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MeSH: humanizované monoklonální protilátky-škodlivé účinky

595 záznamů v Medvik Filtry

Článek

Ocrelizumab in Early-Stage Relapsing-Remitting Multiple Sclerosis: The Phase IIIb ENSEMBLE 4-Year, Single-Arm, Open-Label Trial

Hartung, Hans-Peter
Autor Autorita ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Benedict, Ralph H B
Autor Benedict, Ralph H B From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Berger, Thomas
Autor Berger, Thomas ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Bermel, Robert A
Autor Bermel, Robert A ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Brochet, Bruno
Autor Brochet, Bruno ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Carroll, William M
Autor Carroll, William M ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Freedman, Mark S
Autor Freedman, Mark S ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Holmøy, Trygve
Autor Holmøy, Trygve ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Karabudak, Rana
Autor Karabudak, Rana ORCID From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands
Nos, Carlos
Autor Nos, Carlos From the Department of Neurology (H.-P.H.), UKD, Centre of Neurology and Neuropsychiatry and LVR-Klinikum, Heinrich-Heine University Düsseldorf, Germany Brain and Mind Centre (H.-P.H.), University of Sydney, Australia Department of Neurology (H.-P.H.), Palacky University Olomouc, Czech Republic Department of Neurology (R.H.B.B.), Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, NY Department of Neurology (T.B.), Medical University of Vienna, Comprehensive Center for Clinical Neurosciences and Mental Health, Austria Mellen Center for MS (R.A.B.), Cleveland Clinic, OH Neurocentre Magendie INSERM (B.B.), Université de Bordeaux, France Department of Neurology (W.M.C.), Sir Charles Gairdner Hospital, Perron Institute for Neurological and Translational Science, The University of Western Australia, Nedlands Department of Medicine and the Ottawa Hospital Research Institute (M.S.F.), University of Ottawa, Ontario, Canada Department of Neurology (T.H.), Akershus University Hospital, Lørenskog Institute of Clinical Medicine (T.H.), University of Oslo, Norway Department of Neurology (R.K.), Hacettepe University Faculty of Medicine, Ankara, Turkey Centre d'Esclerosi Mútiple de Catalunya (Cemcat) (C.N.), Vall d'Hebron Hospital Universitari, Barcelona, Spain Department of Medical and Surgical Sciences and Advanced Technologies (F.P.), GF Ingrassia, Neuroscience Section and Multiple Sclerosis Centre, University of Catania PO Policlinico G Rodolico, Italy Loyola University Chicago (A.P.R.), IL Department of Neurology (L.V.), AZ Sint-Jan Brugge-Oostende, Belgium Department of Neurology (T.V.), University of Colorado School of Medicine, Aurora Medical Image Analysis Center (MIAC AG) (J.W.), Department of Biomedical Engineering, University of Basel F. Hoffmann-La Roche Ltd (J.W., S.C., K.K., T.K., I.K., C.R., G.-A.T.), Basel, Switzerland and Department of Neurology (J.K.), VU University Medical Centre, Amsterdam, the Netherlands

