Paulus on the Rationale for Utilizing an External Control Arm in a Single-Arm HER2+ Breast Cancer Trial

“Over the last at least decade, there's been a lot of interest in the power of real-world data, generally, but also specifically to support the development of external control arms to help aid the conclusions we draw from clinical trials, [particularly] those that are only single arm.”

Jessica Paulus, ScD, the senior director of Observational Research at Ontada, explained the rationale for constructing an external control arm to help contextualize clinical trial data in a single-arm HER2-positive metastatic breast cancer trial.

Within the past decade, more researchers have been interested in the effect of real-world data to further synthesize outcomes and data from clinical trials, Paulus began. She emphasized that this is particularly the case for single-arm trials, as there is no comparator arm. Often, when balancing the necessity of a comparator arm with other ethical considerations, it can be difficult to establish whether experimental therapies are as efficacious or safe as the control arm, she added. Thus far, external control arms have been utilized in phase 3 trial settings, she explained. However, the purpose of the current investigation was to identify and extend the methods of utilizing external control arms in a phase 2 trial setting, Paulus emphasized. Although phase 2 studies often involve smaller patient populations, this could add more value to the data, she concluded.

Of note, an external control arm was added to a phase 2 trial (NCT05748834) evaluating the efficacy and safety of tucatinib (Tukysa) plus liposomal doxorubicin in patients with HER2-positive locally advanced or metastatic breast cancer. The subsequent analysis explored whether the construction of an external control arm based on real-world data can help inform clinical interpretations and support early treatment decision-making. Ultimately, results from the study showed that the contemporaneous external controls arm did provide comparative context for efficacy evaluations, supporting their use in contexts where traditional control arms may not be feasible, ethical or efficient. The pilot also provided a framework for external control arm evidence generation in early-phase trials.