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Journal of Clinical Oncology : Official... Jan 2024Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and...
PURPOSE
Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor 2 (HER2)-directed antibody-drug conjugate approved in HER2-expressing breast and gastric cancers and HER2-mutant non-small-cell lung cancer. Treatments are limited for other HER2-expressing solid tumors.
METHODS
This open-label phase II study evaluated T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments. The primary end point was investigator-assessed confirmed objective response rate (ORR). Secondary end points included safety, duration of response, progression-free survival (PFS), and overall survival (OS).
RESULTS
At primary analysis, 267 patients received treatment across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other. The median follow-up was 12.75 months. In all patients, the ORR was 37.1% (n = 99; [95% CI, 31.3 to 43.2]), with responses in all cohorts; the median DOR was 11.3 months (95% CI, 9.6 to 17.8); the median PFS was 6.9 months (95% CI, 5.6 to 8.0); and the median OS was 13.4 months (95% CI, 11.9 to 15.5). In patients with central HER2 IHC 3+ expression (n = 75), the ORR was 61.3% (95% CI, 49.4 to 72.4), the median DOR was 22.1 months (95% CI, 9.6 to not reached), the median PFS was 11.9 months (95% CI, 8.2 to 13.0), and the median OS was 21.1 months (95% CI, 15.3 to 29.6). Grade ≥3 drug-related adverse events were observed in 40.8% of patients; 10.5% experienced adjudicated drug-related interstitial lung disease (ILD), with three deaths.
CONCLUSION
Our study demonstrates durable clinical benefit, meaningful survival outcomes, and safety consistent with the known profile (including ILD) in pretreated patients with HER2-expressing tumors receiving T-DXd. Greatest benefit was observed for the IHC 3+ population. These data support the potential role of T-DXd as a tumor-agnostic therapy for patients with HER2-expressing solid tumors.
Topics: Humans; Female; Carcinoma, Non-Small-Cell Lung; Receptor, ErbB-2; Antibodies, Monoclonal, Humanized; Lung Neoplasms; Trastuzumab; Immunoconjugates; Lung Diseases, Interstitial; Breast Neoplasms
PubMed: 37870536
DOI: 10.1200/JCO.23.02005 -
Journal of Clinical Oncology : Official... Nov 2023Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Trastuzumab deruxtecan (T-DXd) 5.4 and 6.4 mg/kg showed robust antitumor activity in multiple cancer indications; however, T-DXd 5.4 mg/kg has not been evaluated in patients with previously treated human epidermal growth factor receptor 2-mutant (m; defined as single-nucleotide variants and exon 20 insertions) metastatic non-small-cell lung cancer (mNSCLC).
METHODS
DESTINY-Lung02, a blinded, multicenter, phase II study, investigated T-DXd 5.4 mg/kg once every 3 weeks for the first time in previously treated (platinum-containing therapy) patients with m mNSCLC and further assessed T-DXd 6.4 mg/kg once every 3 weeks in this population. The primary end point was confirmed objective response rate (ORR) per RECIST v1.1 by blinded independent central review.
RESULTS
One hundred fifty-two patients were randomly assigned 2:1 to T-DXd 5.4 or 6.4 mg/kg once every 3 weeks. As of December 23, 2022, the median duration of follow-up was 11.5 months (range, 1.1-20.6) with 5.4 mg/kg and 11.8 months (range, 0.6-21.0) with 6.4 mg/kg. Confirmed ORR was 49.0% (95% CI, 39.0 to 59.1) and 56.0% (95% CI, 41.3 to 70.0) and median duration of response was 16.8 months (95% CI, 6.4 to not estimable [NE]) and NE (95% CI, 8.3 to NE) with 5.4 and 6.4 mg/kg, respectively. Median treatment duration was 7.7 months (range, 0.7-20.8) with 5.4 mg/kg and 8.3 months (range, 0.7-20.3) with 6.4 mg/kg. Grade ≥ 3 drug-related treatment-emergent adverse events occurred in 39 of 101 (38.6%) and 29 of 50 (58.0%) patients with 5.4 and 6.4 mg/kg, respectively. 13 of 101 (12.9%) and 14 of 50 (28.0%) patients had adjudicated drug-related interstitial lung disease (2.0% grade ≥ 3 in each arm) with 5.4 and 6.4 mg/kg, respectively.
CONCLUSION
T-DXd demonstrated clinically meaningful responses at both doses. Safety profile was acceptable and generally manageable, favoring T-DXd 5.4 mg/kg.
