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.
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.
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.
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.
Daiichi Sankyo and AstraZeneca.
SAH has received support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received grants or contracts from Ambrx, Amgen, Arvinas, Bayer, Cytomx, Dantar, Dignitana, ...Genentech/Roche, G1-Therapeutics, Gilead, GSK, Immunomedics, Eli Lilly, Macrogenics, Novartis, OBI, Pharma, Orinove, Pfizer, Phoenix Molecular Designs, Pieris, PUMA, Radius, Samumed, Sanofi, Seattle Genetics/Seagen, and Zymeworks; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Daiichi Sankyo and continuing medical education (CME) companies (PER, Clinical Care Options, Research to Practice, etc); has received support for attending meetings or travel from San Antonio Breast Cancer Symposium, American Society of Clinical Oncology, National Comprehensive Cancer Network, and CME companies (PER, Clinical Care Options, and Research to Practice); has participated as a data safety monitoring board member for the I-SPY trial (unpaid); and has served a leadership or fiduciary role in another board for TRIOUS (unpaid chief medical officer of site management organisation). GC has received support for the present manuscript from AstraZeneca and Daiichi Sankyo; has received grants or contracts from Merck and AstraZeneca; has received consulting fees from Roche, BMS, Novartis, Lilly, Pfizer, Seagen, AstraZeneca, Ellipsis, Gilead, Merck, Celcuity, Sanofi, Exact Sciences, and Daiichi Sankyo; has received payment or honoraria for presentations, lectures, speaker bureaus, manuscript writing, or educational events from Novartis, Lilly, Pfizer, Seagen, and Daiichi Sankyo; has received support for attending meetings or travel from AstraZeneca and Daiichi Sankyo; and has participated on a data safety monitoring board or advisory board for Roche, BMS, Novartis, Lilly, Pfizer, Seagen, Ellipsis, Gilead, Merck, Celcuity, AstraZeneca, and Daiichi Sankyo. JC has received support for the present manuscript from Daiichi Sankyo and AstraZeneca; has received institutional grants or contracts from Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F Hoffman-La Roche, Guardant Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; has received consulting fees from Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, and Reveal Genomics; has received payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, and Daiichi Sankyo; has received support for attending meetings or travel from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, AstraZeneca, and Gilead; has patents planned, issued, or pending (WO 2014/199294 A; US 2019/ 0338368 A1); and has stock or stock options with MedSIR, Nektar Pharmaceuticals, and Leuko.
1025 Background: DESTINY-Breast03 (NCT03529110), a randomized, multicenter, open-label, phase 3 study, assessed the efficacy and safety of T-DXd vs T-DM1 in pts with HER2+ mBC treated with ≥1 prior ...anti-HER2 regimen. Median (m) overall survival (OS) was not reached in either arm at the prior data cutoff (DCO; Jul 25, 2022). We report updated survival results, including efficacy and safety, after median duration of follow-up of 41 mo. Methods: Pts were randomized 1:1 to T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg once every 3 weeks. Primary endpoint was progression-free survival (PFS) by blinded independent central review (assessed at prior DCO); key secondary endpoint was OS. Other secondary endpoints included objective response rate (ORR), PFS, duration of response (DoR), PFS from time of randomization to progression on next line of therapy or death (PFS2), and safety. All secondary endpoints were based on investigator assessment. Results: 524 pts were randomized (T-DXd, n = 261; T-DM1, n = 263). As of Nov 20, 2023, median duration of follow-up was 43.0 mo (range, 0.0-62.9) for T-DXd and 35.4 mo (range, 0.0-60.9) for T-DM1. mOS (95% CI) was 52.6 mo (48.7-not evaluable NE) for T-DXd and 42.7 mo (35.4-NE) for T-DM1 (hazard ratio HR, 0.73), with 110 (42.1%) and 126 (47.9%) OS events, respectively. OS rate (95% CI) at 36 mo was 67.6% (61.3-73.0%; T-DXd) vs 55.7% (49.2-61.7%; T-DM1). mPFS was 29.0 mo for T-DXd and 7.2 mo for T-DM1; PFS rate (95% CI) at 24 mo was 55.8% (49.1-62.0%; T-DXd) vs 20.6% (15.4-26.4%; T-DM1). mPFS2 was 45.2 mo (T-DXd) vs 23.1 mo (T-DM1). Median treatment duration was 18.2 mo (range, 0.7-56.6) with T-DXd vs 6.9 mo (range, 0.7-55.2) with T-DM1; rates of treatment-emergent adverse events (TEAEs) were consistent with prior DCO. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 16.7% of pts with T-DXd (4 new events all grade 2 since prior DCO) vs 3.4% with T-DM1 (1 new event grade 1); neither arm had grade 4 or 5 events. Key efficacy and safety results are shown in the table. Conclusions: The superiority of T-DXd over T-DM1 was reinforced in this long-term analysis, as observed by clinically meaningful improvement in OS, PFS, and PFS2, consistent with prior DCO. The safety profile of T-DXd continues to be manageable with no cumulative toxicities observed with longer follow-up. Clinical trial information: NCT03529110 . Table: see text
Abstract
Background: Trastuzumab deruxtecan (T-DXd) is approved in the United States and European Union for use in patients (pts) with HER2+ unresectable/metastatic breast cancer (mBC) after ≥1 prior ...anti–HER2 regimen(s). Approval was based on the randomized, multicenter, open-label, phase 3 DESTINY-Breast03 study (NCT03529110), in which T-DXd demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with trastuzumab emtansine (T-DM1). At the primary interim analysis (data cutoff May 21, 2021), the risk of disease progression or death was reduced by 72% with T-DXd (P < 0.001; Cortes et al. N Engl J Med 2022). Overall survival (OS) data were immature for both treatment groups; although the prespecified cutoff for significance was not reached (NR), a trend toward benefit with T-DXd was observed. With further follow-up, we report results from the prespecified OS analysis of DESTINY-Breast03 (data cutoff July 25, 2022), including updated efficacy and safety.
Methods: Pts with HER2+ mBC previously treated with trastuzumab and a taxane in either the metastatic setting or (neo)adjuvant setting with progression within 6 mo of therapy, who could have received pertuzumab, were randomly assigned 1:1 to receive T-DXd 5.4 mg/kg every 3 weeks (Q3W) or T-DM1 3.6 mg/kg Q3W until disease progression. The primary endpoint was PFS by blinded independent central review (BICR). The key secondary endpoint was OS (80% powered at 2-sided significance level of 5%); other secondary endpoints included objective response rate (ORR), duration of response (DoR), PFS based on investigator assessment, and safety.
Results: 524 pts received either T-DXd (n = 261) or T-DM1 (n = 263). As of the updated data cutoff, median duration of study follow-up was 28.4 mo (range, 0.0-46.9 mo) for T-DXd and 26.5 mo (range, 0.0-45.0 mo) for T-DM1. Median treatment duration was 18.2 mo (range, 0.7-44.0 mo) for T DXd and 6.9 mo (range, 0.7-39.3 mo) for T-DM1. The risk of death was reduced by 36% (HR, 0.64; P = 0.0037) with T-DXd; median OS (mOS) was NR (95% CI, 40.5 mo-not evaluable NE), with 72 (27.6%) OS events, for T-DXd vs NR (95% CI, 34.0 mo-NE), with 97 (36.9%) OS events, for T-DM1. Landmark 12-mo OS rate was 94.1% (95% CI, 90.4-96.4) for T-DXd vs 86.0% (95% CI, 81.1-89.8) for T-DM1; 24-mo OS rate was 77.4% (95% CI, 71.7-82.1) for T-DXd vs 69.9% (95% CI, 63.7-75.2) for T-DM1. The P value for OS crossed the prespecified boundary (P = 0.013) and was statistically significant. mPFS by BICR was 28.8 mo (95% CI, 22.4-37.9 mo) with T-DXd, compared with 6.8 mo (95% CI, 5.6-8.2 mo) with T-DM1; HR, 0.33; nominal P < 0.000001. Key efficacy and safety results are shown in the table. Grade ≥3 treatment-emergent adverse events were experienced by 56.4% of T-DXd-treated pts and 51.7% of T DM1-treated pts. Drug-related interstitial lung disease/pneumonitis, as evaluated by an independent adjudication committee, was experienced by 39 pts (15.2%) in the T-DXd arm and 8 pts (3.1%) in the T DM1 arm; no adjudicated drug-related grade 4 or 5 events were observed in pts who received T-DXd.
Conclusions: Updated results confirm the superiority of T-DXd compared with T-DM1 for pts with HER2+ mBC previously treated with an anti-HER2 therapy, with highly clinically meaningful and statistically significant benefit in OS and PFS and a manageable safety profile with longer treatment duration.
