Abstract PO3-04-02: Exposure-efficacy and safety analysis of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03)
Authors: Li Claire , Wada Russ , Li Hanbin , kastrissios Helen , Abutarif malaz , Garimella Tushar , Khatri Amit 
Published: May 2024

Abstract
Exposure-efficacy and exposure-safety analyses of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03) Authors: Claire Li1, Russ Wada2, Hanbin Li2, Helen Kastrissios2, Malaz Abutarif1, Tushar Garimella1 , Amit Khatri1 1Quantitative Clinical Pharmacology, Daiichi Sankyo, Basking Ridge, NJ, USA 2QuanTx Consulting Mountain View, CA, USA Background: T-DXd, an antibody-drug conjugate composed of a humanized anti-HER2 monoclonal antibody and a topoisomerase I inhibitor payload, is approved for adult patients with unresectable or metastatic HER2+ BC with a prior anti-HER2–based therapy either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. The analysis evaluated the relationship between T-DXd pharmacokinetic (PK) exposure and efficacy/safety endpoints following 5.4 mg/kg Q3W in HER2+ BC subjects. Methods: Exposure-efficacy (E-E) analyses were evaluated from BC subjects in two Phase 3 studies, DB-02 (N=404 for T-DXd; 3L+ BC) and DB-03 (N=257 for T-DXd; 2L+ BC). In studies DB-02 and DB-03, 202 and 263 subjects in control arm were treated with treatment of investigator’s/physician’s choice (TPC) and T-DM1, respectively. Exposure-safety (E-S) analyses were conducted using 12 clinical studies ranging from Phase 1 to 3 (N=2216, 68.7% BC), including DB-02 and DB-03. Population PK-predicted exposure metrics included T-DXd and DXd peak concentration, trough concentration, and AUC in Cycle 1 and at steady state. Key efficacy endpoints were progression-free survival (PFS) based on blinded independent central review (BICR) and overall survival (OS). Safety endpoints included any Grade and Grade ≥ 3 adjudicated drug-related interstitial lung disease (ILD). Exploratory analyses were conducted for other safety endpoints (i.e., Grade ≥ 3 TEAEs). Results: T-DXd exposure was a significant predictor (p&lt; 0.01) of OS in DB-02. In study DB-03, T-DXd exposure was a marginally significant covariate (p&lt; 0.05) for OS in univariate Cox regression but was dropped in the multivariate analysis. The relationship between T-DXd exposure and PFS in both studies were not statistically significant (p &gt;0.01), suggesting a flat E-E relationship due to the narrow exposure range resulting from the single-dose level (5.4 mg/kg Q3W) in both studies. Clinically meaningful efficacy in the T-DXd arm relative to the control arm was observed in both studies (PFS: 17.8 months [T-DXd arm] vs. 6.9 months [TPC arm] in study DB-02 and 28.8 months [T-DXd arm] vs. 6.8 months [T-DM- arm] in study DB-03). Therefore, the E-E analyses supports clinically meaningful efficacy across the entire exposure range with the T-DXd 5.4 mg/kg dose in BC subjects.
For E-S, a statistically significant relationship (p&lt; 0.001) was observed between increasing T-DXd exposures across all the dose levels (0.8 to 8 mg/kg) and increasing hazard of any Grade and Grade ≥ 3 ILD. The predicted Day 360 incidence rate of any Grade and Grade ≥3 ILD at 5.4 mg/kg Q3W T-DXd in BC subjects was 14.8% and 3%, respectively. These findings are consistent with previous safety analyses. Observed rates of the exploratory safety endpoints were also generally consistent with previous model-predicted rates of adverse events in BC1. Conclusions: The E-E analyses support clinically meaningful efficacy (PFS and OS) relative to control with a flat exposure-response relationship in HER2+ BC subjects at the T-DXd 5.4 mg/kg dose. The E-S analyses showed any Grade and Grade ≥ 3 ILD event rates for this dose are comparable to prior studies1. Those event rates appeared to increase with increasing T-DXd exposures. Overall, these model-based analyses continue to support T-DXd 5.4 mg/kg Q3W dosing in previously treated HER2+ BC. Reference:
Yin O, Iwata H, Lin, C, et al. Exposure-Response Relationships in Patients with HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated with Trastuzumab Deruxtecan. J Clin Pharm Ther. 2021; 110(4):986-96
Citation Format: Claire Li, Russ Wada, Hanbin Li, Helen kastrissios, malaz Abutarif, Tushar Garimella, Amit Khatri. Exposure-efficacy and safety analysis of trastuzumab deruxtecan (T-DXd) in patients with advanced/metastatic HER2+ breast cancer (BC): Analyses from Phase 3 Studies DESTINY-Breast02 (DB-02) and DESTINY-Breast03 (DB-03) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-04-02.