Topics: Humans; Camptothecin; Carcinoma, Non-Small-Cell Lung; Immunoconjugates; Lung Neoplasms; Receptor, ErbB-2; Trastuzumab
PubMed: 37694347
DOI: 10.1200/JCO.23.01361 -
MAbs 2024The 'Antibodies to Watch' article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical...
The 'Antibodies to Watch' article series provides an annual summary of commercially sponsored monoclonal antibody therapeutics currently in late-stage clinical development, regulatory review, and those recently granted a first approval in any country. In this installment, we discuss key details for 16 antibody therapeutics granted a first approval in 2023, as of November 17 (lecanemab (Leqembi), rozanolixizumab (RYSTIGGO), pozelimab (VEOPOZ), mirikizumab (Omvoh), talquetamab (Talvey), elranatamab (Elrexfio), epcoritamab (EPKINLY), glofitamab (COLUMVI), retifanlimab (Zynyz), concizumab (Alhemo), lebrikizumab (EBGLYSS), tafolecimab (SINTBILO), narlumosbart (Jinlitai), zuberitamab (Enrexib), adebrelimab (Arelili), and divozilimab (Ivlizi)). We briefly review 26 product candidates for which marketing applications are under consideration in at least one country or region, and 23 investigational antibody therapeutics that are forecast to enter regulatory review by the end of 2024 based on company disclosures. These nearly 50 product candidates include numerous innovative bispecific antibodies, such as odronextamab, ivonescimab, linvoseltamab, zenocutuzumab, and erfonrilimab, and antibody-drug conjugates, such as trastuzumab botidotin, patritumab deruxtecan, datopotamab deruxtecan, and MRG002, as well as a mixture of two immunocytokines (bifikafusp alfa and onfekafusp alfa). We also discuss clinical phase transition and overall approval success rates for antibody therapeutics, which are crucial to the biopharmaceutical industry because these rates inform decisions about resource allocation. Our analyses indicate that these molecules have approval success rates in the range of 14-32%, with higher rates associated with antibodies developed for non-cancer indications. Overall, our data suggest that antibody therapeutic development efforts by the biopharmaceutical industry are robust and increasingly successful.
Topics: Antineoplastic Agents; Trastuzumab; Immunoconjugates; Biological Products
PubMed: 38178784
DOI: 10.1080/19420862.2023.2297450 -
Nature Medicine Aug 2023The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY...
The mechanisms of action of and resistance to trastuzumab deruxtecan (T-DXd), an anti-HER2-drug conjugate for breast cancer treatment, remain unclear. The phase 2 DAISY trial evaluated the efficacy of T-DXd in patients with HER2-overexpressing (n = 72, cohort 1), HER2-low (n = 74, cohort 2) and HER2 non-expressing (n = 40, cohort 3) metastatic breast cancer. In the full analysis set population (n = 177), the confirmed objective response rate (primary endpoint) was 70.6% (95% confidence interval (CI) 58.3-81) in cohort 1, 37.5% (95% CI 26.4-49.7) in cohort 2 and 29.7% (95% CI 15.9-47) in cohort 3. The primary endpoint was met in cohorts 1 and 2. Secondary endpoints included safety. No new safety signals were observed. During treatment, HER2-expressing tumors (n = 4) presented strong T-DXd staining. Conversely, HER2 immunohistochemistry 0 samples (n = 3) presented no or very few T-DXd staining (Pearson correlation coefficient r = 0.75, P = 0.053). Among patients with HER2 immunohistochemistry 0 metastatic breast cancer, 5 of 14 (35.7%, 95% CI 12.8-64.9) with ERBB2 expression below the median presented a confirmed objective response as compared to 3 of 10 (30%, 95% CI 6.7-65.2) with ERBB2 expression above the median. Although HER2 expression is a determinant of T-DXd efficacy, our study suggests that additional mechanisms may also be involved. (ClinicalTrials.gov identifier NCT04132960 .).
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Receptor, ErbB-2; Immunoconjugates; Camptothecin
PubMed: 37488289
DOI: 10.1038/s41591-023-02478-2 -
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 -
BMJ (Clinical Research Ed.) Oct 2023To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with... (Randomized Controlled Trial)
Randomized Controlled Trial
Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial.
OBJECTIVE
To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer.
DESIGN
Randomised, double blind, placebo controlled, multicentre, phase 3 trial.
SETTING
40 centres in China between 6 May 2019 and 17 January 2022.
PARTICIPANTS
590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer.
INTERVENTIONS
Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor's study team were masked to treatment assignment.
MAIN OUTCOME MEASURES
The primary endpoint was progression-free survival as assessed by the investigator.
RESULTS
Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up.
CONCLUSIONS
Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population.
TRIAL REGISTRATION
ClinicalTrials.gov NCT03863223.
