Abstract 4120: Dose selection and dosing optimization of immune checkpoint inhibitors

Background: The differential mechanisms of action of immune checkpoint inhibitors and targeted therapies versus chemotherapy warrant new thinking regarding the conventional maximum-tolerated dose (MTD) approach. Dosing optimization of immune checkpoint inhibitors via flat-dosing compared with body-weight-based dosing reduces dosing errors, provides benefits for patients, and is advantageous for healthcare providers. A review of the strategies used for dose selection and optimization for approved checkpoint inhibitors is presented. Methods: Clinical pharmacology data on dose selection and optimization for FDA-approved immune checkpoint inhibitors from FDA Summary Basis of Approval documents, published research papers, and scientific meeting/congress presentations were summarized. Results: Of the 7 immune checkpoint inhibitors approved by the FDA and/or the EMA, none had an MTD determined during their phase 1 dose-escalation programs. Dose selections were based on the integration of preclinical and clinical information, including in vitro and/or in vivo receptor target engagement, preclinical and clinical pharmacokinetic/pharmacodynamic data, and efficacy and safety data. Chosen regimens were confirmed by exposure–response analyses using phase 3 data. Post-approval optimization strategies were employed to refine the dosing schedules (eg, provide beneficial flexibility to patients and caregivers). Interestingly, 6 of the 7 currently approved immune checkpoint inhibitors use a flat-dosing regimen, with 4 changing prescribing information to flat-dosing after the initial approval of dosing by body weight, and 3 of them with fixed dosing in the initial submission. Conclusion: The new era of oncology therapy, epitomized by the advent of immuno-oncology and molecular targeted agents, has been accompanied by a shift from the MTD-based approach developed for cytotoxic drugs to those that aim to achieve optimized doses and regimens using the totality of preclinical and clinical data. Close collaborations between discovery and biomarker scientists, clinicians, clinical pharmacologists, and pharmacometricians facilitate the selection of optimal regimens. As the number of indications covered by immune checkpoint inhibitors increases, and clinical experience accumulates, it is likely that the transition from body-weight-based to fixed dosing will move to earlier stages of drug development. These efforts enable the early identification of the optimal dosing regimens, reducing development time and increasing the probability of success. Importantly, the utilization of optimized dosing development paradigms enables the development of oncology drugs with improved efficacy and tolerability profiles, thus providing increased benefits to patients and healthcare providers. Citation Format: Jennifer Sheng, Kinjal Sanghavi, Yali Liang, Shivani Srivastava, Akintunde Bello. Dose selection and dosing optimization of immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4120.