Topoisomerase 1 and DNA damage: Pharmacodynamic responses and mechanism of trastuzumab deruxtecan in HER2- expressing advanced solid tumors.
Abstract
3092 Background: Trastuzumab deruxtecan (T-DXd) consists of deruxtecan, a novel topoisomerase 1 (TOP1) inhibitor, covalently bound via a lysosomal protease-cleavable linker to the human epidermal growth factor receptor 2 (HER2)-targeting antibody, trastuzumab. The mechanism(s) underlying the clinical activity seen in multiple tumor types across various HER2 levels is of ongoing, active interest. To investigate the T-DXd mechanism of action, we developed a pilot clinical trial of T-DXd with a detailed pharmacodynamic analysis from TOP1 target engagement to downstream effects of DNA damage in patients with HER2-expressing (IHC 1-3+, HER2 amplified, or HER2 mutated) advanced solid tumors (NCT04294628). Methods: Based on preclinical studies modeling the trial, research tumor biopsies from consenting patients were collected at three time points: pre-treatment, post-dose Cycle 1 (48-96 hours) and pre-dose Cycle 3. The biopsies were evaluated for TOP1 inhibition, induction of stabilized TOP1covalent complexes (TOP1cc) and induction of downstream DNA damage repair (DDR) markers (RAD51, pNBS1, RPA32) using validated, quantitative multiplex immunofluorescence assays on fixed tumor sections with image analysis methodology. In addition, a retrospective analysis of Schlafen 11 expression in baseline biopsies was performed to determine its predictive value of tumor responses to T-DXd. Results: Twenty-one biopsy pairs (pre-treatment and C1, 48-96h post-dose 1) were evaluable for TOP1 molecular response and downstream DDR marker induction. TOP1 target modulation was detected in 15 (71%) of the on-treatment biopsies and markers of DDR were induced in 18 (86%) biopsy pairs. TOP1 target inhibition, robust induction of downstream DNA damage response including stalled replication fork progression, and DNA breaks were observed in HER2-amplified/2+/3+ tumors, and in HER2 1+ tumors. Conclusions: Our results confirm the intended TOP1 molecular mechanism of action of T-DXd in HER2-amplified/2+/3+ and importantly extend that finding to HER2 1+ tumors, resulting in DNA damage in nearly all cases. Pharmacodynamic biomarker studies are poised to yield important insights into the molecular effects of T-DXd in solid tumors.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (14)
Deborah Wilsker
Clinical Pharmacodynamic Biomarker Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD
Sarah Shin
Developmental Therapeutics Clinic/Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD
Geraldine Helen O'Sullivan Coyne
Developmental Therapeutics Clinic/Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD
Angie B. Dull
National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, MD
Huanlian Chen
National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, MD
Stephanie Runkle
National Cancer Institute Frederick National Laboratory for Cancer Research, Frederick, MD
Katherine V. Ferry-Galow
Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD
Elizabeth Katherine Lee
Dana-Farber Cancer Institute, Boston, MA
Arjun Mittra
Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
Cora N. Sternberg
Andrew J. Armstrong, MD, ScM, FACP, Division of Medical Oncology, Department of Medicine, Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, Durham, NC; Arun A. Azad, MBBS, PhD; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia; Fred Saad, MD, University of Montreal Hospital Center, Montreal, QC, Canada; Maha Hussain, MD, FACP, FASCO, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL; Taro Iguchi, MD, PhD, Department of Urology, Kanazawa Medical University, Ishikawa, Japan; Arnulf Stenzl, MD, Department of Urology, University of Tübingen, Tübingen, Germany; and Cora N. Sternberg, MD, FACP, Englander Institute for Precision Medicine, Meyer Cancer Center, Weill Cornell Medicine, New York, NY
Cheryl Ann Pickett-Gies
Cancer Therapy Evaluation Program, Division of Cancer Treatment & Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD
Alice P. Chen
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD
James H. Doroshow
Center for Cancer Research, National Cancer Institute, NIH
Ralph E. Parchment