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The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PK of nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration-time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction-corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two-compartment model with time-varying clearance, zero-order infusion into the central compartment after i.v. dosing, and first-order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well-characterized using the combined s.c./i.v. population PK model. The model-based analysis facilitated a comprehensive benefit-risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation., (© 2023 Bristol-Myers Squibb. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Ipilimumab is a fully human monoclonal antibody approved for the treatment of melanoma as monotherapy and for the treatment of melanoma, renal cell carcinoma, and colorectal cancer in combination with nivolumab. Ipilimumab time-varying clearance (CL) was assessed by a population pharmacokinetics (PPK) model developed using statistically significant covariates identified in a previous PPK analysis plus additional covariates. Data from 3,411 patients who received ipilimumab 0.3-10 mg/kg alone or in combination with nivolumab in 16 clinical trials were analyzed. Ipilimumab CL decreased over time; the change in CL was greater in patients treated with nivolumab combination than ipilimumab alone and in responders vs. nonresponders. Time-varying covariates including body weight, lactate dehydrogenase, albumin, and performance status were evaluated on change in ipilimumab CL. In addition, ipilimumab CL was similar across different tumor types, nivolumab dosing regimens, and lines of therapy. These data suggest an association of ipilimumab CL with disease severity., (© 2019 Bristol-Myers Squibb. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Nivolumab is a fully human monoclonal antibody that inhibits programmed cell death-1 activation. To assess covariate effects on nivolumab clearance (CL), a population pharmacokinetics model was developed using data from 6,468 patients with colorectal cancer, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, or small cell lung cancer who received nivolumab as monotherapy or in combination with ipilimumab or chemotherapy across 25 clinical studies. Nivolumab CL was similar across the tumor types examined; CL was higher for ipilimumab 1 mg/kg every 6 weeks (by 17%) and 3 mg/kg every 3 weeks (by 29%) vs. nivolumab monotherapy. Nivolumab CL over time was partially explained by time-varying covariates. A greater decrease in nivolumab time-varying CL was associated with increased albumin and body weight and a responder status. Our findings support the observed association between nivolumab CL and disease severity., (© 2019 Bristol-Myers Squibb. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies. This review outlines the clinical pharmacology characteristics and development challenges for the 6 approved immunomodulatory monoclonal antibodies that target 2 immune checkpoint pathways: ipilimumab (an anti-cytotoxic T-lymphocyte antigen-4 antibody) and, more recently, nivolumab and pembrolizumab (both anti-programmed death-1 antibodies) and atezolizumab, avelumab, and durvalumab (all anti-programmed death ligand-1 antibodies). These agents have revealed much about the clinical pharmacology features of immune checkpoint inhibitors as a class, as well as the pharmacometric approaches used to support their clinical development and regulatory approval. The development experiences with these pioneering immuno-oncology agents are likely to serve as useful guides in the discovery, progression, and approval of future drugs or combination of drugs in this class. This review includes summaries of the pharmacokinetics and exposure-response of the immune checkpoint inhibitors approved to date, as well as an overview of some quantitative systems pharmacology approaches. The ability of immuno-oncology to meet its full potential will depend on overcoming development challenges, including the need for clear strategies to determine optimal dose and scheduling for monotherapy as well as combination approaches., (© 2017, The American College of Clinical Pharmacology.)

This paper provides an overview of issues in the integration of genetic (related to hereditary DNA) and genomic (related to genes and their functions) information in cancer care for individuals and families who are part of health care systems worldwide, from low to high resourced. National and regional cancer plans have the potential to integrate genetic and genomic information with a goal of identifying and helping individuals and families with and at risk of cancer. Healthcare professionals and the public have the opportunity to increase their genetic literacy and communication about cancer family history to enhance cancer control, prevention, and tailored therapies.