Optimizing Oncology Therapeutics Through Quantitative Translational and Clinical Pharmacology: Challenges and Opportunities

Abstract

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety.

Rendering the 3 + 3 Design to Rest: More Efficient Approaches to Oncology Dose-Finding Trials in the Era of Targeted Therapy

“…The key idea is to bring an evaluation of drug activity and safety into the dose selection process earlier for phase II studies, moving away from an exclusive focus on toxicity and the MTD. Although, randomized dose-finding studies are not routinely conducted in oncology, there is evidence that when conducted they help in rational dose selection (16).…”

Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients

“…The underlying principle stems from the chemotherapy era, where the more drug that is tolerated by the patient, the more efficacy you achieved, but needed to be balanced by safety. With targeted agents, however, it is possible that the exposure–response for safety and efficacy may be separated, and several examples have been presented by academia and regulators on the need for dose optimization on therapeutic proteins in the oncology area 19, 20, 21, 22. This work aims at presenting the exposure–response modeling of safety and efficacy performed with data obtained in squamous NSCLC patients, given gemcitabine‐cisplatin with or without necitumumab 12…”

Challenges and Opportunities in Dose Finding in Oncology and Immuno‐oncology

“…Current challenges lead to opportunities to apply novel approaches such as better trial design and advanced M&S to maximize drug development success as well as patient benefit. Application of M&S methodologies to PD surrogates of efficacy and/or to tumor shrinkage can help immensely in optimal dose selection based on efficacy end points 46, 47. Clearly, drug development requires teamwork, and a siloed‐approach to drug development may only optimize individual pieces of the puzzle but not the whole picture.…”