Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer
| Autor: | Amit Roy, M. Rashford, Georgina V. Long, Claus Garbe, Linda Rollin, J.G. Schneider, Gwenaelle Gravis, Akintunde Bello, Elena Grigoryeva, Xiaochen Zhao, Shruti Agrawal, Scott S. Tykodi |
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| Přispěvatelé: | Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Photonique et de Nanostructures, Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Adult medicine.medical_specialty Drug-Related Side Effects and Adverse Reactions [SDV]Life Sciences [q-bio] Population Phases of clinical research Models Biological Drug Administration Schedule 03 medical and health sciences Young Adult 0302 clinical medicine Antineoplastic Agents Immunological Internal medicine Neoplasms medicine media_common.cataloged_instance Humans Dosing European union education Infusions Intravenous media_common education.field_of_study Dose-Response Relationship Drug business.industry Hematology 3. Good health Clinical trial Regimen 030104 developmental biology Nivolumab Treatment Outcome Oncology Tolerability Clinical Trials Phase III as Topic 030220 oncology & carcinogenesis Disease Progression business |
| Zdroj: | Annals of Oncology Annals of Oncology, 2018, 29 (11), pp.2208-2213. ⟨10.1093/annonc/mdy408⟩ Annals of Oncology, Elsevier, 2018, 29 (11), pp.2208-2213. ⟨10.1093/annonc/mdy408⟩ |
| ISSN: | 0923-7534 1569-8041 |
| Popis: | Background A nivolumab monotherapy flat-dosing regimen of 480 mg every 4 weeks (Q4W) has been approved in several markets, including the United States, Canada, and European Union, as an alternative dosing regimen for several indications. Approvals of this Q4W regimen were based on population pharmacokinetic (PK) analyses, established flat exposure–response relationships, and clinical safety. The objective of this study was to compare the PK exposure of 480 mg Q4W with 3 mg/kg every 2 weeks (Q2W) and 240 mg Q2W using modeling and simulation, and to evaluate clinical safety of the Q4W regimen. Patients and methods Nivolumab PK exposure for the 480 mg Q4W schedule was simulated for 3817 patients across multiple tumor types and compared with those for the 3 mg/kg Q2W and 240 mg Q2W schedules. The safety profile of the Q4W schedule was assessed by analysis of clinical data from 61 patients who transitioned to nivolumab 480 mg Q4W from 3 mg/kg Q2W during four phase III clinical trials. Results Compared with 3 mg/kg Q2W, nivolumab 480 mg Q4W produced similar time-averaged concentration, approximately 16% lower trough concentration, and 45% higher peak concentration at steady state. The peak concentration for 480 mg Q4W was significantly lower than that of 10 mg/kg Q2W, a dose previously shown to have an acceptable tolerability and safety profile. Treatment-related adverse events (TRAEs) that started after transitioning from 3 mg/kg Q2W to 480 mg Q4W were reported in 14.8% of patients, with 1.6% of patients reporting grades 3–4 TRAEs. Pooled safety data for these patients are consistent with those for the 3 mg/kg Q2W schedules, and no new safety signals were identified. Conclusions The time-averaged steady-state exposure and safety profile of nivolumab 480 mg Q4W are consistent with that of 3 mg/kg Q2W across multiple tumor types. Nivolumab 480 mg Q4W represents a new dosing schedule option, and in addition to 240 mg Q2W, provides convenience and flexibility for patient care. Clinical trial numbers NCT01721772, NCT01668784, NCT01673867, NCT01642004 |
| Databáze: | OpenAIRE |
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