New Realities of Phase I Clinical Trials in the Era of
- The development of cancer immunotherapy, particularly durvalumab, has progressed rapidly due to innovative strategies, such as novel study designs.
- Durvalumab, an anti-PD-L1 monoclonal antibody, was developed by AstraZeneca starting in 2012, with initial trials leading to its accelerated approval for urothelial cancer in 2017.
- Dose selection for durvalumab involved pharmacokinetic and pharmacodynamic analyses, resulting in a convenient 1500 mg Q4W dosing schedule.
- Combination regimens pose challenges due to increased toxicity, necessitating updated management guidelines.
- A study-specific dose-escalation committee and independent pharmacovigilance team ensured patient safety in trials.
- The VENTANA SP263 Assay was developed to measure PD-L1 expression, aiding in patient selection and response stratification.
- Emerging biomarkers and tumor-kinetic modeling have identified prognostic and predictive factors for response to durvalumab.
- Ongoing research aims to overcome immunotherapy resistance by exploring combination therapies and using biomarkers for personalized treatment.
- Future studies will focus on adaptive platforms, enriched study designs, and novel endpoints to improve treatment efficacy and patient outcomes.
The rapid emergence of cancer immunotherapy has been driven by unique development strategies including novel study designs, resulting in new therapeutics being brought to the market with unprecedented speed. For example, development of durvalumab, a human immunoglobulin G1 (IgG1) anti-programmed deathligand 1 (PD-L1) monoclonal antibody, was initiated by AstraZeneca in 2012 with a multicenter, open-label, first-timein-human phase I study, later expanded into a phase I/II study in 2014 (Study 1108; NCT01693562; Figure 1). The expansion phase of this study included tumor types selected based on unmet medical need, tumoral PD-L1 expression, and underlying biology. Tolerable safety profiles and durable clinical activity have been observed in patients with various solid tumor types (supplementary Figure S1 and Table S1, available at Annals of Oncology online). While early-phase registrational studies were uncommon in the pre-immuno-oncology (IO) era, there have been several notable examples of phase I studies leading to approval of checkpoint inhibitors, including Study 1108; results from the urothelial cancer (UC) cohort led to accelerated approval in the United States for postplatinum locally advanced or metastatic UC in 2017. Such rapid development is associated with unique challenges, including evolving study parameters and treatment paradigms as well as emerging biomarker research.
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