Pharmacokinetics and safety of subcutaneous nivolumab: results from the phase I/II CheckMate 8KX study

Background CheckMate 8KX was a phase I/II study investigating the pharmacokinetics and safety of subcutaneous (SC) nivolumab±recombinant human hyaluronidase PH20 (rHuPH20). Methods Patients with advanced solid tumors who were immune-checkpoint inhibitor-naïve were included. In parts A and B, patients received one single dose of nivolumab SC 720 mg or 960 mg±rHuPH20 2000 U/mL followed by nivolumab intravenous (IV) 480 mg every 4 weeks (Q4W). Patients receiving nivolumab IV could switch to nivolumab SC 1200 mg+rHuPH20 2000 U/mL Q4W in part C. Patients in part D received nivolumab SC 1200 mg+rHuPH20 Q4W. The primary objective was to describe the pharmacokinetics of nivolumab SC±rHuPH20. Secondary objectives included assessing safety and immunogenicity of nivolumab SC. Exploratory objectives included evaluating patient experience and preference and characterizing biomarker measures of immune function (pretreatment and on-treatment peripheral blood and tumor biopsies). Results A total of 103 patients with various solid tumor types were treated between December 4, 2018 and September 7, 2022. Mean duration of injection was <5 min for nivolumab SC±rHuPH20. Nivolumab exposures over the first dosing interval increased with increasing dose; geometric-mean time to maximum concentration across doses was 117–167 hours (5–7 days). Nivolumab SC+rHuPH20 was well tolerated; grade 3/4 treatment-related adverse events occurred in 0%–11.1% of patients; antidrug antibodies were reported in some patients but were not associated with altered safety; no neutralizing antibodies were detected. Overall, patients preferred SC delivery over IV or had no preference. Increased tumor and peripheral pharmacodynamic biomarkers were observed postnivolumab SC, consistent with historical data for nivolumab IV. Conclusion The pharmacokinetics of nivolumab SC have been well characterized and enabled dose selection for further study. Nivolumab SC has an acceptable safety profile, allows for rapid administration, and is preferred by more patients than nivolumab IV. These results encourage large-scale investigation of nivolumab SC. Trial registration number NCT03656718 .