Paulus on Research With a Real-World External Control Arm in HER2+ Breast Cancer

“What we are seeking to do is show comparability between the trial patients and the real-world patients as a justification for the validity of the external control arm patients to serve as a reference point."

Jessica Paulus, ScD, vice president of Real World Research at Ontada, discussed the design of a pilot study evaluating the development and feasibility of using a real-world external control arm to inform the clinical applicability of findings from an ongoing phase 2 trial (NCT05748834) investigating tucatinib (Tukysa) plus liposomal doxorubicin in patients with HER2-positive locally advanced or metastatic breast cancer.

Paulus began by describing that she and colleagues are in the process of constructing this real-world data–derived external control arm to support the ongoing phase 2 clinical trial, which is being sponsored by the Sarah Cannon Research Institute. Findings from this trial were presented at the 2025 ASCO Annual Meeting and were based on an interim analysis, as the trial remains open for enrollment, she explained. The primary objective of this pilot effort is to dynamically develop a robust external control arm in parallel with trial enrollment, thereby ensuring contemporaneous assembly of the comparator cohort, she emphasized.

At the time of the ASCO presentation, data had been collected and assessed from the first 8 patients enrolled in the investigational trial. Using these patients as the reference population, the investigators identified and constructed a real-world comparator cohort of 33 patients, matched on several baseline clinical and demographic characteristics. The investigators also expanded the number of patients enrolled in the phase 2 trial into a simulated dataset based on the observed distribution of baseline characteristics. The goal of this work was to demonstrate comparability between the trial population and the real-world cohort, thereby supporting the validity of the external control arm as an appropriate reference for subsequent analyses, Paulus reported. Notably, following propensity score matching, covariate balance between the simulated phase 2 trial cohort and the real-world external control arm was mostly achieved.