Real-world outcomes in patients (pts) with metastatic breast cancer (MBC) treated with trastuzumab deruxtecan (T-DXd) based on HER2 expression.

Abstract

e13013 Background: T-DXd is an effective HER2-directed antibody-drug conjugate (ADC) approved for HER2-positive (IHC 3+ or IHC 2+/FISH+), HER2-low (IHC 2+/FISH− or IHC 1+), and hormone receptor-positive (HR+) HER2-ultralow disease (IHC 0). The efficacy of T-DXd is shown to correlate with the degree of HER2 expression. This study evaluates how HER2 expression predicts response to T-DXd in a real-world, racially diverse population. Methods: A retrospective chart review study was conducted for pts with MBC treated with T-DXd at Winship Cancer Institute of Emory University (2020-2024). HER2 IHC/FISH status was recorded from metastatic biopsies performed prior to T-DXd. Results: Of the 230 pts, 45.2% were non-Hispanic White (NHW; n = 104), 42.6% non-Hispanic Black (NHB; n = 98), 8.3% Asian (n = 19), and 3.9% other (n = 9). 8.3% of tumors were IHC 0 (n = 19), 21.3% IHC 1+ (n = 49), 28.3% IHC 2+/FISH− (n = 65), 13.9% IHC 2+/FISH+ (n = 32), and 28.3% IHC 3+ (n = 65). The median duration of T-DXd was 10 cycles. Within the HER2-low subgroup, median overall survival (mOS) was longer for IHC 2+/FISH− compared with IHC 1+ (18.5 vs 10.1 months, p = 0.0203), while median progression free survival (mPFS) was similar (6.6 vs 6.1 months). Compared with IHC 1+ tumors, IHC 0 tumors had a longer mPFS (12.1 vs 6.1 months) and mOS (15.8 vs 10.1 months), although this difference was not statistically significant. Across all IHC/FISH categories, NHB patients had shorter mPFS (8.6 vs 11.4 months; p = 0.0635) and mOS (16.4 vs 18.3 months) compared with NHW patients. Conclusions: OS and PFS generally increased with higher HER2 expression, with notable exceptions. The difference in OS between IHC 1+ and IHC 2+/FISH− tumors indicates heterogeneity within HER2-low disease. Despite a small sample size in the IHC 0 group, the longer PFS and OS suggest deviation from a linear association between HER2 expression and T-DXd response and support further prospective evaluation in HER2-null tumors using high-sensitivity HER2 assays. NHB patients experienced poorer outcomes than NHW patients following ADC therapy, warranting further investigation into the underlying cause of this disparity. Median progression free survival and median overall survival in months by HER2 expression. IHC/FISH status Number of Patients mPFS (months)* mOS (months)** Hazard ratio for mOS IHC 0 19 12.1 [3.2-17.7] 15.8 [4.0-30.9] 2.1 [1.0-4.4] IHC 1+ 49 6.1 [4.7-8.4] 10.1 [7.0-13.0] 3.3 [1.9-5.8] IHC 2+/FISH- 65 6.6 [3.5-10.0] 17.9 [10.8-29.8] 1.7 [1.0-2.9] IHC 2+/FISH+ 32 12.1 [8.3-17.5] 22.0 [16.8-30.1] 1.4 [0.7-2.6] IHC 3+ 65 25.2 [12.3-37.6] 35.5 [18.3-43.8] n/a *p=0.0001, **p=0.0001 indicate significant differences in OS & PFS among HER2 IHC/FISH subgroups. Square brackets = 95% confidence interval. Hazard ratios were generated with multivariable Cox model in comparison to IHC 3+, adjusting for race, BMI, HR+ status, and prior lines of therapy.