Assessment of nivolumab benefit-risk profile of a 240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors
| Autor: | Akintunde Bello, Xiaoning Wang, J. Shen, A. Achanta, H.E. Vezina, Yan Feng, Xiaochen Zhao, M. Hruska, Shruti Agrawal, Satyendra Suryawanshi, M.B. McHenry, Amit Roy, Ian M. Waxman |
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| Rok vydání: | 2017 |
| Předmět: |
Oncology
medicine.medical_specialty Population Antineoplastic Agents 030226 pharmacology & pharmacy law.invention 03 medical and health sciences Onco-Immunology exposure–response relationship 0302 clinical medicine Pharmacokinetics law Internal medicine Neoplasms medicine Humans Dosing Adverse effect education Dose Modification nivolumab education.field_of_study Clinical pharmacology cancer immunotherapy Dose-Response Relationship Drug business.industry Melanoma Antibodies Monoclonal Hematology solid tumors medicine.disease Original articles Editor's Choice 030220 oncology & carcinogenesis clinical pharmacology Nivolumab business flat dosing |
| Zdroj: | Annals of Oncology |
| ISSN: | 1569-8041 |
| Popis: | Background Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). However, flat dosing is expected to shorten preparation time and improve ease of administration. With knowledge of nivolumab safety, efficacy, and pharmacokinetics across a wide dose range in body weight (BW) dosing, assessment of the benefit–risk profile of a 240-mg flat dose relative to the approved 3-mg/kg dose was approached by quantitative clinical pharmacology. Patients and methods A flat dose of 240 mg was selected based on its equivalence to the 3-mg/kg dose at the median BW of ∼80 kg in patients in the nivolumab program. The benefit–risk profile of nivolumab 240 mg was evaluated by comparing exposures at 3 mg/kg Q2W and 240 mg Q2W across BW and tumor types; clinical safety at 3 mg/kg Q2W by BW and exposure quartiles in melanoma, NSCLC, and RCC; and safety and efficacy at 240 mg Q2W relative to 3 mg/kg Q2W in melanoma, NSCLC, and RCC. Results The median nivolumab exposure and its distribution at 240 mg Q2W were similar to 3 mg/kg Q2W in the simulated population. Safety analyses did not demonstrate a clinically meaningful relationship between BW or nivolumab exposure quartiles and frequency or severity of adverse events. The predicted safety and efficacy were similar across nivolumab exposure ranges achieved with 3 mg/kg Q2W or 240 mg Q2W flat dose. Conclusion Based on population pharmacokinetic modeling, established flat exposure–response relationships for efficacy and safety, and clinical safety, the benefit–risk profile of nivolumab 240 mg Q2W was comparable to 3 mg/kg Q2W. The quantitative clinical pharmacology approach provided evidence for regulatory decision-making on dose modification, obviating the need for an independent clinical study. |
| Databáze: | OpenAIRE |
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