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Assessment of nivolumab exposure and clinical safety of 480?mg every 4 weeks flat-dosing schedule in patients with cancer.

ABSTRACT: 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.

SUBMITTER: Long GV

PROVIDER: S-EPMC6290887 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.

Long G V GV Tykodi S S SS Schneider J G JG Garbe C C Gravis G G Rashford M M Agrawal S S Grigoryeva E E Bello A A Roy A A Rollin L L Zhao X X

Annals of oncology : official journal of the European Society for Medical Oncology 20181101 11

<h4>Background</h4>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 wee ...[more]

PMID: 30215677

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Project description:PurposeCheckMate 032 is an open-label, multicohort study that includes patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) treated with nivolumab 3 mg/kg monotherapy every 2 weeks (NIVO3), nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO3+IPI1), or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks (NIVO1+IPI3). We report on the expanded NIVO1+IPI3 cohort and extended follow-up for the NIVO3 and NIVO3+IPI1 cohorts.MethodsPatients with platinum-pretreated mUC were enrolled in this phase I/II multicenter study to receive NIVO3, NIVO3+IPI1, or NIVO1+IPI3 until disease progression or unacceptable toxicity. Primary end point was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, including duration of response.ResultsSeventy-eight patients were treated with NIVO3 (minimum follow-up, 37.7 months), 104 with NIVO3+IPI1 (minimum follow-up, 38.8 months), and 92 with NIVO1+IPI3 (minimum follow-up, 7.9 months). Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Median duration of response was more than 22 months in all arms. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. Grade 5 treatment-related pneumonitis occurred in one patient each in the NIVO3 and NIVO3+IPI1 arms.ConclusionWith longer follow-up, NIVO3 demonstrated sustained antitumor activity alone and in combination with ipilimumab. NIVO1+IPI3 provided the greatest antitumor activity of all regimens, with a manageable safety profile. This result not only supports additional study of NIVO1+IPI3 in mUC, but demonstrates the potential benefit of immunotherapy combinations in this disease.

Dataset Information

Assessment of nivolumab exposure and clinical safety of 480?mg every 4 weeks flat-dosing schedule in patients with cancer.

Publications

Assessment of nivolumab exposure and clinical safety of 480 mg every 4 weeks flat-dosing schedule in patients with cancer.

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