Editorial Acknowledgment
Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, and Rachel Hood, PhD, of ApotheCom, and was funded by Daiichi Sankyo.
Funding
This study was funded by Daiichi Sankyo and AstraZeneca.
Table. Summary of Efficacy Results for T-DXd and T-DM1
Citation Format: Sara Hurvitz, Roberto Hegg, Wei-Pang Chung, Seock-Ah Im, William Jacot, Vinod Ganju, Joanne Win Yang Chiu, Binghe Xu, Erika Hamilton, Srinivasan Madhusudan, Hiroji Iwata, Sevilay Altintas, Jan-Willem Henning, Giuseppe Curigliano, José Manuel Pérez-García, Anton Egorov, Yali Liu, Jillian Cathcart, Shahid Ashfaque, Javier Cortés. GS2-02 Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03 abstract. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS2-02.
Households are considered ideal settings for studying the transmission dynamics of an infectious disease.
A prospective study was conducted, based on the World Health Organization FFX protocol from ...October 2020 to January,2021. Household contacts of laboratory-confirmed index cases were followed up for their symptomatic history, nasal swabs for RT-PCR,and blood samples for anti-SARS CoV-2 antibodies were collected at enrollment and days 7, 14 and 28. We estimated secondary attack rate (SAR), effective household case cluster size and determinants of secondary infection among susceptible household contacts using multivariable logistic regression.
We enrolled 77 index cases and their 543 contacts. Out of these, 252 contacts were susceptible at the time of enrollment. There were 77 household clusters, out of which, transmission took place in 20 (25.9%) giving rise to 34 cases. The acquired secondary attack rate (SAR) was 14.0% (95% CI 9.0–18.0). The effective household case cluster size was 0.46 (95%CI 0.33,0.56). Reported symptoms of nausea and vomiting (aOR, 7.9; 95% CI, 1.4–45.5) and fatigue (aOR, 9.3; 95% CI, 3.8–22.7) were associated with SARS-CoV-2 transmission.
We observed a low SARS-CoV-2 secondary attack rate in the backdrop of high seroprevalence and asymptomatic transmission among households in Karachi, Pakistan.
Paracetamol (PCM) ingestion is one of the most frequent global causes of toxicity.
L. is a plant that among many other effects exhibits potent antioxidant, anti-inflammatory, antimicrobial, and ...anticancer effects. In this study, we investigated the possible protective effect of
aqueous extract in the PCM overdose-induced liver and kidney injury and hematological changes in a mice model.
Mice were given PCM with and without
pretreatment. Blood cell counts and liver and kidney function biomarkers were measured. Liver and kidney samples were histologically examined.
A single overdose of PCM caused significant elevations of alanine and aspartate transaminases, alkaline phosphate, bilirubin, urea, uric acid, and creatinine compared with the control group. In addition, PCM toxicity significantly lowered red blood cell count but insignificantly increased both white blood cell and platelet counts in comparison to the control mice. Pretreatment with
significantly prevented PCM-induced changes in hepatic and renal biomarkers.
also caused marked reversal of hematological changes. Histologically, the liver and kidney showed inflammation and necrosis after PCM treatment, which were significantly reduced in mice pretreated with
.
Taken together,
significantly inhibited PCM-induced renal, hepatic, and hematological toxicity, pointing to its possible use in the treatment of liver and renal disorders.
