Keith T. Schmidt 1, Sophie Merrick 2, Matthew Nankivell 2, Cara Sheath 2, Ehsan Ghorani 3, Naina Patel 3, Kehinde Olubanjo 1, William D. Figg 1, Duncan C. Gilbert 2
1 Clinical Pharmacology Program, Office of the Clinical Director, Center for Cancer Research, NCI, NIH, DHHS (Bethesda, United States of America), 2 MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, 2nd Floor 90 High Holborn (London , United Kingdom), 3 Imperial College London, Division of Cancer, 1st Floor, ICTEM, Du Cane Road (London, United Kingdom)
Introduction:
Nivolumab, an immune checkpoint inhibitor (ICI) targeting programmed cell death protein 1 (PD-1), is an ideal candidate for reduced frequency dosing because of an insignificant dose-efficacy relationship and a prolonged half-life.[1] Minimal differences in PD-1 receptor occupancy were reported between subjects receiving intravenous (IV) nivolumab doses ranging from 0.1 to 10 mg/kg.[2] Based on steady-state concentrations of subjects receiving nivolumab 0.3 mg/kg IV every 3 weeks, the minimum effective concentration (MEC) of nivolumab was previously determined to be 1.5 μg/mL. Simulations of nivolumab 480 mg IV every 8 week (Q8W) dosing (standard of care is 480 mg IV every 4 weeks [Q4W]) demonstrated that >95% of virtual subjects with baseline clearances <0.5 L/day maintained Cmin,ss levels above the MEC.[1] These nivolumab dosing simulations have provided the rationale to investigate less frequent dosing strategies to reduce healthcare costs and increase quality of life while maintaining efficacy.
The REduced Frequency ImmuNE checkpoint inhibition in cancers (REFINE) study is a phase II basket trial evaluating extended interval dosing regimens in subjects with renal cell carcinoma or melanoma eligible for nivolumab or pembrolizumab treatment.[3] Subjects receive 12 weeks of lead-in standard of care ICI therapy (ipilimumab + nivolumab or pembrolizumab) prior to randomization to either standard interval (SI) or extended interval (EI; twice the standard interval) dosing in the maintenance therapy setting. Following a variable time frame from post-lead-in dosing to randomization, trough (Cmin) samples are collected at baseline and prior to scheduled doses up to Week 32 for use in pharmacokinetic/pharmacodynamic analyses. The current interim pharmacometric analysis aims to evaluate maintenance of the MEC in real-world subjects receiving EI nivolumab dosing on the REFINE trial.
Objectives:
- Estimate individual PK parameters in real-world subjects receiving IV nivolumab using a pre-existing popPK model and sparse sampling
- Use simulations to compare cumulative drug exposure (cAUC) and Cmin values between SI and EI dosing regimens
- Assess the percentage of real-world subjects eligible for EI dosing (Nivolumab 480 mg IV Q8W or Q12W)
Methods:
A two-compartment model with time-varying clearance (via Hill equation incorporation) was adapted from Liu et al.[4] using NONMEM version 7.6 and companion software packages (Pirana, PsN, R).[5] Relevant covariates for model-predicted PK parameters included sex, body weight, performance status, tumor type, objective response, baseline albumin, and renal function.[4] Empirical Bayesian Estimates (EBEs) of inter-individual variability (IIV) in relevant PK parameters (CL, Tmax, Vc, & Vp)[4] were calculated for each subject using available nivolumab trough measurements via the POSTHOC option. Individual-predicted concentration-time curves for nivolumab 480 mg IV Q4W, Q8W and Q12W dosing schedules were simulated for each subject. Cmin and cAUC values are reported as mean (range).
Results:
As of February 2026, 50 subjects enrolled on the REFINE study receiving IV-administered nivolumab were analyzed (26 subjects [52%] received SI dosing, 24 [48%] received EI dosing). 256 of 260 measured trough concentrations (98%) were above the MEC of 1.5 μg/mL (all samples below the MEC were collected at baseline, 13-16 weeks after the last lead-in dose). EBEs of IIV were determined using an average of 6 and 4 trough sample measurements per subject in the SI and EI arms, respectively. Both nivolumab 480 mg IV Q4W and Q8W simulations maintained concentrations above the MEC for all subjects (N=50). The EI regimen led to a 2-fold reduction in Cycle 1 Cmin (Q8W: 8.98 (2.40-24.96) μg/mL vs. Q4W: 20.38 (11.34-41.06) μg/mL) and a 3-fold reduction in Week 24 Cmin (Q8W: 19.77 (5.00-53.14) μg/mL vs. Q4W: 57.94 (23.44-117.94) μg/mL). The EI regimen also decreased drug exposure by 46%, as measured by cAUC following 40 weeks of dosing (Q8W: 15200 (7810-46100) day*μg/mL vs. Q4W: 27900 (14400-77000) day*μg/mL). In an exploratory simulation of 480 mg IV Q12W dosing, 7 of 50 (14%) subjects had cycle 1 Cmin values below the MEC; at Week 24, one subject (2%) with a baseline albumin below limit of normal and a baseline clearance >0.4 L/day was below the MEC.
Conclusions:
Nivolumab 480 mg IV Q8W dosing maintained Cmin values above our inferred MEC for all subjects evaluated, suggesting real-world feasibility of this dosing strategy. Furthermore, most subjects may be eligible for Q12W dosing. Enrollment on the REFINE trial is ongoing with a planned primary endpoint assessing progression-free survival.
References:
[1] Peer et al. J Clin Pharmacol. (2022) 62(4):532-540
[2] FDA. Clinical pharmacology and biopharmaceutic review (nivolumab). Application Number 125554Orig1s000.
[3] https://clinicaltrials.gov/study/NCT04913025; NCT04913025
[4] Liu et al. Clin Pharmacol Ther. (2017) 101(5):657–666
[5] Keizer et al. CPT PSP. (2013) 2(6):e50.
Reference: PAGE 34 (2026) Abstr 11900 [www.page-meeting.org/?abstract=11900]
Poster: Clinical Applications