, vomiting, fatigue, constipation and diarrhea, occurring in greater than 30% of cases. In terms of adverse events of grade 3 or more, only anemia and neutropenia occurred at a relatively high rate. Median PFS ranged from 11.1 to 22.1 months. There was evidence of a benefit of T-DXd compared to controls in terms of both PFS (OR: 0.38; 95% CI: 0.32, 0.45) and OS (OR: 0.61; 95% CI: 0.48, 0.78). ORRs ranged from 37% to 79.9%. The present systematic review shows evidence that T-DXd is a safe and effective agent in the treatment of breast cancer based on currently available data. The most common adverse events affected the blood, lymphatic and gastrointestinal systems. Interstitial lung disease (ILD) is a notable and potentially serious adverse event.
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Camptothecin; Neutropenia; Anemia; Receptor, ErbB-2
PubMed: 37775347
DOI: 10.1016/j.clbc.2023.09.005 -
Cancer Treatment Reviews Jul 2023Antibody drug conjugates (ADCs) represent a revolutionary drug class in cancer therapy, combining the precision of targeted therapy with the cytotoxic effects of... (Review)
Review
BACKGROUND
Antibody drug conjugates (ADCs) represent a revolutionary drug class in cancer therapy, combining the precision of targeted therapy with the cytotoxic effects of chemotherapy. Promising activity of novel ADCs, namely Trastuzumab Deruxtecan and Patritumab Deruxtecan, has been observed in hard-to treat molecular subtypes, such as HER2-positive and heavily pretreated EGFR-mutant Non-Small Cell Lung Cancer (NSCLC). However, therapeutic advances are expected in certain subgroups of lung cancer patients, including non-oncogene-addicted NSCLC after failure of current standard of care (e.g., immunotherapy with or without chemotherapy, chemo-antiangiogenic treatment). Trophoblastic Cell Surface Antigen 2 (TROP-2) is a surface transmembrane glycoprotein member of the epithelial cell adhesion molecule (EpCAM) family. TROP-2 represents a promising therapeutic target in refractory non-oncogene-addicted NSCLC.
METHODOLOGY
We performed a systematic literature search of the clinical trials about TROP-2 directed ADCs in NSCLC referenced in the pubmed.gov database, Cochrane Library database and clinicaltrial.gov database.
RESULTS
First-in-humans ADCs targeting TROP-2, namely Sacituzumab Govitecan (SN-38) and Datopotamab Deruxtecan (Dxd), yielded promising activity signals in NSCLC with a manageable safety profile. Most common grade ≥ 3 adverse events (AEs) of Sacituzumab Govitecan included neutropenia (28 %), diarrhea (7 %), nausea (7 %), fatigue (6 %), and febrile neutropenia (4 %). Nausea and stomatitis were the most common all grade AEs with Datopotamab Deruxtecan; dyspnea, amylase increase, hyperglycemia and lymphopenia were reported as grade ≥ 3 AEs in less than 12 % of patients.
CONCLUSION
As more effective strategies are needed for patients with refractory non-oncogene-addicted NSCLC, the design of novel clinical trials with ADCs targeting TROP-2 is encouraged as both a monotherapy or combination strategy with existing agents (e.g., monoclonal antibodies targeting immune checkpoint inhibitors or chemotherapy).
Topics: Humans; Antineoplastic Agents; Camptothecin; Carcinoma, Non-Small-Cell Lung; Immunoconjugates; Irinotecan; Lung Neoplasms
PubMed: 37230055
DOI: 10.1016/j.ctrv.2023.102572 -
Journal of Clinical Oncology : Official... Aug 2023To update ASCO-College of American Pathologists (CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. The Panel is aware...
PURPOSE
To update ASCO-College of American Pathologists (CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. The Panel is aware that a new generation of antibody-drug conjugates (ADCs) targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification.
METHODS
An Update Panel conducted a systematic literature review to identify signals for updating recommendations.
RESULTS
The search identified 173 abstracts. Of five potential publications reviewed, none constituted a signal for revising existing recommendations.
RECOMMENDATIONS
The 2018 ASCO-CAP recommendations for HER2 testing are affirmed.
DISCUSSION
HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 ADCs. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, while it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This Update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences.Additional information is available at www.asco.org/breast-cancer-guidelines.
Topics: Humans; Female; Breast Neoplasms; In Situ Hybridization, Fluorescence; Pathologists; Receptor, ErbB-2; Biomarkers, Tumor
PubMed: 37284804
DOI: 10.1200/JCO.22.02864 -
ESMO Open Aug 2023Trastuzumab deruxtecan (T-DXd) has been shown to benefit progression-free survival and overall survival in patients with metastatic breast cancer (mBC) after progression... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Trastuzumab deruxtecan (T-DXd) has been shown to benefit progression-free survival and overall survival in patients with metastatic breast cancer (mBC) after progression on ≥1 human epidermal growth factor receptor 2 (HER2)-targeted therapies. However, interstitial lung disease (ILD) and cardiotoxicity are the most significant toxicities associated with T-DXd. Therefore, we conducted a systematic review and meta-analysis to assess the incidence and severity of these toxicities in mBC patients treated with T-DXd.
