Abstract PD13-11: Interim analysis results for the effectiveness and safety of trastuzumab deruxtecan in patients with HER2-low breast cancer and brain metastases: The HALLOW study

Abstract Background: The DESTINY-Breast04 (DB-04) trial established trastuzumab deruxtecan (T-DXd) as the standard of care for patients (pts) with the metastatic breast cancer (mBC) newly classified as HER2-low status (HER2 IHC 1+, or 2+/ISH−). However, in the DB-04 trial, the number of pts with hormone receptor-negative (HR−)/HER2-low mBC was limited, and pts with stable brain metastases (BMs) were included, while those with active BMs were excluded. The HALLOW study (UMIN000051259) is a large-scale ongoing prospective observational study conducted in Japan with the aim of providing effectiveness and safety data for T-DXd in these clinically important populations, which were underrepresented in the DB-04 trial. Here, we report the interim analysis results for pts with BMs. Methods: The HALLOW study enrolled, from June 2023, approximately 600 pts diagnosed with HER2-low mBC (HR+/−, with/without BMs, including active BMs) who had previously received chemotherapy and were scheduled to receive T-DXd treatment. This interim analysis included pts diagnosed with BMs (current or past) by local investigators. For the effectiveness analysis, only those with BMs confirmed by Brain-independent central review (ICR) based on brain MRI and/or CT images were included. Active BMs were defined as cases where no local treatment was performed on the brain lesion or where there was regrowth or symptom worsening after local treatment. Effectiveness outcomes included intracranial progression-free survival (IC-PFS) and intracranial objective response rate (IC-ORR) assessed by Brain-ICR according to RECIST version 1.1, while progression-free survival (PFS) and overall survival (OS) were assessed by investigators. For the safety analysis, pts who had received T-DXd at least once were included. Safety outcomes include incidence of treatment-emergent adverse events (TEAEs) graded by CTCAE, including ≥ grade (Gr) 3 TEAEs, ≥ Gr1 interstitial lung disease (ILD), and ≥ Gr1 TEAEs that led to discontinuation of T-DXd treatment. Follow-up plan will continue until July 2026. Results: At the data cutoff date of August 31, 2024, 42 pts had physician-diagnosed BMs, of whom 33 were Brain-ICR confirmed and met the criteria for active BMs. In this set, the median age was 55 (range: 42-79) years; the median prior line of chemotherapy in the metastatic setting was 2 (range: 0-7); HER2 status at each local site was IHC 2+/ISH− in 7 pts (21%) and IHC 1+ in 26 pts (79%); 25 pts (76%) were HR+, 8 pts (24%) were HR−. 5 pts (15%) had Brain-ICR-confirmed leptomeningeal disease. At a median follow-up period of 4.1 months (mo) (range: 1.4-12.6), the median IC-PFS was 8.0 mo (95% confidence interval CI: 3.9-not estimated), and the 6-mo IC-PFS rate was 57.6% (95% CI: 30.7-77.4) until the data cutoff date. A total of 22 pts was eligible for proper tumor evaluation during the follow-up period by Brain-ICR. Among the 22 pts who could be properly evaluated, the IC-ORR was 9.1% (complete response n=0, partial response n=2; 95% CI: 1.1-29.2). The median PFS was 6.7 mo (95% CI: 4.0-11.1), with a 6-mo PFS rate of 59.0% (95% CI: 34.9-76.7). The median OS was not reached, and the 6-mo survival rate was 77.1% (95% CI: 51.5-90.3). In the safety analysis set (n=42; median follow-up period: 4.1 mo range: 0.4-12.6), ≥ Gr3 TEAEs and ≥ Gr3 TEAEs related to T-DXd treatment occurred in 18 (43%) and 11 (26%) pts, respectively. ≥ Gr1 ILD occurred in 2 pts (5%), 1 (2%) of whom experienced Gr 5 ILD, and ≥ Gr1 TEAEs that led to T-DXd discontinuation occurred in 3 pts (7%), with two of these being ILD and the other seizure. Conclusions: While longer follow-up and additional data are needed to confirm these findings, the current data provide tentative support for the effectiveness and safety of T-DXd in this BMs population including active BMs, which was not included in the DB-04 trial. Citation Format: N. Niikura, T. Yamanaka, Y. Aoyama, A. Kataoka, T. Toyama, S. Sakai, M. Endo, K. Kaneko, H. Iwata, T. Yamashita, J. Tsurutani, R. Horii, Y. Kikawa, Y. Hirakawa, S. Yamazaki, W. Hashimoto, E. Tokuda, S. Saji. Interim analysis results for the effectiveness and safety of trastuzumab deruxtecan in patients with HER2-low breast cancer and brain metastases: The HALLOW study abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD13-11.