The use of pharmacodynamic results for recommended phase II decision making in oncology clinical trials

Pharmacodynamic analyses are increasingly important to early-phase oncology drug development, however these analyses use invasive methods to collect patient material. Yet, their role in guiding recommended phase II dose (RP2D) decisions remains unclear. Therefore, this review evaluates how pharmacodynamic analyses assisted the determination of the recommended phase II dose (RP2D) in first-in-human cancer trials of small-molecule agents.

First-in-human dose finding clinical trials of single-agent small-molecule anticancer therapies published between 2022 and 2025 that included pharmacodynamic assessments, were investigated. Clinical trials were evaluated for correlation of pharmacodynamic results at the analyzed doses and their influence in the RP2D decision-making process.

In total, 535 records were identified and 34 articles, reporting on 34 separate trials, were included. A correlation was found between the pharmacodynamic results and the analyzed dose levels in 92% (n = 31/34). However, only half of the clinical trials (n = 17/34) reported their pharmacodynamic results in the RP2D decision-making process, while 41% (n = 14/34) did not. In most of the clinical trials that did not use their pharmacodynamic results in the RP2D decision-making process, only one pharmacodynamic analysis was performed (n = 9/14, 64%) and they often determined their RP2D solely based on safety and/or tolerability (n = 7/14, 50%). Invasive procedures were often performed without clear utilization of pharmacodynamic data, raising ethical considerations.

These findings underscore the need for appropriate sample sizes planning and validated, fit-for-purpose pharmacodynamic assays to ensure meaningful use in dose selection, optimizing patient benefit and trial design.