Exposure-Response Relationships in Patients With HER2-Positive Metastatic Breast Cancer and Other Solid Tumors Treated With Trastuzumab Deruxtecan.

Trastuzumab deruxtecan (T-DXd) is a HER2-targeting antibody-drug conjugate composed of a novel enzyme-cleavable linker and membrane-permeable topoisomerase I inhibitor payload. T-DXd has been approved for HER2-positive metastatic breast cancer (BC) and for HER2-positive metastatic gastric cancer. The approval in BC was based on results from the DESTINY-Breast01 (U201; NCT03248492) and J101 (NCT02564900) trials. Here we present dose justification for the approved 5.4 mg/kg every-3-weeks (Q3W) dose based on exposure-efficacy evaluated in HER2-positive patients with BC (N=337) from these 2 trials. Exposure-safety was assessed in patients with all tumor types (N=639, n=512 with BC) across 5 trials, including J101 and DESTINY-Breast01. T-DXd doses ranged from 0.8-8.0 mg/kg Q3W; most patients received 5.4 (n=312) or 6.4 mg/kg (n=291). For each endpoint, multivariate logistic or Cox regression analysis was performed using various exposure metrics of T-DXd and released drug. A statistically significant association was observed between intact T-DXd AUC and confirmed ORR (P=.028). No significant exposure-response relationships were observed between intact T-DXd or released drug and DOR or PFS; however, follow-up was limited. All evaluated safety endpoints demonstrated a significant (P<.05) relationship with either intact T-DXd or released drug, with higher adverse event (AE) rates projected at higher exposures. Dose-response projections suggested an increase in ORR (67.5% vs 62.9%) and toxicity (eg, grade ≥3 all-cause treatment-emergent AEs: 61% vs 54%) with T-DXd 6.4 vs 5.4 mg/kg. Results demonstrate the benefit-risk profile at different doses and guide clinicians in the use of the 5.4-mg/kg Q3W dose in patients with HER2-positive metastatic BC.