One of the major obstacles in human epidermal growth factor receptor 2 (HER2)-specific trastuzumab antibody immunotherapy of HER2-positive breast cancer is the development of trastuzumab resistance, ...warranting the search for other therapeutic strategies. Using mouse models, we previously demonstrated that ovalbumin (OVA)-specific dendritic cell (DC)-released exosome (EXO
OVA
)-targeted CD4
+
T cell-based (OVA-T
EXO
) vaccine stimulates efficient cytotoxic T lymphocyte (CTL) responses via exosomal peptide/major histocompatibility complex (pMHC)-I, exosomal CD80 and endogenous IL-2 signaling; and long-term CTL memory by means of via endogenous CD40L signaling. In this study, using two-photon microscopy, we provide the first visual evidence on targeting OVA-T
EXO
to cognate CD8
+
T cells in vivo via exosomal pMHC-I complex. We prepared HER2/neu-specific Neu-T
EXO
and HER2-T
EXO
vaccines using adenoviral vector (AdVneu and AdV
HER2
)-transfected DC (DCneu and DC
HER2
)-released EXOs (EXOneu and EXO
HER2
), and assessed their stimulatory effects on HER2/neu-specific CTL responses and antitumor immunity. We demonstrate that Neu-T
EXO
vaccine is capable of stimulating efficient neu-specific CTL responses, leading to protective immunity against neu-expressing Tg1-1 breast cancer in all 6/6 transgenic (Tg) FVBneuN mice with neu-specific self-immune tolerance. We also demonstrate that HER2-T
EXO
vaccine is capable of inducing HER2-specific CTL responses and protective immunity against transgene HLA-A2
+
HER2
+
BL6-10
A2/HER2
B16 melanoma in 2/8 double Tg HLA-A2/HER2 mice with HER2-specific self-immune tolerance. The remaining 6/8 mice had significantly prolonged survival. Furthermore, we demonstrate that HER2-T
EXO
vaccine stimulates responses of CD8
+
T cells capable of not only inducing killing activity to HLA-A2
+
HER2
+
BL6-10
A2/HER2
melanoma and trastuzumab-resistant BT474
A2
breast cancer cells in vitro but also eradicating 6-day palpable HER2
+
BT474
A2
breast cancer (3–4 mm in diameter) in athymic nude mice. Therefore, the novel T cell-based HER2-T
EXO
vaccine may provide a new therapeutic alternative for women with HER2
+
breast cancer, especially for trastuzumab-resistant HER2
+
breast cancer patients.
This study aimed to determine perceptions of hepatitis and make available an educational intervention session regarding the infection among roadside barbers and their clients.
A cross-sectional study ...using convenience random sampling technique was conducted on all barbers and one each of their clients during January to June, 2011, in Karachi, Pakistan. After informed consent was taken and confidentiality ensured, respondents answered an anonymous questionnaire of closed-ended questions regarding hepatitis. The interview was followed by an educational intervention session. Data was analyzed using SPSS version 17.
About 51% and 32% of the barbers and clients respectively had knowledge regarding hepatitis. Razors were recognized as agents for transmitting the infection by 12% and 42% of the barbers and clients respectively. Most (96%) barbers disinfected the razor before use and 49% of the clients confirmed that the razor was sterilized before shaving, while 79% insisted on new blade. Though 50% and 30% of the barbers and clients respectively knew that hepatitis is a preventable disease, only 2% and 7% of the respective barbers and clients were vaccinated against Hepatitis B. Reasons for not being vaccinated were non-awareness and cost of the HBV vaccine. Only half of the barbers and clients considered themselves to be at risk for hepatitis.
In Karachi, barbers and clients have poor knowledge of hepatitis and the means of transmissions, as well as low vaccination rates against HBV infection. Hence barbers and their clients must be educated about hepatitis and its prevention.
Pretreatment with Salvadora persica L Alaraj, Mohd; Acar, Tolgahan; Kosinska, Irena ...
Veterinary World,
03/2021, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Background and Aim: Paracetamol (PCM) ingestion is one of the most frequent global causes of toxicity. Salvadora persica L. is a plant that among many other effects exhibits potent antioxidant, ...anti-inflammatory, antimicrobial, and anticancer effects. In this study, we investigated the possible protective effect of S. persica aqueous extract in the PCM overdose-induced liver and kidney injury and hematological changes in a mice model. Materials and Methods: Mice were given PCM with and without S. persica pretreatment. Blood cell counts and liver and kidney function biomarkers were measured. Liver and kidney samples were histologically examined. Results: A single overdose of PCM caused significant elevations of alanine and aspartate transaminases, alkaline phosphate, bilirubin, urea, uric acid, and creatinine compared with the control group. In addition, PCM toxicity significantly lowered red blood cell count but insignificantly increased both white blood cell and platelet counts in comparison to the control mice. Pretreatment with S. persica significantly prevented PCM-induced changes in hepatic and renal biomarkers. S. persica also caused marked reversal of hematological changes. Histologically, the liver and kidney showed inflammation and necrosis after PCM treatment, which were significantly reduced in mice pretreated with S. persica. Conclusion: Taken together, S. persica significantly inhibited PCM-induced renal, hepatic, and hematological toxicity, pointing to its possible use in the treatment of liver and renal disorders. Keywords: hematology, kidney, liver, mice, paracetamol, Salvadora persica L.
PDF
