Effect of ERBB2 activating mutations on enhanced internalization and activity of trastuzumab deruxtecan in HER2-non-amplified metastatic breast cancer.

Abstract

1045 Background: Trastuzumab Deruxtecan (T-DXd) is a HER2-targeting antibody drug conjugate approved for the treatment of HER2 low metastatic breast cancer (MBC). Whether HER2 activating mutations define a distinct clinical subset within HER2 low MBC is unknown. Here we present a single institution retrospective study of patients treated with T-DXd and report real world progression free survival (PFS), in patients with mutant vs. wild type (wt) HER2. We further modeled the impact of various HER2 mutations on T-DXd internalization and activity preclinically to characterize mechanistic and mutation-specific differences. Methods: All patients who had received T-DXd for HER2-low and HER2-null MBC at Memorial Sloan Kettering Cancer Center were eligible for inclusion. Clinicopathologic data were abstracted from patient records. PFS was determined clinically and calculated using the Kaplan-Meier method. Univariable and multivariable associations between PFS and patient characteristics were assessed using Cox-proportional hazards models. ERBB2 mutations were modeled in breast cell lines and examined for kinetics of fluorescence-labeled T-DXd cell internalization and potency of T-DXd antitumor effects. Results: We found 278 patients who received T-DXd for HER2 non-amplified MBC. Thirty-one had triple negative breast cancer and 247 had estrogen receptor positive MBC. Median age was 59 and TDXd was the median 6 th line of systemic treatment for MBC. Median PFS for all patients was 6.97 months (95%CI 5.73-8.4). ERBB2 mutations were found in 23 (8.2%) patients on genomic sequencing via MSK-IMPACT. Among mutations, 20 were known oncogenic mutations per OncoKB (eg D769Y, L755S, S310F, V777L), while 3 were variants of unknown significance (L35R, P378L, R1169K). ERBB2 activating mutations were significantly associated with prolonged T-DXd PFS; median 6.28 months in the wt population vs 10.58 months with an ERBB2 mutation (HR 0.55, 95%CI 0.31-0.98, p = 0.04). After adjusting for age, treatment line, and ER status, ERBB2 mutations were independently associated with longer PFS. Among patients with ERBB2 activating mutations, 9 had HER2 IHC 0 disease, while the remaining 14 were at least HER2 IHC 1+. There was no statistically significant difference in PFS between patients with HER2 IHC 0 vs 1+ (HR 1.74, 95%CI 0.53-5.7, p = 0.35) among those with ERBB2 mutations. Finally, expression of the most common ERBB2 mutants in MCF10A cells lead to more rapid internalization of labeled TDX-d into cells and lower IC50 for inhibition of proliferation. Conclusions: ERBB2 activating mutations are associated with longer T-DXd PFS in HER2-non-amplified MBC, even when HER2 IHC was 0, likely due to enhanced ADC internalization. The data imply that ERBB2 mutant breast cancers may be uniquely sensitive to T-DXd, independent of HER2 expression levels.