Abstract P5-05-11: Systematic review of ADCs vs chemotherapy in 2L+ Her2+ mBC

Abstract Antibody-drug conjugates (ADCs), which combine monoclonal antibodies with cytotoxic payloads, have revolutionized cancer treatment by providing more effective and selective therapies with less toxicity than traditional chemotherapy. A systematic search in LARVOL CLIN- a database of 100k+ trials, 95k+ Kaplan-Meier (KM) curves, and 15k+ Hazard Ratios (HRs)- was conducted to identify trials comparing ADCs and chemotherapy in 2L+ for Her2+ metastatic breast cancer (mBC). A meta-analysis was performed on phase 3 trials using digitized KM data and HRs extracted from forest plots. Biomarker subgroup populations were evaluated in the context of ADC response and were verified using VERI, a precision oncology database. Only 5 trials had mature survival data on ADCs vs chemotherapy. All trials used trastuzumab as the antibody, and ADCs varied in payload and linker. TH3RESA and EMILIA assess T-DM1 (trastuzumab emtansine); DESTINY-Breast02 and DESTINY-Breast04 evaluate T-DXd (trastuzumab deruxtecan); and TULIP examines T-Duo (trastuzumab duocarmazine). The primary outcome in all these trials was progression-free survival (PFS) and for TH3RESA and EMILIA Overall survival (OS) as well. The evaluated ADCs prove their efficacy in treating Her2+ mBC compared to the respective controls (HR PFS: 0.52* [TH3RESA]; 0.69* [EMILIA]; 0.3* [DESTINY-Breast02]; 0.36* [DESTINY-Breast04]; 0.64* [TULIP]; and HR OS: 0.68*. [TH3RESA]; 0.75* [EMILIA]; 0.69* [DESTINY-Breast02]). However, ADC benefit may be higher for T-DXd compared to T-Duo (ORR: 74.1% vs 27.2% [DESTINY-Breast02]; 52% vs 16% [DESTINY-Breast04] and 27.8% vs 29.5% [TULIP]). In contrast to standard chemotherapy, patients benefit from T-DM1 and T-XDd regardless of PIK3CA mutation status (HR PFS for PIK3CA mutated vs PIK3CA wild-type: 0.44* vs 0.47* [TH3RESA]; 0.45* vs 0.74 [EMILIA]; 0.6* vs 0.5* [DESTINY-Breast04]) and PTEN expression levels (HR PFS for increased PTEN expression vs decreased PTEN expression: 0.4* vs 0.49* [TH3RESA]; 0.78 vs 0.55* [EMILIA]). Regarding Her2 expression, while DESTINY-Breast04 evaluated Her2+ low mBC, patients with higher mRNA expression levels benefit most from ADC treatment (HR PFS for Her2 expression high vs Her2 expression low: 0.68* vs 0.4* [TH3RESA]; 0.64* vs 0.65* [EMILIA]; 0.55* vs 0.48* [DESTINY-Breast04]). ADC-targeted therapies open significant new opportunities with more than 200 trials in phase 3. T-DM1 with DM1 as payload and T-DXd with deruxtecan are approved for Her2+ mBC patients after anti-Her2 regimens. However, T-Duo with seco-DUBA as payload, despite fulfilling its PFS primary outcome, did not reach OS statistical significance, causing FDA approval to be paused. Regardless of PIK3CA mutations and PTEN loss, which could be expected to drive Her2 pathway activation, T-DM1 and T-DXd are effective. While T-DM1 and T-DXd demonstrate enhanced benefit with relatively elevated Her2 mRNA levels, bot∫h remain effective even in cases of low Her2+ mBC. Citation Format: Bruno Larvol, Mark Gramling. Systematic review of ADCs vs chemotherapy in 2L+ Her2+ mBC [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 P5-05-11.