A groundbreaking pilot study has revealed that real-world external control arms can be rapidly assembled alongside ongoing phase 2 clinical trials. This approach may significantly accelerate the development of drugs for patients with HER2-positive breast cancer. Research presented by Jessica Paulus, ScD, at the 2025 ASCO Annual Meeting, demonstrated the feasibility of this method using the ongoing trial of tucatinib (Tukysa) combined with liposomal doxorubicin.
The interim analysis focused on a single-arm phase 2 trial (NCT05748834) that aims to treat patients with HER2-positive locally advanced or metastatic breast cancer. At the time of the analysis, the trial had enrolled eight patients. To enhance the study’s findings, the researchers created a simulated dataset of 40 patients, matched against a real-world data external control arm consisting of 77 patients. This technique allowed for a successful match of 82% of the simulated cohort with the external control group.
Significant Findings from the Pilot Study
The research team achieved a commendable balance in baseline characteristics such as mean age, number of prior treatments, and previous exposure to tucatinib. The phase 2 trial is set to enroll a total of 36 patients and is currently seeking individuals aged 18 or older with a specific performance score and measurable disease as defined by RECIST 1.1 criteria.
The primary endpoint of the study is the overall response rate, while key secondary endpoints include safety and progression-free survival. In an interview with OncLive®, Paulus emphasized the importance of this research in demonstrating the viability of using real-world data to support phase 2 studies.
Paulus noted that there has been growing interest in leveraging real-world data to enhance clinical trials. Traditionally, external control arms have been primarily utilized in phase 3 studies. This pilot study aims to adapt those methods for phase 2 trials, which often feature smaller sample sizes and lack comparator arms.
Future Implications for Drug Development
The researchers are collaborating with the Sarah Cannon Research Institute in Nashville, Tennessee, to develop this external control arm dynamically as the trial progresses. Paulus highlighted the achievement of quickly assembling a valid external control arm that mirrors the ongoing trial’s enrollment.
The interim results are based on the initial eight trial patients, around which a real-world cohort of 36 patients was constructed, matched on several baseline characteristics. As the trial continues to enroll participants, the researchers anticipate further improving the balance between the two cohorts.
With plans to increase the real-world data cohort, the team aims for an approximate 3-to-1 ratio between the external control arm and the phase 2 trial population. This growth is expected to enhance the statistical robustness of the findings and provide more reliable evidence for progressing to phase 3 trials.
The study represents a significant step toward expediting drug development for HER2-positive breast cancer, potentially leading to faster and more evidence-based decisions in the clinical development pipeline. According to Paulus, “As we triple the enrollment on the real-world data side, we expect to see those differences minimized as the sample size approaches 100 overall.” This innovative approach could reshape how clinical trials are conducted, ensuring that new therapies reach patients more efficiently.
