Abstract 33P
Background
TROP2 is highly expressed in breast cancer. TROP2 antibody drug conjugates (ADCs) have shown antitumor activity in breast cancer, however the determinants of response remain controversial. Datopotamab deruxtecan (Dato-DXd) is an ADC consisting of a humanized anti-TROP2 IgG1 monoclonal antibody covalently linked to a highly potent topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. We assessed the antitumor activity in a panel of breast cancer PDXs varying in TROP2 expression.
Methods
11 PDX models that differed by TROP2 expression, generated from residual breast tumors after neoadjuvant chemotherapy were treated with Dato-DXd and Isotype control-DXd at 1 mg/kg and 10 mg/kg every 3 weeks. Antitumor activity was assessed by objective response (30% or more growth inhibition compared with baseline) and event-free survival (EFS, time to tumor doubling). Pharmacodynamic effects were assessed at 24 and 72 hours. TROP2 was overexpressed by viral transduction in cell lines derived from two different TROP2-low Dato-DXd-resistant PDXs.
Results
Dato-DXd had dose-dependent activity. PDX models differed in sensitivity to both Isotype-Dxd and Dato-DXd, with tumor regression observed with isotype DXd in two models. Dato-DXd 10 mg/kg led to objective response in 4 (36%) models and statistically significant prolongation of EFS in 8 (73%) models. TROP2 expression was significantly higher by RNAseq and by immunohistochemistry in Dato-DXd-sensitive models. Dato-DXd led to an increase in H2AX in the 2 sensitive PDXs and not in a Dato-DXd resistant model. In Dato-DXd-sensitive models, antitumor activity was further enhanced with the combination with PARP inhibitor olaparib. In isogenic breast cancer cell lines, overexpression of TROP2 expression conferred in vitro antitumor activity of Dato-DXd, as demonstrated by a dramatically lower IC50, increase in internalization, DNA damage response signaling and apoptosis.
Conclusions
Dato-DXd is active in models resistant to traditional chemotherapy. Dato-DXd has TROP2 dependent and independent mediators of activity. Further study is needed into predictors of intrinsic resistance and rational combinations.
Legal entity responsible for the study
The University of Texas MD Anderson Cancer Center.
Funding
Daiichi Sankyo.
Disclosure
F. Meric-Bernstam: Financial Interests, Personal, Other, Consultant: AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Tyra Biosciences, Xencor, Zymeworks, OnCusp Therapeutics; Financial Interests, Personal, Advisory Board, Advisory Board/Consultant: Seagen; Financial Interests, Personal, Advisory Board: Silverback Therapeutics, Zentalis, Karyopharm, Biovica, Eisai; Financial Interests, Personal, Other, Consulting: Tallac Therapeutics, Lengo Therapeutics, LOXO-Oncology, Black Diamond, Infinity Pharmaceuticals, AbbVie; Financial Interests, Institutional, Other, Local PI / Research Grant: Aileron Therapeutics, Bayer Healthcare, CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., eFFECTOR Therapeutics, Taiho Pharmaceutical Co.; Financial Interests, Institutional, Other, Local PI / Research Grant / Coordinating PI: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Calithera Biosciences, Curis Inc., Debiopharm International, Guardant Health Inc., Klus Pharma, Novartis, PPD Investigator Services; Financial Interests, Institutional, Other, Local PI / Steering Committee Member: Genentech Inc.; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical Co., Puma Biotechnology Inc., Repare. T. Maejima: Financial Interests, Personal, Other, Employer: Daiichi Sankyo. L.A. Byers: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Corp, Arrowhead, Chugai Pharmaceutical Co., AstraZeneca Pharmaceuticals, Genetech Inc, AbbVie, Jazz Pharmaceuticals, Puma Biotechnology, Amgen, Daiichi Sanyo, BeiGene; Financial Interests, Institutional, Funding, Research funding: AstraZeneca Pharmaceuticals, Amgen. D. Tripathy: Financial Interests, Personal, Advisory Board, Serving on Steering Committee for TrialsEducational Lectures: Novartis; Financial Interests, Personal, Advisory Board, Steering Committee for and ongoing trial: Pfizer; Financial Interests, Personal, Advisory Board, Advisory council for design and interpretation of trials: GlaxoSmithKline; Financial Interests, Personal, Invited Speaker, Educational Lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, To discuss and interpret clinical trial data: Immunomedics; Financial Interests, Personal, Advisory Board, Advice on clinical trial design: OncoPep; Financial Interests, Personal, Invited Speaker, Lecture on gene profiling: Exact Sciences; Financial Interests, Personal, Advisory Board, Consulting: Sermonix; Financial Interests, Personal, Advisory Board, Consultant: Personalis, Puma Biotechnology, Gilead; Financial Interests, Institutional, Research Grant, Funding for laboratory experiments on the inhibition of CXCR4 in breast cancer cells: Polyphor; Financial Interests, Institutional, Invited Speaker, Global PI on one trial and local PI on another trial: Novartis. D. Okajima: Financial Interests, Personal, Other, Employer: Daiichi Sankyo, Ltd. All other authors have declared no conflicts of interest.