(S-082) Model-Based Approach to Support Nivolumab Subcutaneous Dose Selection in Pediatric Patients (12 to <18 Years) in Multiple Solid Tumor Indications

Elizabeth Gibson – Bristol Myers Squibb; Yue Zhao – Bristol Myers Squibb; Li Zhu – Bristol Myers Squibb; Heather Vezina – Bristol Myers Squibb; Anna Kondic – Bristol Myers Squibb

Objectives: To recommend a nivolumab subcutaneous (nivo SC) pediatric dosing regimen without clinical data using a model informed drug delivery (MIDD) approach. The objective of this approach was to predict and compare nivo exposures across nivo SC vs. the approved nivo intravenous (IV) dosing regimens in pediatric patients (12 to < 18 years) with unresectable or metastatic melanoma, adjuvant treatment of melanoma, and microsatellite instability high or mismatch repair deficient metastatic colorectal cancer. The recommended nivo SC pediatric dosing regimen was needed to achieve PK non-inferiority (geometric mean ratio [GMR] >1) compared to the approved nivo IV regimen exposures in pediatric patients.

Methods: Previously established nivo population PK (popPK) models for the different tumor types were utilized. Stochastic simulations were performed using a pediatric population created from the NHANES database (2020-2023). To ensure sufficient subjects were included across a wide body-weight range (30 kg to ≥110 kg ), 800 subjects aged 12 to < 18 years were randomly sampled from the database. Height and creatinine clearance from the NHANES database were utilized in the Schwartz equation to calculate estimated glomerular filtration rate (eGFR) for each sampled subject. Other covariates utilized from NHANES included, body weight, lean body mass, sex, and race. Another population of adult subjects (N = 500) was created by random sampling from the included adult subjects in each popPK dataset. Sensitivity analyses were performed to evaluate the impact of variations in SC bioavailability (F) and absorption rates (ka) on PK exposures.

Results: The nivo SC dosing regimens recommended for pediatric patients included nivo 1200 mg SC Q4W and nivo 600 mg SC Q2W for patients weighing ≥ 40 kg, and nivo 600 mg SC Q4W and nivo 300 mg SC Q2W for patients weighing < 40 kg. The nivo 1200 mg SC Q4W and nivo 600 mg SC Q2W dosing regimens are the approved adult dosing regimens across a range of tumor types. In the assessments conducted, the GMRs were above 1.0 for all evaluated indications indicating that noninferiority was met. All pediatric SC median exposures fell within the 5th and 95th percentile of adult SC exposures at the proposed dosing recommendations. The simulated median exposures (Cavgd28, Cavgss, Cminss, Cmaxss), including subjects across the entire body weight range for all SC dosing regimens were below the median adult exposures for nivo 10 mg/kg IV Q2W, a dosing regimen considered safe and tolerable. In addition, no meaningful differences in exposures were observed with the sensitivity analyses for ka and F.

Conclusions: Based on the totality of the data, the exposures of the proposed dosing regimens for nivo SC in pediatric patients (12 to < 18 years) are expected to result in a comparable benefit-risk profile as in adults. Utilizing MIDD approaches to support dose selection in pediatric patients is a powerful tool to support dose recommendations in patient populations with limited clinical data.

Citations: [1] National Health and Nutrition Examination Survey (NHANES)Database 2020-2023. https://wwwn.cdc.gov/nchs/nhanes/
[2] OPDIVO QVANTIG (nivolumab and hyaluronidase-nvhy) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2024.

Keywords: pediatric oncology, subcutaneous, dose selection