Abstract P5-03-09: Evaluating Post-T-DXd Treatment Strategies in HER2-positive Metastatic Breast Cancer

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Abstract Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) that has proven highly effective in the treatment of HER2-positive metastatic breast cancer (MBC). However, drug resistance and disease progression eventually occur in the majority of patients. A critical examination of treatment strategies in the post-T-DXd setting is imperative in order to appropriately care for patients with TDXd-resistant breast cancer. Methods: We retrospectively examined baseline characteristics and clinical outcomes for patients after they had received T-DXd for HER2-positive metastatic breast cancer at MSKCC. We delineated six categories of treatment in the post-T-DXd setting: monoclonal antibodies (mABs), ADC, chemotherapy-based treatment, hormone therapy, tyrosine kinase inhibitor (TKI) based therapy, and clinical trials/novel combinations. Median overall survival time (OS) and progression free survival (mPFS) were estimated, as well as the mPFS per treatment line, further stratified by treatment type, using the Kaplan-Meier method. Progression free survival (PFS) analyses were performed using Cox proportional hazards regression, clustering by patient and in multivariate analysis, adjusting for treatment line, T-DXd stop reason, hormone receptor (HR) status, and the presence of brain metastases. Results: We identified 81 patients with HER2-positive MBC who continued treatment after T-DXd. The median age was 52 years, 60% had ER+ disease, and 54% had brain metastases. T–DXd was given as the 4th line of therapy, on average, in this population. Median OS from the time of T-DXd completion was 19 months; 52% of patients had died at the time of data cutoff. Of the patients included in this study, 78% stopped T-DXd due to disease progression, 11% stopped due to pneumonitis/ILD, and 11% stopped due to other toxicity complications. After T-DXd, patients received a median of 2 lines of further therapy (range 1-9) with a mPFS of 3.7 months per treatment line; a total of 199 lines of treatment were included in this analysis. Chemotherapy (including eribulin or gemcitabine plus trastuzumab) was the most frequently given treatment, received by 50 patients (62%), with mPFS of 3.4 months. Forty-two (52%) patients received TKI-based treatments (with trastuzumab, tucatinib, and capecitabine being the most common), and exhibited a mPFS of 3.9 months. Twenty-one (26%) patients were enrolled in clinical trials or received novel drug combinations, demonstrating a mPFS of 4.2 months. ADCs (most commonly T-DM1) were given to 16 (20%) patients, with a mPFS of 2.4 months. Eleven (14%) patients received hormone therapy, and 7 (8.6%) received mAB, with a mPFS of 9.1 months and 14 months, respectively. In multivariate analysis, patients who stopped T-DXd due to toxicity (rather than disease progression) had a dramatically improved mPFS on subsequent lines of treatment (HR 0.35; p <0.001). Later treatment line and the presence of brain metastases were numerically associated with shorter mPFS (HR 1.06; p=0.06 and HR 1.23; p=0.2 respectively), and HR status had no effect. Conclusion: We observe that prognosis is generally poor in the post-T-DXd setting. No therapeutic approach could be identified as clearly superior in our cohort, however, a subset of patients seemed to benefit from hormone therapy or TKI-based therapy, which warrants further investigation. Of special note, the reason for ending T-DXd treatment was a strong predictor of response to subsequent therapies, such that patients who stopped treatment due to toxicity had a 65% reduction in risk of disease progression or death. Overall, our study indicates that patients emerge from T-DXd treatment with highly refractory disease. Characterizing T-DXd resistance and finding new therapeutic options for this population represents an urgent clinical need. Citation Format: Sophia Zelizer, Grace Gallagher, Emanuela Ferraro, Chau Dang, Mithat Gonen, Shanu Modi, Sarat Chandarlapaty, Josh Drago. Evaluating Post-T-DXd Treatment Strategies in HER2-positive Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-03-09.

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