PI-062 - CONCENTRATION-QTC ANALYSIS OF PATRITUMAB DERUXTECAN IN PATIENTS WITH HER3-EXPRESSING METASTATIC BREAST CANCER OR METASTATIC OR UNRESECTABLE NON-SMALL CELL LUNG CANCER

M. Lee¹, Y. Xu¹, M. Pane², G. O'Brien², R. Byrne², T. Waterhouse², S. Patel¹, T. Garimella¹, L. Li¹; ¹Daiichi Sankyo, Basking Ridge, NJ, USA, ²Metrum Research Group, Tarrifville, CT, USA.

Background: Patritumab deruxtecan (HER3-DXd) is a HER3-targeting antibody-drug conjugate with a topoisomerase I inhibitor payload (DXd) with a drug-to-antibody ratio of approximately 8. It is currently being investigated in multiple tumor types, including breast cancer (BC) and non-small cell lung cancer (NSCLC). This analysis evaluated the relationship between concentrations of DXd and QT interval corrected using Fridericia’s formula (QTcF) or population-specific correction factor (QTcP) in patients with HER3-expressing metastatic BC treated in the phase 1/2 Study U31402-A-J101 (J101) or with metastatic/unresectable NSCLC treated in the phase 1 Study U31402-A-U102 (U102).

Methods: Electrocardiogram (ECG) monitoring was conducted in Studies J101 and U102 by 12-lead ECG recordings extracted in triplicate, which were coupled with HER3-DXd pharmacokinetic (PK) collections. Nonlinear mixed-effects modeling using NONMEM software (Version 7.5) was performed using observed DXd concentrations and time-matched mean ECG measurements.

Results: The analysis dataset included 1337 and 2111 observations of ECG with time-matched PK from 164 patients with BC and 209 patients with NSCLC, respectively, treated over the dose range of 1.6 to 8.0 mg/kg, Q2W or Q3W, administered via IV infusion. Observed QTcF and QTcP had a shallow positive relationship with DXd concentration in patients with BC and NSCLC. The upper bounds of the 90% two-sided CIs were below the 10 ms threshold (cited by the ICH E14 guideline for establishing a negative thorough QT/QTc study[1]) of predicted mean ΔQTcP (6.92 ms in Study J101; 6.11 ms in Study U102) and ΔQTcF (7.39 ms in Study J101; 4.06 ms in Study U102) at the highest geometric mean Cmax of DXd (23.2 ng/mL following 6.4 mg/kg Q3W dosing in Study J101 and 22.8 ng/mL following 5.6 mg/kg Q3W dosing in Study U102).

Conclusion: HER3-DXd did not demonstrate a clinically significant risk of QT prolongation at the studied dose levels. Although a positive relationship between DXd concentration and ΔQTc was identified in Studies J101 and U102, predicted ΔQTcP and ΔQTcF upper bounds of the 90% CIs did not approach the 10 ms threshold at the Cmax observed in either study, indicating no clinically meaningful risk of QT prolongation exists with HER3-DXd at the recommended dose level of 5.6 mg/kg Q3W in NSCLC.