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

Background: Trastuzumab emtansine has been recently suspected to be associated with the development of pulmonary arterial hypertension (PAH).

Research question: Is there an association between trastuzumab, trastuzumab emtansine, or trastuzumab deruxtecan and the development of PAH?

Study design and methods: 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]).

Results: 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.

Interpretation: 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.