MATERIALS AND METHODS
We searched PubMed, Cochrane, and Scopus databases, and conferences websites for randomized clinical trials and nonrandomized studies of intervention including HER2-low or HER2-positive mBC patients who received at least one dose of T-DXd. Statistical analysis was carried out using R software.
RESULTS
We included 15 studies comprising 1970 patients with a mean follow-up of 13.3 months. Median age ranged from 53 to 59 years, 61.9% were non-Asian, and 67.4% had hormone receptor-positive mBC. In a pooled analysis, the incidence of ILD was 11.7% [222 patients; 95% confidence interval (CI) 9.1% to 15.0%]. Patients receiving T-DXd dose of 6.4 mg/kg developed a significantly higher rate of ILD (22.7%) compared to those receiving a dose of 5.4 mg/kg (9.3%) (P < 0.01). Most cases of ILD (80.2%; 174/217 patients) were mild (grade 1 or 2). Grade 3 or 4 ILD was reported in 29 patients (13.4%), and grade 5 in 14 patients (6.4%). The incidence of decreased left ventricular ejection fraction (LVEF) was 1.95% (95% CI 0.65% to 3.73%), and the QT interval (QTi) prolongation was 7.77% (95% CI 2.74% to 20.11%). Most patients were asymptomatic, but four had LV dysfunction and heart failure (0.26%).
CONCLUSIONS
In this meta-analysis of 1970 patients with mBC, treatment with T-DXd was associated with a 11.7% incidence of ILD, 7.7% incidence of prolonged QTi, and 1.9% incidence of reduced LVEF. Early detection and management of T-DXd-related toxicity by a multidisciplinary team may ultimately improve patient outcomes.
Topics: Humans; Middle Aged; Female; Breast Neoplasms; Cardiotoxicity; Incidence; Stroke Volume; Ventricular Function, Left; Lung Diseases, Interstitial
PubMed: 37481956
DOI: 10.1016/j.esmoop.2023.101613 -
Archives of Pathology & Laboratory... Sep 2023To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2)...
PURPOSE.—
To update the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer. An Update Panel is aware that a new generation of antibody-drug conjugates targeting the HER2 protein is active against breast cancers that lack protein overexpression or gene amplification.
METHODS.—
The Update Panel conducted a systematic literature review to identify signals for updating recommendations.
RESULTS.—
The search identified 173 abstracts. Of 5 potential publications reviewed, none constituted a signal for revising existing recommendations.
RECOMMENDATIONS.—
The 2018 ASCO-CAP recommendations for HER2 testing are affirmed.
DISCUSSION.—
HER2 testing guidelines have focused on identifying HER2 protein overexpression or gene amplification in breast cancer to identify patients for therapies that disrupt HER2 signaling. This update acknowledges a new indication for trastuzumab deruxtecan when HER2 is not overexpressed or amplified but is immunohistochemistry (IHC) 1+ or 2+ without amplification by in situ hybridization. Clinical trial data on tumors that tested IHC 0 are limited (excluded from DESTINY-Breast04), and evidence is lacking that these cancers behave differently or do not respond similarly to newer HER2 antibody-drug conjugates. Although current data do not support a new IHC 0 versus 1+ prognostic or predictive threshold for response to trastuzumab deruxtecan, this threshold is now relevant because of the trial entry criteria that supported its new regulatory approval. Therefore, although it is premature to create new result categories of HER2 expression (eg, HER2-Low, HER2-Ultra-Low), best practices to distinguish IHC 0 from 1+ are now clinically relevant. This update affirms prior HER2 reporting recommendations and offers a new HER2 testing reporting comment to highlight the current relevance of IHC 0 versus 1+ results and best practice recommendations to distinguish these often subtle differences. Additional information is available at www.asco.org/breast-cancer-guidelines.
