PI-038 - REVERSE-TRANSLATIONAL FINDINGS FOR DATOPOTAMAB DERUXTECAN (DATO-DXD) HUMAN EFFICACIOUS DOSE PREDICTION BASED ON MECHANISTIC PK/TUMOR GROWTH INHIBITION ANALYSIS FOR PATIENT-DERIVED AND CANCER CELL LINE-DERIVED XENOGRAFT MICE.

T. Karibe¹, D. Okajima¹, S. Yasuda², T. Maejima², T. Nakamura³, N. Tajima³, K. Lim⁴, Y. Jiang⁴, C. Vasalou⁵, M. Sung⁶, Y. Hong²; ¹Daiichi Sankyo, Tokyo, Japan, ²Daiichi Sankyo, Basking Ridge, NJ, United States, ³Daiichi Sankyo, Shinagawa-ku, Tokyo, Japan, ⁴AstraZeneca R&D, Gaithersburg, MD, United States, ⁵AstraZeneca, Waltham, MA, United States, ⁶AstraZeneca PLC, Waltham, MA, United States.

Background: Dato-DXd is an antibody-drug conjugate (ADC) that comprises a recombinant human anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody, which is covalently conjugated to a drug-linker via thioether bonds. The released drug, DXd, inhibits DNA topoisomerase I and leads to apoptosis of target cells. The objectives of this study were (1) to describe PK/PD relationship in patient-derived xenograft (PDX) and cancer cell line-derived xenograft (CDX) mice models using tumor growth inhibition (TGI) as a PD index following intravenous (IV) administration of Dato-DXd and (2) to compare efficacious concentration estimated from preclinical studies with clinical human PK profiles (TP01, ClinicalTrials.gov ID: NCT03401385) in patients with non-small cell lung cancer (NSCLC) and breast cancer (BC) as part of reverse-translational research.

Methods: A two-compartment model was adopted to describe the plasma PK profile of Dato-DXd in mice. Mechanistic PK/TGI model analysis described by Simeoni et al. (Cancer Res. (2004) 64: 1094–101) was conducted to estimate the tumor static concentration (TSC), which represents the plasma concentration of Dato-DXd that leads to equal rates of tumor growth and death in the xenograft models. To evaluate the relevance of preclinical TSC to clinical optimal dose (6 mg/kg), clinical human PK profiles in patients with NSCLC and BC following multiple IV dosing of Dato-DXd (0.27-10 mg/kg) were compared to the preclinical TSCs.

Results: The mean TSC was 12.2 μg/mL for BC PDX (6 models) and 10.1 μg/mL for NSCLC PDX (6 models). These values were similar to those estimated in Lung CDX models (8.27 μg/mL in 4 models: Calu-3, EBC-1, HCC827, and NCI-H2170). The overall mean TSC in all preclinical models tested was 10.0 μg/mL (25 models in total). In NSCLC and BC patients received at 6 mg/kg of Dato-DXd, the plasma concentration of Dato-DXd at steady state mostly remained within or above the range of mean TSC (10.0 – 12.2 μg/mL) estimated in the respective preclinical models.

Conclusion: These findings suggest that preclinical PK/TGI analysis is a reliable way to estimate the clinical efficacious concentration of Dato-DXd in patients with NSCLC and BC, thereby providing the rationale for supporting 6 mg/kg as the optimal dose of Dato-DXd for clinical study design and strategy.