ERBB2 Activating Mutations Promote Enhanced Internalization and Activity of Trastuzumab Deruxtecan in HER2-non-amplified Metastatic Breast Cancer

Abstract Purpose: Trastuzumab Deruxtecan (T-DXd) is a HER2-targeting ADC approved for HER2-positive and HER2-low metastatic breast cancer (MBC). Whether activating mutations in ERBB2 potentiate response to T-DXd in MBC is unknown. Experimental Design: Patients who received T-DXd for non-HER2-amplified MBC and had somatic sequencing were eligible. Real-world progression free survival (rwPFS) was calculated using the Kaplan-Meier method. Uni-and multivariable associations were assessed using Cox-proportional hazards models. Activating ERBB2 mutations (per OncoKB) were modeled in breast cell lines and examined for kinetics of T-DXd internalization and potency of antitumor effects. Results: 272 patients received T-DXd for HER2-non-amplified MBC. ERBB2 mutations were found in 20 (7.3%) patients and were associated with prolonged median rwPFS on T-DXd (11 vs 6.2 months for wild-type ERBB2). After adjusting for age, treatment line, ER status, and HER2 IHC, ERBB2 mutations were independently associated with longer rwPFS (HR 0.49, 95%CI 0.25-0.96, p=0.038). Nine patients (45%) with ERBB2 mutations had HER2 IHC 0 disease; no difference in rwPFS was observed between HER2 IHC 1-2+ vs 0 (HR 1.37, 95%CI 0.35-5.34, p=0.7). Expression of common ERBB2 mutants in CAMA-1, T47D, and MCF10A cells lead to more rapid T-DXd internalization (1.3x (L755S, p<0.05 t test) to 1.96x (D769Y,p<0.001 t test )) and lower IC50 (0.017 to 0.070 µg/mL versus 2.86 µg/mL) compared to cells expressing WT HER2. Conclusions: ERBB2 activating mutations are associated with longer T-DXd rwPFS in HER2-non-amplified MBC, even when HER2 IHC was 0. ERBB2 mutant breast cancers are more sensitive to T-DXd, independent of HER2 expression levels.