LAUSR

AIM Patients with solid tumors were treated with the anti-PD-1 antibody dostarlimab in the Phase I GARNET trial. This study aimed to examine dostarlimab's effect on corrected QT (QTc) interval and the systemic concentration-QTc interval relationship. METHODS In GARNET Part 2B, patients received 500 mg dostarlimab every 3 weeks (Q3W) for 4 cycles, then 1000 mg Q6W. Triplicate 12-lead ECGs were recorded and time-matched pharmacokinetic (PK) samples collected at screening, on Day 1 of Cycles 1, 4, 5, 8, 12 (pre-dose and 0.5 h after infusion end), and at treatment end. Concentration-change from baseline QTcF (ΔQTcF) analysis using a linear mixed effects model, summary statistics, incidence of clinically noteworthy ECG values, and rhythm abnormalities were evaluated. RESULTS 377 patients were considered for evaluation (n=15 excluded from concentration-ΔQTcF). There was a non-significant concentration-ΔQTcF relationship (0.001589 ms/μg/ml; p=0.5906). Mean ΔQTcF increase was <6 ms (upper-bound two-sided 90% confidence interval [CI], <10 ms at all post-dose timepoints). Highest geometric mean concentration was 414.1 μg/ml (Cycle 5 Day 1, 0.5 h) with predicted mean ∆QTcF of 3.064 ms (upper-bound two-sided 90% CI: 5.071). Mean QTcF prolongation (all concentrations) was 2.4 ms. QTcF prolongation ≥500 ms occurred in five patients (1.3%); 51 (13.6%) and nine patients (2.4%) had ΔQTcF ≥30 ms and ≥60 ms, respectively. Ten patients (2.7%) reported rhythm abnormalities. No U wave abnormalities, Torsades de Pointes, ventricular tachycardia, or ventricular fibrillation/flutter were observed. CONCLUSION Dostarlimab does not cause clinically significant QTcF prolongation exceeding the regulatory concern threshold.