Neurology. 2024 ; 103 (12) : e210049. [pub] 20241203

ISSN 1526-632X
Medvik
Zdroj

BACKGROUND AND OBJECTIVES: Early treatment of multiple sclerosis (MS) reduces disease activity and the risk of long-term disease progression. Effectiveness of ocrelizumab is established in relapsing MS (RMS); however, data in early RMS are lacking. We evaluated the 4-year effectiveness and safety of ocrelizumab as a first-line therapy in treatment-naive patients with recently diagnosed relapsing-remitting MS (RRMS). METHODS: ENSEMBLE was a prospective, 4-year, international, multicenter, single-arm, open-label, phase IIIb study. Patients were treatment naive, aged 18-55 years, had early-stage RRMS with a disease duration ≤3 years, Expanded Disability Status Scale (EDSS) score ≤3.5, and ≥1 clinically reported relapse(s) or ≥1 signs of brain inflammatory activity on MRI in the prior 12 months. Patients received IV ocrelizumab 600 mg every 24 weeks. Effectiveness endpoints over 192 weeks were proportion of patients with no evidence of disease activity (NEDA-3; defined as absence of relapses, 24-week confirmed disability progression [CDP], and MRI measures, with prespecified MRI rebaselining at week 8), 24-week/48-week CDP and 24-week confirmed disability improvement, annualized relapse rate (ARR), mean change in EDSS score from baseline, and safety. Cognitive status, patient-reported outcomes, and serum neurofilament light chain (NfL) were assessed. Descriptive analysis was performed on the intention-to-treat population. RESULTS: Baseline characteristics (N = 678) were consistent with early-stage RRMS (n = 539 patients, 64.6% female, age 40 years and younger; median age: 31.0 years; duration since: MS symptom onset 0.78 years, RRMS diagnosis 0.24 years; mean baseline EDSS score [SD] 1.71 [0.95]). At week 192, most of the patients had NEDA-3 (n = 394/593, 66.4%), 85.0% had no MRI activity, 90.9% had no relapses, and 81.8% had no 24-week CDP over the study duration. Adjusted ARR at week 192 was low (0.020, 95% CI 0.015-0.027). NfL levels were reduced to and remained within the healthy donor range, by week 48 and week 192, respectively. No new or unexpected safety signals were observed. DISCUSSION: Disease activity based on clinical and MRI measures was absent in most of the patients treated with ocrelizumab over 4 years in the ENSEMBLE study. Safety was consistent with the known profile of ocrelizumab. Although this single-arm study was limited by lack of a parallel group for comparison of outcome measures, the positive benefit-risk profile observed may provide confidence to adopt ocrelizumab as a first-line treatment in newly diagnosed patients with early RMS. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that adult patients with early-stage MS who were treatment naive maintained low disease activity (NEDA-3) over 4 years with ocrelizumab treatment; no new safety signals were detected. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier NCT03085810; first submitted March 16, 2017; first patient enrolled: March 27, 2017; available at clinicaltrials.gov/ct2/show/NCT03085810.

Článek

Ofatumumab: State of the art 2024 - Kde jsme nyní a kam směřujeme
[Ofatumumab: State of the art in 2024 - Where are we now and where are we going]

Česká a slovenská neurologie a neurochirurgie. 2024 ; 87 (5) : 313-316.

ISSN 1210-7859
Medvik
Zdroj

Ofatumumab představuje první plně humánní anti-CD20 monoklonální protilátku, vyvinutou pro subkutánní autoaplikaci v měsíčních intervalech. Je určen k terapii aktivní relabující-remitující RS (RR-RS) a u pacientů se známkami nepříznivé prognózy nemoci ho lze uplatnit v první linii léčby. V registračních klinických studiích prokázal jasnou superioritu oproti teriflunomidu a data z extenzí klinických hodnocení potvrzují jeho setrvalou účinnost, příznivý bezpečnostní profil i vysokou míru adherence pacientů k léčbě. Z pohledu pacienta se jedná o atraktivní možnost terapie vysoce účinným lékem s jednoduchou podkožní aplikací v domácím prostředí, bez nutnosti premedikace. Ofatumumab splňuje předpoklady moderní farmakoterapie a je jedním z průlomových přípravků, který může významně zlepšit prognózu pacientů s RR-RS.

Ofatumumab represents the first fully human anti-CD20 monoclonal antibody, developed for subcutaneous self-administration once a month. It is indicated for the treatment of active relapsing-remitting multiple sclerosis (RR-MS) and can be used as a first-line therapy in patients with negative prognostic factors suggestive of an unfavorable disease course. Ofatumumab demonstrated clear superiority over teriflunomide in registration clinical trials and long-term data from open-label extension studies which confirmed its sustained efficacy, favorable safety profile, and also a high level of patient compliance. From the patient‘s point of view, it is an attractive treatment option with a high-efficacy drug that is easy to administer via subcutaneous injection at home, requiring no premedication. Ofatumumab meets the requirements of modern pharmacotherapy and is one of the breakthrough drugs that can significantly improve the prognosis of patients with RR-MS.

Klíčová slova
ofatumumab,
MeSH
adherence k farmakoterapii MeSH
antigeny CD20 škodlivé účinky terapeutické užití MeSH
humanizované monoklonální protilátky * škodlivé účinky terapeutické užití MeSH
imunosupresiva terapeutické užití MeSH
injekce subkutánní MeSH
klinická studie jako téma MeSH
lidé MeSH
relabující-remitující roztroušená skleróza farmakoterapie MeSH
Check Tag
lidé MeSH

Článek

Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial

Journal of clinical oncology. 2024 ; 42 (1) : 47-58. [pub] 20231023

J. clin. Oncol.
ISSN 1527-7755
Medvik
Zdroj

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.