Topics: Humans; Female; Breast Neoplasms; In Situ Hybridization, Fluorescence; Receptor, ErbB-2; In Situ Hybridization; Biomarkers, Tumor
PubMed: 37303228
DOI: 10.5858/arpa.2023-0950-SA -
American Journal of Cancer Research 2023Trastuzumab deruxtecan (T-DXd, DS-8201) is a targeted antibody-drug conjugate that specifically targets human epidermal growth factor receptor 2 (HER2). In 2019, it was... (Review)
Review
Trastuzumab deruxtecan (T-DXd, DS-8201) is a targeted antibody-drug conjugate that specifically targets human epidermal growth factor receptor 2 (HER2). In 2019, it was approved by the US Food and Drug Administration for the treatment of HER2-positive breast cancer. However, ongoing research is exploring its potential efficacy in other solid tumors, such as non-small-cell lung cancer and colorectal cancer, as well as in tumors with low HER2 levels. It is important to examine the safety and effectiveness of trastuzumab deruxtecan in these various types of solid tumors, as some studies have raised concerns about potential serious adverse events associated with its use. In this meta-analysis, we conducted a comprehensive search of PubMed, EMBASE, Cochrane Library, and Web of Science to identify randomized controlled trials (RCTs) that evaluated the efficacy and safety of trastuzumab deruxtecan in solid tumors. We used RevMan 5.4 software to perform a meta-analysis, calculating odds ratios (OR), risk ratios (RR), and weighted mean differences (WMD) with 95% confidence intervals (CIs). After an exhaustive search, we identified three articles that met our inclusion criteria, which included a total of 1268 patients. The results of the meta-analysis showed that the treatment group had significantly higher overall survival (WMD=5.12, 95% CI (2.79, 7.44), P<0.0001), progression-free survival (WMD=3.45, 95% CI (0.8, 6.1), P=0.01), overall response rate (OR=6.49, 95% CI (4.90, 8.58), P<0.00001), and disease control rate (OR=4.68, 95% CI (2.78, 7.89), P<0.00001), TRAEs (RR=6.93, 95% CI (2.06, 23.25), P=0.002). However, there was no significant difference in TRAEs≥3 (RR=1.08, 95% CI (0.75, 1.56), P=0.68) between the trials. Based on the available evidence, trastuzumab deruxtecan appears to be an effective and safe treatment option for HER2-positive solid tumors. Although the number of studies included in this analysis is limited, ongoing trials are being conducted, further evaluating its potential in various solid tumors. The results of these trials will enhance our understanding of trastuzumab deruxtecan and potentially expand its applications, bringing hope to more patients with solid tumors.
PubMed: 37693138
DOI: No ID Found -
Biochimica Et Biophysica Acta. Reviews... Nov 2023This study aimed to explore the efficacy and safety of trastuzumab plus tyrosine kinase inhibitors (TKIs) compared with those of trastuzumab monotherapy in patients with... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This study aimed to explore the efficacy and safety of trastuzumab plus tyrosine kinase inhibitors (TKIs) compared with those of trastuzumab monotherapy in patients with human epidermal growth factor receptor (HER2)-positive breast cancer.
METHODS
The PubMed, Embase, Cochrane, and Web of Science databases were systematically searched for relevant articles from inception until September 2022. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Subgroup analyses were performed based on disease status, TKI type, and hormone receptor status.
RESULTS
Sixteen studies were included in the current analysis. Trastuzumab plus TKI significantly improved OS and PFS compared to trastuzumab monotherapy. In the neoadjuvant setting, trastuzumab plus TKI significantly increased the pathologic complete response (pCR) rate compared to trastuzumab monotherapy. Moreover, a higher objective response rate (ORR) was observed with trastuzumab plus TKI. Patients who received the combination therapy had a higher incidence of discontinuation, all-grade diarrhea, and grade ≥ 3 diarrhea.
CONCLUSIONS
Trastuzumab plus TKI was better than trastuzumab monotherapy for treating different stages of HER2-positive breast cancer. The safety of trastuzumab plus TKI anti-HER2 therapy was controllable. The different efficacies of TKIs combined with trastuzumab may be related to the mechanism of action of the different TKIs, needing further investigations.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Tyrosine Kinase Inhibitors; Receptor, ErbB-2; Protein Kinase Inhibitors; Diarrhea
PubMed: 37640146
DOI: 10.1016/j.bbcan.2023.188969 -
Frontiers in Pharmacology 2023Doxorubicin-induced cardiotoxicity represents a prevalent adverse effect encountered in patients undergoing treatment with doxorubicin. To date, there has been no...
