Association of Pulmonary Hypertension With Trastuzumab Emtansine: An Analysis of French Pulmonary Hypertension Registry and WHO Pharmacovigilance Database.

Abstract

Trastuzumab emtansine has been recently suspected to be associated with the development of pulmonary arterial hypertension (PAH). Is there an association between trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan and the development of PAH? Characteristics of incident PAH cases treated with trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan were analyzed from the French Pulmonary Hypertension Registry, the VIGIAPATH program, concurrently with a pharmacovigilance disproportionality analysis using the World Health Organization pharmacovigilance database using a broad definition of pulmonary hypertension (PH) and a narrow definition of PAH. A signal of disproportionate reporting was deemed significant if the lower boundary of the 95% credibility interval of the information component (IC) was superior to 0. The variables were expressed as median (interquartile range [IQR]). In the French PH Registry, we identified 8 incident cases of PAH after trastuzumab emtansine exposure and none with trastuzumab alone or trastuzumab deruxtecan. All cases occurred in female patients (age, 56; IQR, 49-61 years) with breast cancer. The delay between first exposure and PAH diagnosis was 43 months (IQR, 4.5-55). At diagnosis, 5 were in New York Heart Association functional class III/IV with severe hemodynamic impairment (mean pulmonary artery pressure, 42 mm Hg; cardiac index, 2.51 L/min/m²; pulmonary vascular resistance, 9.7 Wood units). Disproportionality analysis showed that only trastuzumab emtansine demonstrated a significant signal of disproportionate reporting using both a broad definition of PH (IC, 1.46; 0.86-1.95) and a narrow definition of PAH (IC, 1.76; 0.83-2.46). Trastuzumab displayed a significant signal using only the broad definition of PH, whereas trastuzumab deruxtecan was not associated with any significant signals of disproportionate reporting. Our results suggest that more patients exposed to trastuzumab emtansine developed PH compared with trastuzumab alone. Further assessment of this safety signal and exploration of pathophysiologic mechanisms is needed.