Topics: Female; Humans; Middle Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Docetaxel; Double-Blind Method; Receptor, ErbB-2; Trastuzumab; Treatment Outcome
PubMed: 37907210
DOI: 10.1136/bmj-2023-076065 -
Current Oncology (Toronto, Ont.) Nov 2023Antibody drug conjugates (ADCs) have emerged as a highly effective treatment strategy across breast cancer (BC) subtypes, including human epidermal growth factor... (Review)
Review
Antibody drug conjugates (ADCs) have emerged as a highly effective treatment strategy across breast cancer (BC) subtypes, including human epidermal growth factor receptor 2-positive (HER2+), hormone-receptor positive (ER/PR+), and triple-negative breast cancer (TNBC). Over the past twenty years, ADCs have undergone relevant evolutions, from target diversity to payload ratio, to linker design, allowing for a progressive increase in their efficacy. From the first-generation ADC, trastuzumab emtansine (T-DM1), approved in 2013 for HER2+ breast cancer, to next generation ADCs such as sacituzumab govitecan and trastuzumab deruxtecan, to emerging ADCs on the horizon, we continue to see unparalleled efficacy compared to traditional chemotherapy. However, each ADC has brought a new cadre of adverse events for clinicians and patients to manage. Importantly, with the development and approval of several ADCs to treat metastatic breast cancer, there are unanswered clinical questions surrounding how to optimally sequence treatment for patients who may be candidates for more than one ADC and, in general, how to treat patients beyond progression on ADCs. From bench to bedside, in this review, we will discuss the pharmacology and current indications for the novel ADCs trastuzumab deruxtecan and sacituzumab govitecan. Highlighting emerging ADCs and ongoing clinical trials, we will anticipate the changes in the breast cancer treatment paradigm. Lastly, we will outline the available data and current approaches for adverse event management and sequencing strategies for ADCs in clinical practice, including proposed mechanisms of resistance.
Topics: Humans; Ado-Trastuzumab Emtansine; Triple Negative Breast Neoplasms; Immunoconjugates
PubMed: 38132377
DOI: 10.3390/curroncol30120743 -
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 -
Free Radical Biology & Medicine Sep 2023Trastuzumab (TRZ) is a first-line chemotherapeutic agent for HER-2 (ErbB2)-positive breast cancer. Unfortunately, its clinical use is limited due to its cardiotoxicity,...
Trastuzumab (TRZ) is a first-line chemotherapeutic agent for HER-2 (ErbB2)-positive breast cancer. Unfortunately, its clinical use is limited due to its cardiotoxicity, referred to as TRZ-induced cardiotoxicity (TIC). However, the exact molecular mechanisms underlying the development of TIC remain unclear. Iron and lipid metabolism and redox reactions participate in the development of ferroptosis. Here, we show that ferroptosis-mediated mitochondrial dysfunction is involved in TIC in vivo and in vitro. We first established TIC models with BALB/c mice or neonatal rat cardiomyocytes and confirmed cardiomyopathy with echocardiography and inhibition of cell viability with a cell counting kit-8 examination, respectively. We showed that TRZ downregulated glutathione peroxidase 4 (GPx4) and elevated lipid peroxidation by-products, 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), by inactivating the ErbB2/PI3K/AKT/Nrf2 signalling pathway. Additionally, upregulated mitochondrial 4-HNE binds to voltage-dependent anion channel 1 (VDAC1), increases VDAC1 oligomerization, and subsequently induces mitochondrial dysfunction, as evidenced by mitochondrial permeability transition pore (mPTP) opening and decreased mitochondrial membrane potential (MMP) and ATP levels. Concomitantly, TRZ affected the mitochondrial levels of GSH/GSSG and iron ions and the stability of mitoGPx4. Ferroptosis inhibitors, such as ferrostatin-1 (Fer-1) or the iron chelator deferoxamine (DFO), ameliorate TRZ-induced cardiomyopathy. Overexpression of mitoGPx4 also suppressed mitochondrial lipid peroxidation and prevented TRZ-induced ferroptosis. Our study strongly suggests that targeting ferroptosis-mediated mitochondrial dysfunction is a potential cardioprotective strategy.
Topics: Female; Animals; Mice; Mice, Inbred BALB C; Specific Pathogen-Free Organisms; Ferroptosis; Trastuzumab; Antineoplastic Agents, Immunological; Cardiomyopathies; Rats; Myocytes, Cardiac; Iron; Lipid Peroxidation; Mitochondria; Phospholipid Hydroperoxide Glutathione Peroxidase
PubMed: 37392951
DOI: 10.1016/j.freeradbiomed.2023.06.019