• Camille Poisson, Alex Hlavaty, Nicolas Favrolt, Marie-Camille Chaumais, Julien Grynblat, Etienne-Marie Jutant, Benoît Lechartier, Arnaud Maurac, Pierre Mouillot, Sylvain Palat, Laurie Rambach, Fabrice Antigny, Vincent Cottin, Guillaume Beltramo, Marc Humbert, KhouriCharlesCUniv. Grenoble-Alpes, Pharmacovigilance Unit, Grenoble-Alpes University Hospital, 38000 Grenoble, France; Univ. Grenoble-Alpes, Inserm CIC1406, CHU de Grenoble, 38000 Grenoble, France; Univ. Grenoble-Alpes, HP2 Laboratory, Inserm U1300, 3800, Philippe Bonniaud, and David Montani.
• Service de Pneumologie et Soins Intensifs Respiratoire, Centre de Référence Constitutif des Maladies Pulmonaires Rares de l'Adultes de Dijon, réseau OrphaLung, Filière RespiFil, Centre Hospitalier Universitaire de Bourgogne, Dijon, France; INSERM U1231, Equipe HSP-pathies, Faculty of Medicine and Pharmacy, University of Bourgogne-Franche Comté, Dijon, France.
• Chest. 2024 Nov 19.

BackgroundTrastuzumab-emtansine have been recently suspected to be associated with the development of pulmonary arterial hypertension (PAH).Research QuestionIs there an association between trastuzumab, trastuzumab-emtansine, or trastuzumab-deruxtecan and the development of PAH?Study Design And MethodsCharacteristics 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).ResultsIn 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.InterpretationOur 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.Copyright © 2024. Published by Elsevier Inc.

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