Pulmonary hypertension associated with Trastuzumab-Emtansine: an analysis of French PH registry and WHO pharmacovigilance database

Abstract

Background: Trastuzumab-emtansine have 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 PH Registry, the VIGIAPATH program, concurrently with a pharmacovigilance disproportionality analysis using the WHO pharmacovigilance database using a broad definition of PH and a narrow definition of PAH. A signal of disproportionate reporting was deemed significant if the lower boundary of the 95% credibility interval (95%CI) of the Information Component (IC) was superior to 0. The variables were expressed as median (interquartile range).

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 occured in women (age of 56 (49-61) years) suffering from breast cancer. The delay between first exposure and PAH diagnosis was 43 (4.5-55) months. At diagnosis, 5 were in NYHA functional class III/IV with severe hemodynamic impairment (mean pulmonary artery pressure of 42 mmHg, cardiac index 2.51 L/min/m², and pulmonary vascular resistance of 9.7 WU). Disproportionality analysis showed that only trastuzumab-emtansine demonstrated a significant signal of disproportionate reporting using both broad definition of PH (IC 1.46, 0.86-1.95) and narrow definition of PAH (IC 1.76, 0.83-2.46). Trastuzumab displayed a significant signal using only the broad definition of PH, while 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 to trastuzumab alone. Further assessment of this safety signal and exploration of pathophysiological mechanisms is needed.

Keywords: Chemotherapy; Emtansine; Pharmacovigilance; Pulmonary hypertension; Trastuzumab; disproportionality analysis.