Electrophysiological consequences of acute mobocertinib exposure in isolated rat and guinea-pig hearts and transfected cell lines

Mobocertinib is a first-in-class oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor approved for NSCLC with EGFR exon 20 insertions. Clinical trials indicate a signal for QT prolongation and heart failure, but the underlying mechanisms remain undefined. We used ex-vivo hearts and transfected cell lines to determine direct, acute electrophysiological consequences of mobocertinib in animal models. Isolated Langendorff-perfused hearts from male Sprague-Dawley rats and Dunkin-Hartley guinea pigs were exposed to 0.3, 0.9, 3 or 9 μM mobocertinib (1.4- to 42-fold clinical Cmax). 64-channel electrical mapping recorded ECG intervals, conduction velocity and ventricular effective refractory period (ERP). Whole-cell patch-clamp in hERG-HEK293, Kv4.3-HEK293, Nav1.5-CHO and acutely isolated guinea-pig ventricular myocytes yielded concentration-inhibition curves for IKr, Ito, INa and ICaL, respectively. In both species mobocertinib concentration-dependently prolonged PR, QRS and QTc intervals and slowed left-ventricular conduction (p < 0.01). ERP was modestly lengthened only at the highest concentrations. Patch-clamp studies revealed IC50 values of 4.96 ± 0.21 μM for hERG, 12.60 ± 0.09 μM for Cav1.2, and ≥30 μM for Nav1.5 and Kv4.3. These data suggest that mobocertinib exerts acute, direct cardiac electrophysiological effects-predominantly via hERG and Cav1.2 inhibition-providing a mechanistic basis for observed QT prolongation and conduction delay in patients.