MeSH
humanizované monoklonální protilátky škodlivé účinky MeSH
imunokonjugáty * škodlivé účinky MeSH
intersticiální plicní nemoci * chemicky indukované farmakoterapie MeSH
lidé MeSH
nádory plic * farmakoterapie MeSH
nádory prsu * farmakoterapie MeSH
nemalobuněčný karcinom plic * farmakoterapie MeSH
receptor erbB-2 metabolismus MeSH
trastuzumab škodlivé účinky MeSH
Check Tag
lidé MeSH
ženské pohlaví MeSH
Publikační typ
časopisecké články MeSH
klinické zkoušky, fáze II MeSH

Článek

The Safety Profiles of Adalimumab, Infliximab, Etanercept, Secukinumab and Ustekinumab in Psoriasis - A 30-month Observational Cohort Prospective Study of Adverse Events in Biologic Therapy

Acta dermatovenerologica Croatica : ADC. 2024 ; 32 (1) : 7-16. [pub] -

Acta Dermatovenerol Croat
ISSN 1847-6538
Medvik
Zdroj

BACKGROUND: Although biologic agents are very effective, long-term comparative studies demonstrating their safety relative to one another are still lacking. METHODS: A total of 124 patients with psoriasis were followed up for 30 months; 74 received anti-TNF-alpha inhibitors (adalimumab, etanercept, infliximab), 33 were on ustekinumab, and 17 were treated with secukinumab. The rates of adverse events in these groups were recorded and statistically analyzed. RESULTS: Infliximab-treated patients showed a high occurrence of asymptomatic, but increased liver enzymes, fatigue, and respiratory as well as dermatologic infections. Adalimumab-treated patients were more often affected by musculoskeletal disorders and infections of all types. Patients treated with secukinumab presented with higher rates of cardiovascular disorders as well as respiratory and dermatologic infections. The group receiving etanercept was more often diagnosed with musculoskeletal and reproductive disorders, specifically menstrual disorders. The rates of therapy discontinuation and serious adverse events did not reach statistically significant values. CONCLUSION: A higher incidence of adverse events was observed among adalimumab-, and infliximab-treated patients, with ustekinumab found to have the safest profile. Our results demonstrate that a personalized approach, including evaluation of a patient's risk profile, is necessary before commencing a biologic. Further research is warranted to confirm the findings of our study.

Článek

Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial

Current medical research and opinion. 2024 ; 40 (11) : 1863-1871. [pub] 20241014

Curr Med Res Opin
ISSN 1473-4877
Medvik
Zdroj

OBJECTIVE: We report patient-reported outcomes (PROs) measuring health-related quality of life (HRQoL) from the ROSEWOOD trial (NCT03332017), which demonstrated superior efficacy and a manageable safety profile with zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) in patients with heavily pretreated relapsed/refractory follicular lymphoma (R/R FL). METHODS: PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30) and EQ-5D-5L questionnaires at baseline and subsequently every 12 weeks. All QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores were analyzed descriptively. At the key clinical timepoints (weeks 12 and 24), a mixed model for repeated measures (MMRM) analysis was used to evaluate the key PRO endpoints, including global health status, physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting. Clinically meaningful change was defined as a ≥ 5-point mean difference from baseline and between the ZO and O arms. RESULTS: Patients were randomized to ZO (n = 145) or O (n = 72). By week 48, descriptive analysis results indicated that patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm. Both groups experienced improvements in pain symptoms. EQ-5D-5L VAS scores showed no observable differences between treatment arms through week 48. MMRM analysis revealed that the global health status/quality of life of patients treated with ZO improved, as did fatigue, at week 12. At week 24, patients in the ZO arm experienced a clinically meaningful improvement in role functioning, pain, and fatigue. CONCLUSIONS: In patients with R/R FL, ZO was associated with improved PROs compared with O. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab. TRIAL REGISTRATION: The ROSEWOOD trial is registered on ClinicalTrials.gov (BGB-3111-212; ClinicalTrials.gov identifier: NCT03332017).

Článek

Atypický hemolyticko-uremický syndrom
[Atypical haemolytic uremic syndrome]

Transfuze a hematologie dnes. 2024 ; 30 (S1) : 36-47.

