Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case.
BACKGROUND
BRAF and MEK are component of the MAPK/ERK pathway and inhibitors of these proteins have significantly improved the outcome of metastatic melanoma. We report for the first time two sequential episodes of pneumonitis presumably induced by trametinib (a MEK inhibitor) and vemurafenib (a BRAF inhibitor) in a 50 year-old man.


METHODS
While receiving trametinib for a metastatic melanoma, the patient developed non-febrile acute respiratory failure in the context of bilateral ground-glass opacities and sub pleural reticulations on high resolution computed tomography. An excess of lymphocytes was found in the bronchoalveolar lavage fluid. Outcome was favorable after simple drug discontinuation. He subsequently developed a similar clinical-imaging picture 6 months into vemurafenib. A transthoracic lung biopsy disclosed interstitial lymphocytic infiltrate, poorly-formed granulomas with multinucleated giant cells and scattered eosinophils. Outcome was again favorable after simple drug discontinuation.


CONCLUSIONS
These two episodes in the same patient suggest that MAPK/ERK inhibitors may cause interstitial lung disease and may exert cross toxicity. This side effect is of particular interest for physicians in charge of patients with melanoma but this drug family is currently under development for several other solid tumors.
AP-HP, Department of Pulmonary Medicine and Thoracic Oncology, Hôpital A. Paré, Boulogne, & université de Versailles SQY, Boulogne, France. violaine.giraud@aphp.fr.|Service de Pneumologie et d'Oncologie Thoracique, