Pharmacokinetic and pharmacodynamic analyses of PD-1 blockade with nivolumab at varying doses and schedules supports administration at markedly reduced dose and frequency

Abstract

Background Immune checkpoint inhibitors (ICI), specifically agents blocking PD-1/PD-L1, have revolutionized cancer treatment with durable responses and improved survival in numerous malignancies. However, their unprecedented success has come with tremendous financial and logistical burden on delivery of cancer care. There is increasing interest in de-escalated dosing regimens to improve access and reduce burden. We report the results of detailed pharmacokinetic (PK) and pharmacodynamic (PD) analyses of anti-PD-1 antibody, specifically nivolumab, administered at low dose (LD; 40 mg) and reduced frequency dosing (RFD; every 12 weeks) in patients with advanced cancer. Methods We collected 122 serial blood samples at multiple timepoints from 19 patients receiving nivolumab at different doses [40 to 480 mg] and at varying frequencies [every 4 to 12 weeks]. We quantified serum nivolumab concentration in serum samples with the use of a validated enzyme-linked immunosorbent assay.1 2 We assessed PD-1 receptor occupancy (PD-1 RO) on CD4+ and CD8+ T-cell subsets in peripheralblood mononuclear cells (PBMCs) by detecting bound antibody on PD-1 receptors of circulating T cells.3 Results We found high levels of PD-1 RO following nivolumab infusions at all 3 dose levels (40mg, 240 mg, 480 mg) (figure 1). In patients treated at RFD, PD-1 RO was generally preserved for >12 weeks regardless of the dose level. Serum nivolumab concentration was maintained at levels above the previously described minimum effective concentration (MEC; 1.5ug/mL) for > 8 months after the last infusion at standard dose (240 mg) and >2 months at LD (figure 2).4 Besides high PD-1 RO, there was also strong clinical evidence of immune activation with LD nivolumab in 6 of 7 patients, suggested by ongoing disease control (5/7) and/or immune-mediated toxicity (3/7) (figure 3). Deep immune profiling and functional characterization of T-cells with spectral cytometry is underway and will be reported at the meeting. Conclusions Our PK/PD analyses suggest sustained PD-1 RO and maintained serum drug concentrations of nivolumab administered at markedly lower doses (40 mg) and at reduced frequency (every 12 weeks). These data have potential practice-changing implications for the use of PD-1 blockade in cancer patients, including 1) improving access and affordability at a global level, 2) facilitating easier incorporation of ICI into combination immunotherapy trials, 3) reducing financial and time toxicity of ICI, 4) explaining the kinetics of delayed immune-related adverse events after ICI discontinuation, and 5) revisiting the standards for drug washout and PD-1 refractoriness in clinical trials.