(M-074) Exposure-efficacy analysis of datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate, in patients with advanced non-small cell lung cancer

Yuzhuo Pan, PhD – Director, Daiichi Sankyo, Inc.; Sofia Friberg Hietala, PhD – Principal Consultant, Pharmetheus; Sophie Peigné, PhD – Senior Consultant, Pharmetheus; Deise Uema, MD – Senior Director, Daiichi Sankyo; Ricardo Zwirtes, MD – Executive Director, Daiichi Sankyo; David Dai, PhD – Associate Director, AstraZeneca; Diansong Zhou, PhD – Senior Director, AstraZeneca; Naoyuki Tajima, PhD – Senior Director, Daiichi Sankyo; Tushar Garimella, PhD – Executive Director, Daiichi Sankyo; Malaz Abutarif, PhD – Vice President, Daiichi Sankyo; Ying Hong, PhD – Senior Director, Daiichi Sankyo

Objectives: Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) in clinical development for the treatment of advanced non-small cell lung cancer (NSCLC) and other tumor types. The released drug, DXd, inhibits DNA topoisomerase 1, promoting apoptosis of target tumor cells. The aim of this analysis was to analyze the relationship between Dato-DXd exposure and overall response rate (ORR) and progression-free survival (PFS) assessed by blinded independent central review (BICR) and interim overall survival (OS) in patients with advanced NSCLC.

Methods: The analysis included data from 644 NSCLC subjects receiving Dato-DXd doses ranging from 0.27 to 10 mg/kg Q3W in three clinical studies (Phase 3 Study TROPION-Lung01, Phase 2 Study TROPION-Lung05, and Phase 1 Study TROPION-PanTumor01), among them 484 subjects received the recommended dose of 6 mg/kg Q3W. Individual Dato-DXd exposure metrics area under the concentration-time curve in the first cycle (AUC1), average concentration to the end of event cycle (Cav), and time-varying AUC during a dosing interval (AUCτ) were predicted using a population pharmacokinetic model of Dato-DXd and DXd [1]. Next, parametric time-to-event models were developed for OS and PFS, and a logistic regression model was developed for ORR. For each endpoint, the significance of Dato-DXd exposure metrics (AUC1 for OS analysis, AUCτ for PFS analysis, AUC1 or Cav for ORR analysis) on the base hazard/probability was tested. Finally, the effect of pre-determined covariates on the base hazard/probability was evaluated using the stepwise covariate model building procedure with adaptive scope reduction.

Results: Significant exposure-response (ER) relationships were identified for all three efficacy endpoints. A linear drug effect with Dato-DXd AUC1 was implemented in the ER-OS model. The drug effect on PFS and ORR was respectively described by a Emax function of Dato-DXd AUCτ and Cav. Significant covariates associated with positive outcome were non-squamous histology (OS, PFS, ORR), high albumin (OS, PFS), no liver metastases (OS, PFS), female sex (OS, PFS), ECOG status=0 (OS), region Japan (OS), low baseline tumor size (OS), older age (PFS), immunotherapy as last prior line therapy (PFS), and number of prior line therapies>2 (ORR). Compared to a reference subject who received Dato-DXd 4 mg/kg Q3W, the hazard ratio (HR) of 6 mg/kg Q3W was predicted to be 0.91 (90%CI: 0.837, 1.00) for OS and 0.778 (90%CI: 0.742, 0.890) for PFS, and the odds ratio (OR) was 1.35 (90%CI: 1.17, 1.54) for ORR.

Conclusions: The exposure-efficacy analysis identified significant relationships between Dato-DXd exposure and OS, PFS, and ORR and provided necessary benefit-risk assessment to support Dato-DXd 6 mg/kg Q3W dosing regimen for the treatment of patients with advanced non-squamous NSCLC.

Citations: [1] Peigné et al. Population Pharmacokinetic analysis of datopotamab deruxtecan (Dato-DXd), a TROP2-targeting antibody-drug conjugate. 32nd Population Approach Group Europe (PAGE) Meeting, Rome, Italy, 26-28 June 2024 (Submitted).