ISSN 1213-5763
Medvik
Zdroj

Atypický (komplementem mediovaný) hemolyticko-uremický syndrom (aHUS) je vzácné onemocnění s vysokým rizikem závažného orgánového postižení a smrti. Řadí se mezi trombotické mikroangiopatie a je charakterizován kombinací neimunitní hemolytické anemie, konsumpční trombocytopenie a poškození endotelu s následnou poruchou mikrocirkulace vedoucí k ischemickému poškození cílových orgánů, zejména ledvin. Laboratorní a klinické charakteristiky trombotických mikroangiopatií však splňuje celá řada stavů různé etiologie, což značně ztěžuje diferenciální diagnostiku tohoto onemocnění. Příčinou aHUS je geneticky podmíněné či získané narušení rovnováhy mezi aktivátory a regulátory alternativní dráhy komplementu, vedoucí k její trvalé aktivaci, tvorbě terminálních lytických komplexů a orgánovému postižení. U více než 50 % nemocných s aHUS je možné identifikovat mutaci v genech pro komplementární faktory, asi u 5–10 % pak nacházíme protilátky proti složkám komplementu (resp. faktoru H). U nositelů mutací může díky inkompletní genetické penetranci klinické onemocnění propuknout až v přítomnosti spouštěčů amplifikace komplementu, jako jsou např. infekce, operace či těhotenství. Identifikace kauzální mutace není pro diagnózu aHUS nezbytná, je ale důležitá pro stanovení prognózy, rizika relapsu při přerušení léčby či po transplantaci ledviny. Prognóza tohoto onemocnění se v posledních letech dramaticky zlepšila díky možnosti specifické léčby spočívající v podávání inhibitorů C5 složky komplementu, přesto zůstává limitována zejména rychlou a správnou diagnostikou a včasným zahájením léčby. Dosud nevyřešenými otázkami jsou také délka léčby, podmínky jejího ukončení či přerušení a také další sledování pacientů po prodělané atace tohoto vzácného onemocnění.

Atypical (or complement-mediated) haemolytic uremic syndrome (aHUS) is a rare disease with a high risk of severe organ damage and death. As a representative of thrombotic microangiopathies, it is defined by microangiopathic haemolytic anaemia, thrombocytopenia and endothelial cell damage resulting in ischemic target organ injury, especially kidney failure. A variety of clinical scenarios can have the features of thrombotic microangiopathies thus impeding the differential diagnosis of the underlying condition. aHUS is caused by a genetic or acquired defect in the regulation of the alternative complement pathway resulting in its persistent activation, formation of terminal membrane attacking complexes, microvascular endothelial damage and ischemic organ injury. Roughly 50% of patients have rare germline variants in complement genes, detection of antibodies against complement factors (CFH) is much less common. In carriers of these genetic mutations, due to the incomplete genetic penetrance of aHUS, a clinically significant disease often requires a complement-amplifying trigger such as infection, surgery or pregnancy. Identification of germline variants is not necessary for the diagnosis of aHUS; however, it is important for the estimation of prognosis and risk of relapse after treatment termination or kidney transplant. Thanks to new specific treatment options represented by complement inhibitors, the prognosis of patients with aHUS has improved rapidly, however, it remains dependent on rapid and correct diagnostics and early treatment initiation. Further discussed and unsolved questions relate to treatment duration and the possibility of its termination as well as further management and follow-up of patients after the episode of aHUS.

Klíčová slova
eculizumab,
MeSH
atypický hemolyticko-uremický syndrom * diagnóza patofyziologie terapie MeSH
diferenciální diagnóza MeSH
humanizované monoklonální protilátky aplikace a dávkování škodlivé účinky terapeutické užití MeSH
inhibitory komplementu terapeutické užití MeSH
lidé MeSH
mutace genetika MeSH
plazmaferéza MeSH
renální insuficience etiologie MeSH
trombotické mikroangiopatie klasifikace MeSH
Check Tag
lidé MeSH
Publikační typ
přehledy MeSH

Článek

Interleukin-receptor antagonist and tumour necrosis factor inhibitors for the primary and secondary prevention of atherosclerotic cardiovascular diseases

The Cochrane database of systematic reviews. 2024 ; 9 (9) : CD014741. [pub] 20240919

