特別演講1:2022台灣醫學週台灣聯合醫學會學術演講會
       開幕典禮及大會特別演講節目程序表

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P-3
Antibody Drug Conjugates: Changing the Therapeutic Landscape of Triple Negative Breast Cancer
Leif W. Ellisen, M.D., Ph.D.
Professor of Medicine, Harvard Medical School
Breast Cancer Program Director, Mass General Cancer Center
Investigator, Ludwig Center at Harvard

  Antibody-drug conjugates (ADCs) are comprised of a monoclonal antibody targeting a tumor-selective antigen, coupled to a cytotoxic agent or other therapeutic payload. Sacituzumab Govitecan (SG), the first ADC FDA approved in the US for triple-negative breast cancer (TNBC), incorporates the antibody hRS7 targeting Trophoblast cell-surface antigen 2 (TROP2), conjugated to a topoisomerase-1 (TOP1) inhibitor payload. In the phase 3 ASCENT trial involving patients with heavily pre-treated metastatic TNBC, SG increased Progression-Free Survival (PFS) from 1.7 to 5.6 months, and Overall Survival from 6.7 to 12.1 months vs. chemotherapy Treatment of Physicians Choice (TPC). Despite its importance as an emerging therapeutic, little is known about de novo or acquired resistance mechanisms relevant to SG. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pre-treatment and post-progression specimens. In our initial series, one patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1 E418K resistance mutation and subsequent frameshift TOP1 mutation, while a distinct branch exhibited a novel TACSTD2/TROP2 T256R missense mutation. Reconstitution experiments demonstrated that TROP2 T256R confers SG resistance via defective plasma membrane localization and reduced cell surface binding by hRS7. Thus, we identified parallel genomic alterations in both antibody and payload targets associated with resistance to SG. Complementing this work is our pre-clinical studies of SG response and resistance through genome-wide CRISPR screens in TNBC cells. This approach yielded the anticipated pathways involving DNA repair and replication associated with TOP1 inhibitor sensitivity, and most notably highlighted the PARP pathway as a key determinant of SG response. We thus hypothesized that combination SG and PARP inhibitor (PARPi) would synergize for tumor killing, and that employing an innovative sequential dosing schedule for SG and PARPi would enhance the therapeutic window. Accordingly, we are carrying out a Phase 1/2 clinical trial of SG and Talazoparib delivered on a sequential schedule for patients with metastastic TNBC (NCT04039230). The dose escalation phase of this trial demonstrated the superiority of sequential over simultaneous dosing. In addition, pre-clinical studies revealed the mechanism of PARP inhibitor synergy, which involves stabilization of the TOP1 inhibitor-induced DNA cleavage complex (TOP1CC), leading to enhanced DNA damage and tumor cell death. Collectively, these studies highlight the specificity of SG, and they illustrate how mechanisms of response and resistance will inform future drug sequencing strategies and therapeutic combinations.