Abstract B037: A pharmacodynamic pilot study of DS8201a in patients with HER2 expressing advanced solid tumors
Authors: Shin Sarah J , O'Sullivan-Coyne Geraldine , Lee Elizabeth K , Mittra Arjun , Sternberg Cora N , Ong Mary Jane , Wilsker Deborah , Ferry-Galow Katherine , Foster Jared , Juwara Lamin , Takebe Naoko , Pickett Cheryl A , Parchment Ralph , Doroshow James , Chen Alice 
Published: December 2023

Abstract
Background: DS-8201a (Trastuzumab (T) deruxtecan(D)) is an antibody-drug conjugate consisting of the HER2-targeting antibody T covalently bound via a lysosomal protease-cleavable linker to the novel topoisomerase 1 (Top1) inhibitor D with activity in tumors with low HER2 IHC scores of 1+ or 2+. The primary purpose of this study is to investigate the pharmacodynamic (PD) mechanisms underlying the activity of DS-8201a in advanced solid tumors, including those with low HER2 expression.
Methods: This multicenter pilot study enrolled patients (pts) with advanced solid tumors expressing HER2 as defined by CLIA-certified labs i.e., a HER2 IHC score of 1+ or greater or ERBB2 amplifications (amp) or mutations (mut). DS-8201a was administered at 5.4 mg/kg intravenously once every 3 weeks, in 21-day cycles (C). PD biomarkers of Top1 target engagement by D payload, consequent DNA damage and repair (DDR), and immune microenvironment changes were analyzed in mandatory tumor biopsies collected at baseline, post-dose C1 and pre-dose C3. Blood samples for biomarker analyses were taken at several time points. Safety and overall response were also evaluated.
Results: As of June 16, 2023, a total of 48 pts have been enrolled with diverse HER2 status distribution: 11 IHC 1+, 20 IHC 2+, 6 IHC 3+, 7 ERBB2 amp, 3 ERBB2 mut, and 1 with both IHC 1+ and ERBB2 amp. Median number of prior lines of systemic therapy was 3.5 (range 1-13) and 11 pts received prior Top1 inhibitor therapy. Grade (Gr) 3 or higher treatment-related adverse events (trAEs) were reported in 12 pts (25%). The most common Gr3/4 trAEs were myelosuppression. There were 7 pts (15%) with Gr2 and 1 pt (2%) with Gr3 pneumonitis. One pt with Gr2 pneumonitis was retreated after trAE resolution with steroid therapy and continued for another 9 Cs prior to progression. Of the evaluable patients, 1 pt (2%) had complete response (cervical, HER2 2+), 6 pts (13%) had confirmed partial response (PR) (uterine, 2+; ovarian, 2+; bladder, ERBB2 mut; uterine carcinosarcoma, 2+; 2 head and neck cancers, 1+ and 2+), 4 pts (8%) had unconfirmed PR (breast, 1+; extramammary Paget’s disease, 2+; pancreas, ERBB2 amp; uterine, 2+), and 17 pts (35%) had stable disease as their best response. Median progression free survival was 3.4 months (range 0.5-17.2). Top1 target engagement and induction of nuclear biomarkers of DDR (RAD51, pNBS1) were observed in more than half of the paired biopsies tested to date. DDR biomarker response was associated with both HER2 1+ and 2+ status. PD analyses are currently ongoing.
Conclusion: DS-8201a demonstrated responses in various tumor types outside of breast cancer with HER2 low/ERBB2 alteration status. Preliminary PD data demonstrated expected Top1 target engagement and DDR induction, the extent of which is possibly independent of the degree of HER 2 staining. Analyses are currently underway to further define the effect of DS-8201a in advanced solid tumors.
Citation Format: Sarah J Shin, Geraldine O'Sullivan-Coyne, Elizabeth K Lee, Arjun Mittra, Cora N Sternberg, Mary Jane Ong, Deborah Wilsker, Katherine Ferry-Galow, Jared Foster, Lamin Juwara, Naoko Takebe, Cheryl A Pickett, Ralph Parchment, James Doroshow, Alice Chen. A pharmacodynamic pilot study of DS8201a in patients with HER2 expressing advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B037.