Abstract PD3-08: Evidence Accumulates Against Sequencing Topo1-ADCs in HER2-Low Metastatic Breast Cancers: results from International, retrospective, real-world ADC-Low-Europe cohort

Abstract Background. Sequential use of topoisomerase-1 inhibitor ADCs (TOPO1-ADCs) is currently recommended in HER2-low metastatic breast cancer (MBC). However, several real-world data suggest poor outcomes with a second ADC (ADC2), raising concerns of potential acquired cross-resistance after a first ADC (ADC1). Nonetheless, the prior cohorts, including ours, included heavily pretreated patients (pts) and those with rapidly progressing disease under ADC1, limiting applicability. Methods. We conducted an European, retrospective, real-world study in pts with HER2-low MBC who received Sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd), either sequentially or not. The primary endpoint was progression-free survival with ADC2 (PFS2). Results. Among 331 pts, 103 and 228 had HR- or HR+ MBC respectively. SG was used as ADC1 in 85.4% of pts with HR- MBC and was given mainly as 1st or 2nd line of treatment (58% of those pts). T-DXd was ADC1 in 77.6% of pts with HR+ MBC but was administered as 1st or 2nd in only 20.3% of pts. The median duration of ADC1 was 7 cycles (range: 2-24) for SG in pts with HR- MBC, and 8 cycles (range: 1-35) with T-DXd in pts with HR+ MBC. The median progression-free interval with ADC1 (PFI1) was 5.4 months 95% CI: 4.7-6.4 for HR- pts treated with SG, and 6.3 months 95% CI: 5.5-8.1 for HR+ pts treated with T-DXd. A total of 206 pts (62.2%) received intermediate treatment between ADC1 and ADC2. The median progression-free interval (PFI) following ADC1 was 2.9 months 95% CI: 2.7-3.6 in the overall population, 2.7 months 95% CI: 2.5-3.5 with eribulin (n=79) and 4.2 months 95% CI: 2.7-5.7 with capecitabine (n=30). At ADC2 initiation, 81.3%, 7.6% and 22.7% of the pts had visceral, bone-only and brain/meningeal metastases, respectively. ADC2 was administered after a median of 4 lines (range: 1-11). With a median follow-up of 8.6 months, the median PFS2 was 2.6 months 95% CI: 2.4-2.8. By subgroup, mPFS2 was 2.4 months 95% CI: 2.2-2.8 for HR+ pts receiving SG as ADC2 and 2.7 months 95% CI: 2.4-3.4 for HR- pts receiving T-DXd as ADC2. There was no difference in PFS2 depending on the number of lines of treatment (multivariate analysis, continuous variable, p=0.056). Multivariate analysis demonstrated longer PFS2 with consecutive use of ADC1-ADC2 treatment (mPFS2 3.0 months, HR: 0.70, p = 0.009) and when T-DXd was used as ADC2 (mPFS2 2.9 months, HR: 0.44, p 0.001). At the time of this 1st analysis, 57 pts are still receiving ADC2 and are not evaluable for ADC2 response. Primary resistance to ADC1 (Progressive Disease as best response) occurred in 25.4% of pts, increasing to 65.6% for ADC2. Among 226 evaluable pts who did not show primary resistance to ADC1, 63.3% developed primary resistance to ADC2. Primary resistance to ADC2 was found in 73.3% of pts treated with SG and in 54.4% of those treated with T-DXd as ADC2. Similar findings were observed for early ADC2 use (≤3rd line, n=39): mPFS2 2.9 months (95%CI: 2.0-4.5), with 60% being primary resistant. Conclusions. This new, retrospective, real-world study of 331 pts confirms previous findings of poor outcomes with sequential use of TOPO1-ADCs. About 60% of patients exposed to this sequence had progression at the first assessment, regardless of line for ADC2 administration or HR status. Consecutive use of ADC1-ADC2 seems to be associated with longer PFS2. However, non-targeted cytotoxics might be clinically relevant due to similar efficacy as ADC2. These results highlight the need: first to develop biomarkers to better identify pts that could be sensible to a second TOPO1-ADC; second to better select the choice of ADC1 since it has the greatest impact on natural history. About 150 additional pts from French and European centers are currently being enrolled and will be included to the final presentation. Citation Format: F. Poumeaud, M. Morisseau, S. Cavaillon, S. Bécourt, R. Vion, E. Volant, J. Frenel, A. Patsouris, C. Lévy, M. Brunet, L. Drouin, H. Bischoff, E. Deluche, A. Deleuze, T. Grellety, T. Reverdy, C. Rivier, F. Fiteni, A. de Nonneville, M. Pagliuca, N. Isambert, F. Vaz, R. Sobral, M. Reich, S. Ladoire, F. Dalenc. Evidence Accumulates Against Sequencing Topo1-ADCs in HER2-Low Metastatic Breast Cancers: results from International, retrospective, real-world ADC-Low-Europe cohort 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 PD3-08.