Doxorubicin-induced cardiotoxicity represents a prevalent adverse effect encountered in patients undergoing treatment with doxorubicin. To date, there has been no bibliometric study to summarize the field of doxorubicin-induced cardiotoxicity. In our study, we aim to determine the current status and frontiers of doxorubicin-induced cardiotoxicity by bibliometric analysis. The documents concerning doxorubicin-induced cardiotoxicity are obtained from the Web of Science Core Collection database (WOSCC), and VOSviewer 1.6.16, CiteSpace 5.1.3 and the WOSCC's literature analysis wire were used to conduct the bibliometric analysis. In total, 7,021 publications were encompassed, which are produced by 37,152 authors and 6,659 organizations, 1,323 journals, and 101 countries/regions. The most productive author, institution, country and journal were Bonnie Ky with 35 publications, University of Texas with 190 documents, the United States with 1,912 publications, and with 120 documents. The first high-cited article was published in the NEJM with 8,134 citations authored by DJ Slamon et al., in 2001. For keyword analysis, there are four clusters depicted in distinct directions. The keywords in the red cluster are oxidative stress, apoptosis, and cardiomyopathy. The keywords in the green cluster are cardiotoxicity, heart failure, and anthracycline. The keywords in the blue cluster are chemotherapy, trastuzumab, and paclitaxel. The keywords in the purple cluster are doxorubicin, adriamycin, and cancer. Most of the documents were derived from the United States, China and Italy (4,080/7,021, 58.1%). The number of studies from other countries should be increased. In conclusion, the main research hotspots and frontiers in the field of doxorubicin-induced cardiotoxicity include the role of doxorubicin in cardiotoxicity, the mechanisms underlying doxorubicin-induced cardiotoxicity, and the development of treatment strategies for doxorubicin-induced cardiotoxicity. More studies are needed to explore the mechanisms and treatment of doxorubicin-induced cardiotoxicity.
PubMed: 38026961
DOI: 10.3389/fphar.2023.1255158 -
Radiotherapy and Oncology : Journal of... Sep 2023In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
In recent years, the treatment landscape for breast cancer has undergone significant advancements, with the introduction of several new anticancer agents. One such agent is trastuzumab emtansine (T-DM1), an antibody drug conjugate that has shown improved outcomes in both early and advanced breast cancer. However, there is currently a lack of comprehensive evidence regarding the safety profile of combining T-DM1 with radiation therapy (RT). In this study, we aim to provide a summary of the available data on the safety of combining RT with T-DM1 in both early and metastatic breast cancer settings.
MATERIALS AND METHODS
This systematic review and meta-analysis project is part of the consensus recommendations by the European Society for Radiotherapy and Oncology (ESTRO) Guidelines Committee on integrating RT with targeted treatments for breast cancer. A thorough literature search was conducted using the PUBMED/MedLine, Embase, and Cochrane databases to identify original studies focusing on the safety profile of combining T-DM1 with RT.
RESULTS
After applying eligibility criteria, nine articles were included in the meta-analysis. Pooled data from these studies revealed a high incidence of grade 3 + radionecrosis (17%), while the rates of grade 3 + radiation-related pneumonitis (<1%) and skin toxicity (1%) were found to be very low.
CONCLUSION
Although there is some concern regarding a slight increase in pneumonitis when combining T-DM1 with postoperative RT, the safety profile of this combination was deemed acceptable for locoregional treatment in non-metastatic breast cancer. However, caution is advised when irradiating intracranial sites concurrently with T-DM1. There is a pressing need for international consensus guidelines regarding the safety considerations of combining T-DM1 and RT for breast cancer.
Topics: Humans; Female; Ado-Trastuzumab Emtansine; Trastuzumab; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Maytansine; Treatment Outcome; Breast Neoplasms
PubMed: 37437610
DOI: 10.1016/j.radonc.2023.109805 -
Japanese Journal of Clinical Oncology Jul 2023We performed a meta-analysis to assess the efficacy and safety of T-DXd in the treatment of HER2-expressing solid tumours. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
We performed a meta-analysis to assess the efficacy and safety of T-DXd in the treatment of HER2-expressing solid tumours.
METHODS
We systematically searched PubMed, Web of Science, Embase and the Cochrane Library and collected studies published before March 17, 2023, on T-DXd for HER2-expressing tumours for a meta-analysis. We performed a subgroup analysis based on the different cancer types and the doses used.
RESULTS
There were 11 studies including 1349 HER2-expressing patients in this meta-analysis. The pooled ORR was 47.91%, and the pooled DCR was 87.01%. The mPFS and mOS combined were 9.63 and 10.71 months, respectively. The most common adverse reactions in grades 1-2 were decreased appetite (49.3%) and vomiting (43.0%). The netropemia (31.2%) and leukopenia (31.2%) were the most common grade 3 and higher adverse reactions. Subgroup analysis showed that breast cancer had the best ORR and DCR, with 66.96 and 96.52%, respectively.
CONCLUSIONS
Overall, the efficacy of T-DXd in treating HER2-expressing solid tumours is encouraging, especially breast and non-small cell lung cancers, and has an acceptable safety profile. However, concerns remain about potentially serious treatment adverse events (e.g. interstitial lung disease/pneumonia). More well-designed, large-scale randomized controlled trials are needed to demonstrate our study.
Topics: Female; Humans; Breast Neoplasms; Camptothecin; Immunoconjugates; Lung Neoplasms; Receptor, ErbB-2; Trastuzumab
PubMed: 37114934
DOI: 10.1093/jjco/hyad036