Pharmacometrics and systems pharmacology of immune checkpoint inhibitor nivolumab in cancer translational medicine

Abstract

<p>Nivolumab, a fully human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that targets the programmed cell death-1 (PD-1) inhibitory receptor expressed on lymphocytes and dendritic cells, has been approved for metastatic melanoma, advanced squamous non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma. In this review, pharmacology and pharmacometrics systems of this immunopharmaceutical are discussed. Mechanistic actions of T-cell biology with respect to both “priming phase” (anti-cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA-4) mAb; ipilimumab) and “effector phase” (anti-PD-1 mAb; nivolumab) was discussed, respectively. Key pharmacometric variables in anticancer efficacy of nivolumab such as target engagement, metabolism, pharmacology systems and clearance are elucidated with an emphasis on current knowledge from pre-clinical as well as phase 1, 2 and 3 clinical trials information, including the data presented at the American Society of Clinical Oncology (ASCO) 2015 and European Cancer Congress 2015. Nivolumab biomarkers, safety, and synergistic combination immunotherapies are delineated. Nivolumab, administered via intravenous infusion, has an acceptable safety profile and good efficacy. Indeed, the way forward to leverage maximum benefits for the cancer patient may be to synergize anti-PD-1 blockade with complementary targets in immune checkpoint pathways or other oncogenic signal transduction pathways. The encouraging results with nivolumab lend credence to the promise of immune checkpoint blockade as a therapeutic strategy that has been come-of-age in clinical oncology. Of necessity, the burden of “financial toxicity” on cancer patients and families must be factored in considering nivolumab therapy. The problem of ligand PD-L1 being a weak biomarker in clinical practice was discussed. Appropriate patient selection methods including immunopharmacogenomics may be used to identify those patients who are most likely to benefit from anti-PD-1 therapy. Taken together, the potential success of nivolumab strengthens the case for accelerated development of immunopharmaceuticals and basic drug discovery in oncology, and potentially non-oncology indications, by stakeholders such as clinical oncologists, pharmacists and scientists in academia and the pharmaceutical industry in a concerted fashion.</p>