Pharmacokinetics and systems pharmacology of monoclonal antibody olaratumab for inoperable soft tissue sarcoma

Abstract

Olaratumab, a human IgG1 monoclonal antibody, has received accelerated approval from the US Food and Drug Administration (FDA), and conditional marketing authorization by the european Medicines Agency's (eMA) accelerated assessment program, for metastatic soft tissue sarcoma. This is a heterogeneous group of diseases with several subtypes, and the current standard of care since the past few decades has been primarily doxorubicin. Olaratumab is an antagonist of platelet-derived growth factor receptor alpha (PDGFRα) that prevents the binding of PDGF ligands to this receptor, consequently inhibiting subsequent dimerization of the receptor and downstream signal transduction, thereby inhibiting carcinogenesis. In Phase 1 and Phase 2 clinical trials, olaratumab demonstrated acceptable safety profile including lack of cardiac toxicity or immunogenicity, with most common adverse effects being nausea, fatigue, infusion-related reactions, and neutropenia. encouragingly, patients who were administered olaratumab in combination with doxorubicin received an overall survival benefit of 11.8 months as compared to doxorubicin alone. The Phase 3 trial of olaratumab is ongoing and a pediatric Phase 1 trial is also underway. Future studies may help to stratify the target population and leverage the power of precision medicine to benefit patients through tailor-made olaratumab or olaratumab/doxorubicin regimens and the use of potential companion diagnostics to optimize and personalize therapy. The "financial toxicity" of olaratumab is also discussed in light of the rising costs of cancer care and the associated burden to patients, families, and caregivers.Keywords: olaratumab; orphan drug; cancer; sarcoma; PDGFR; monoclonal antibody; pharmacokinetics; pharmacology; precision medicine; financial toxicity Citation: Nair S, Iyer A, vijay v, Bandlamudi S, Llerena A. Pharmacokinetics and systems pharmacology of monoclonal antibody olaratumab for inoperable soft tissue sarcoma. Adv Mod Oncol Res 2017; 3(3): 114-125 http://dx.doi.

Emerging Roles for Clinical Pharmacometrics in Cancer Precision Medicine

“…We have previously described [33] in detail key pharmacometric variables in the anticancer efficacy of anti-PD-1 immune checkpoint inhibitor nivolumab including target engagement, metabolism, systems pharmacology, and clearance. We have also summarized [34] ongoing and completed Phase 1, 2 and 3 clinical trials investigating the safety and anticancer efficacy of anti-PDGFR alpha mAb olaratumab which recently received accelerated approval, orphan drug status, fast track and breakthrough therapy designation from the US FDA for metastatic soft tissue sarcoma. Since PD-L1, a ligand for PD-1, is a weak biomarker for nivolumab therapy in clinical practice [33], model predictions for the best responders in a stratified patient population when coupled with immunopharmacogenomic studies would enable greater therapeutic success through tailoring the precise treatment to the right patients and also serve to lower the “financial toxicity” to patients and families.…”

“…Since PD-L1, a ligand for PD-1, is a weak biomarker for nivolumab therapy in clinical practice [33], model predictions for the best responders in a stratified patient population when coupled with immunopharmacogenomic studies would enable greater therapeutic success through tailoring the precise treatment to the right patients and also serve to lower the “financial toxicity” to patients and families. Similarly, since soft tissue sarcomas are heterogeneous with 50 different histologic subtypes, pharmacometric model-based approaches can help understand and investigate (i) whether subsets of patients with higher PDGFR alpha expression might have potentially longer progression free survival or overall survival benefit on treatment with olaratumab, or (ii) whether any subset of PDGFR alpha-expressing patients may not respond to olaratumab but may benefit from combination therapy with olaratumab and doxorubicin, the current standard of care [34].…”