Cochrane Database Syst Rev
ISSN 1469-493X
Medvik
Zdroj

BACKGROUND: Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events. OBJECTIVES: The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD. SEARCH METHODS: The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set. SELECTION CRITERIA: RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events. DATA COLLECTION AND ANALYSIS: Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence. MAIN RESULTS: We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias. Primary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I2 = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I2 = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I2 = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I2 = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I2 = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome. IL-6 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I2 = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I2 = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I2 = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I2 = 33%, 5 trials). No trial assessed unstable angina. TNF inhibitors The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I2 = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I2 = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I2 = 51%, 13 trials). No trial assessed unstable angina or PVD. Secondary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I2 = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I2 = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I2 = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I2 = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I2 = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I2 = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I2 = 0%, 6 trials). IL6-RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I2 = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I2 = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I2 = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I2 = 0%, 4 trials). No trial assessed PVD or heart failure. TNF inhibitors The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I2 = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I2 = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I2 = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke. Adverse events may be underestimated and benefits inflated due to inadequate reporting. AUTHORS' CONCLUSIONS: This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.

Článek

ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer

Annals of oncology. 2024 ; 35 (11) : 968-980. [pub] 20240914

Ann Oncol
ISSN 1569-8041
Medvik
Zdroj

BACKGROUND: Pembrolizumab plus chemotherapy provides clinically meaningful benefit as first-line therapy for advanced (locoregional extension and residual disease after surgery)/metastatic/recurrent mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR) endometrial cancer, with greater magnitude of benefit in the dMMR phenotype. We evaluated the addition of pembrolizumab to adjuvant chemotherapy (with/without radiation therapy) among patients with newly diagnosed, high-risk endometrial cancer without any residual macroscopic disease following curative-intent surgery. METHODS: We included patients with histologically confirmed high-risk [International Federation of Gynecology and Obstetrics (FIGO) stage I/II of non-endometrioid histology or endometrioid histology with p53/TP53 abnormality, or stage III/IVA of any histology] endometrial cancer following surgery with curative intent and no evidence of disease postoperatively, with no prior radiotherapy or systemic therapy. Patients were randomised to pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for six cycles added to carboplatin-paclitaxel followed by pembrolizumab 400 mg or placebo every 6 weeks (Q6W) for six cycles per treatment assignment. Radiotherapy was at the investigator's discretion. The primary endpoints were investigator-assessed disease-free survival (DFS) and overall survival in the intention-to-treat population. RESULTS: A total of 1095 patients were randomised (pembrolizumab, n = 545; placebo, n = 550). At this interim analysis (data cut-off, 4 March 2024), 119 (22%) DFS events occurred in the pembrolizumab group and 121 (22%) occurred in the placebo group [hazard ratio 1.02, 95% confidence interval (CI) 0.79-1.32; P = 0.570]. Kaplan-Meier estimates of 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo groups, respectively. The hazard ratio for DFS was 0.31 (95% CI 0.14-0.69) in the dMMR population (n = 281) and 1.20 (95% CI 0.91-1.57) in the pMMR population (n = 814). Grade ≥3 adverse events (AEs) occurred in 386 of 543 (71%) and 348 of 549 (63%) patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 AEs occurred. CONCLUSIONS: Adjuvant pembrolizumab plus chemotherapy did not improve DFS in patients with newly diagnosed, high-risk, all-comer endometrial cancer. Preplanned subgroup analyses for stratification factors suggest that pembrolizumab plus chemotherapy improved DFS in patients with dMMR tumours. Safety was manageable. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04634877; EudraCT, 2020-003424-17. RESEARCH SUPPORT: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Článek

Durvalumab after Chemoradiotherapy in Limited-Stage Small-Cell Lung Cancer

The New England journal of medicine. 2024 ; 391 (14) : 1313-1327. [pub] 20240913

N Engl J Med
ISSN 1533-4406
Medvik
Zdroj

BACKGROUND: Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy. METHODS: In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded. RESULTS: A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P = 0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P = 0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group. CONCLUSIONS: Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.).

Článek

Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial

Lancet. 2024 ; 404 (10460) : 1321-1332. [pub] 20240914

ISSN 1474-547X
Medvik
Zdroj

BACKGROUND: At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. METHODS: Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2-IIB with node-positive disease or stage III-IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2-IIB node positive vs III-IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. FINDINGS: Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab-chemoradiotherapy group and 531 patients in the placebo-chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3-34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4-86·1) in the pembrolizumab-chemoradiotherapy group and 74·8% (70·1-78·8) in the placebo-chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50-0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 371 (70%) of 530 in the placebo-chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab-chemoradiotherapy group and 90 (17%) of 530 patients in the placebo-chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. INTERPRETATION: Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co.

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