Abstract PS5-01-22: Efficacy of second- or third-line Tucatinib, Trastuzumab, and Capecitabine (TTC) following trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer: A multicenter French cohort study

Abstract Background: Trastuzumab deruxtecan (T-DXd) is currently the standard second-line therapy for HER2-positive metastatic breast cancer (MBC). Recent results from the DESTINY-Breast09 (DB-09) trial suggest it may soon be considered for first line setting. However, optimal treatment sequences after T-DXd remain unclear. Currently, data regarding the efficacy of the combination of tucatinib, trastuzumab, and capecitabine (TTC) administered as second- or third-line therapy after T-DXd is limited. Materials and Methods: We conducted a cohort study across 17 French cancer centers. Eligible patients had HER2-positive MBC and received TTC as second- or third-line therapy in the metastatic setting after prior treatment with T-DXd. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to next treatment (TTNT), overall survival (OS), objective response rate (ORR). Results: Between July 2021 and June 2025, 103 patients were enrolled. The median age at TTC initiation was 54.6 years (range: 21.0-86.0), 42.7% had de novo metastatic disease and 55.3% had brain metastases. Prior (neo)adjuvant chemotherapy and anti-HER2 therapy were administered to 55.3% of patients, while 88.3% had received pertuzumab as treatment for metastatic disease. Most patients (91.3%) progressed on T-DXd, while 8.7% discontinued due to toxicity or other reasons. The median duration of prior T-DXd therapy was 8.0 months (range: 0.7-37.2). TTC was administered as second-line therapy in 8.7% and third line in 91.3%, immediately following T-DXd in all cases. After a median follow-up of 12.7 months (95% CI: 11.0-17.0), 74 patients (71.8%) had discontinued TTC due to disease progression, 26 patients (25.2%) remained on treatment, and 3 patients (3.0%) discontinued TTC because of toxicity. Median PFS with TTC was 4.7 months (95% CI: 3.5-5.7), median TTNT was 6.6 months (95% CI: 4.8-9.6), and median OS was 12.3 months (95% CI: 10.5-19.5). Among the 96 RECIST-evaluable patients, 9.4% achieved a complete response, 20.8% had a partial response, 27.1% showed stable disease, and 42.7% experienced progressive disease as best response. Patients treated with T-DXd for >18 months (n=15) had a median PFS of 6.9 months (95% CI: 4.8-NR) and a median TTNT of 8.9 months (95% CI: 5.9-NR) compared to to a median PFS of 3.9 months (95% CI: 3.2-5.3) and a median TTNT of 5.5 months (95% CI: 4.2-9.6) in those treated with T-DXd for ≤ 18 months (n=88). Patients with brain metastases had a median PFS of 5.0 months (95% CI: 3.8-7.4) and a median TTNT of 8.5 months (95% CI: 5.5-11.7). For those without brain metastases, median PFS was 3.5 months (95% CI: 2.7-6.8) and median TTNT was 4.8 months (95% CI: 3.4-9.6). Following TTC progression, 60 patients received further therapy, with a median PFS of 2.7 months (95% CI: 2.5-3.9). Conclusion: In this multicenter French cohort, TTC showed clinically meaningful activity as a second- or third-line therapy in HER2-positive MBC patients previously treated with T-DXd, especially among long-responders (PFS>18 months) to T-DXd. Final updated results will be presented at the meeting. Citation Format: J. S. Frenel, A. de Nonnevile, C. Guerin-Charbonnel, J. Zeghondy, L. Mathiot, A. Mailliez, F. Poumeaud, N. Isambert, M. Arnedos, F. Le Du, L. Galland, R. Kabirian, S. Guiu, L. Poestch, E. Deluche, F. Cherifi, F. Dalenc, E. Volant, B. Pistilli, T. San, T. Bachelot, A. Patsouris, F. Bocquet, L. Larrouquere, D. Loirat. Efficacy of second- or third-line Tucatinib, Trastuzumab, and Capecitabine (TTC) following trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer: A multicenter French cohort study [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 PS5-01-22.