The AGILE trial of ivosidenib plus azacitidine versus azacitidine alone: How many limitations is too many?

The AGILE trial compared ivosidenib and azacitidine versus azacitidine for IDH1-mutant acute myeloid leukemia (AML) in elderly patients who were ineligible to receive intensive chemotherapy. While the results of this trial appear encouraging, various concerns become evident from the study design and methodology. First, the AGILE trial did not use post-protocol therapy that met the current standard of care. Second, researchers continued patient enrollment despite knowledge of the survival benefit of azacitidine plus venetoclax shown in the VIALE-A trial, resulting in an inferior control arm. Third, the primary endpoint of AGILE was changed from overall survival (OS) to event-free survival (EFS), and the sample size was reduced to expedite the results. Finally, the trial was halted early based on a non-primary endpoint, which likely led to exaggerated effect size or misleading results. We discuss these limitations and continue to advocate for careful analysis of study design to ensure that appropriate and accurate outcomes are implemented in future studies.