Abstract PS5-01-12: Real-world time to next treatment in HER2+ breast cancer patients with brain metastases: trastuzumab deruxtecan vs tucatinib based therapy as second-line treatment

Abstract Background: Brain metastases (BrM) are a frequent and clinically challenging manifestation of HER2-positive (HER2+) metastatic breast cancer (mBC), affecting up to 50% of patients (pts) over the course of their disease. Current guidelines recommend trastuzumab deruxtecan (T-DXd) as the preferred second-line therapy for HER2+ mBC overall, while the combination of tucatinib, trastuzumab, and capecitabine (TTC) remains an important option for pts with active or progressing BrM disease due to its proven intracranial activity. However, there is a lack of real-world data comparing treatment outcomes with these regimens specifically among pts with BrM involvement. This study evaluates real-world time to next treatment (TTNT) in pts with prior HER2+ therapy and documented BrM treated with second-line T-DXd vs TTC. Methods: We used the IntegraConnect PrecisionQ de-identified electronic health record database, which includes data on over 3 million cancer pts across more than 500 care sites, to identify individuals with HER2+ mBC who received either T-DXd or TTC as second-line therapy on or after January 1, 2020. Eligible pts had documented BrM prior to initiating second-line treatment. HER2+ status was inferred based on receipt of at least one HER2-targeted therapy during first-line metastatic treatment. Individuals who received T-DXd in their first-line of metastatic therapy were excluded from the analysis. The index date was defined as the start of second-line therapy with either TTC or T-DXd. Descriptive statistics were used to summarize demographic and clinical characteristics by treatment group, including age at index date, race, ethnicity, health insurance, BMI, ECOG performance status, estrogen receptor status, first-line metastatic regimen (grouped as ado-trastuzumab emtansine, trastuzumab (H) +pertuzumab (P) + taxane, endocrine therapy +/- HP, or other regimens), and presence of liver, bone, or lung metastases. TTNT was analyzed using Kaplan-Meier survival curves, with median estimates reported. Multivariable Cox proportional hazards regression was used to evaluate the association between treatment and TTNT, adjusting for the aforementioned demographic and clinical covariates. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are presented. Results: A total of 255 pts met study eligibility, of whom 138 (54%) received T-DXd as second-line therapy. Pts treated with T-DXd were slightly older than those who received TTC (median age: 58 vs 55 years; Wilcoxon p=0.026). A lower proportion of pts in the T-DXd group were classified as overweight (BMI 25-30) compared to the TTC group (17% vs 29%; chi-square p=0.026). No other significant differences in demographic or clinical characteristics were observed between treatment groups. Median TTNT was significantly longer among pts who received T-DXd compared to TTC (17 vs 11 months; log-rank p=0.006). This difference remained significant after adjustment for demographic and clinical covariates, with T-DXd associated with a 48% reduced likelihood of requiring subsequent therapy (HR: 0.52; 95% CI: 0.37-0.74; p0.001). Conclusions: In this real-world analysis of pts with prior HER2+ therapy and documented BrM, second-line treatment with T-DXd was associated with significantly longer TTNT compared to TTC among pts with BrM. These findings may help inform treatment decisions in this high-risk population. However, interpretation is limited by the retrospective design, potential selection bias, and the use of treatment patterns to infer HER2 status. Most importantly, granular clinical data on BrM, including prior local therapies (radiation and/or surgery) and CNS-specific outcomes, were unavailable. Further prospective studies are needed to validate these findings. Citation Format: V. Gorantla, R. Choksi, F. Kudrik, D. Patt, S. Reddy, S. Reganti, S. Rosenfeld, G. Cioffi, T. Sura, D. Parris, A. Rui, M. Gart, C. Wall, B. Wang, P. Varughese, J. Donegan, L. Morere, R. Geller, J. Scott, R. Mahtani. Real-world time to next treatment in HER2+ breast cancer patients with brain metastases: trastuzumab deruxtecan vs tucatinib based therapy as second-line treatment 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 PS5-01-12.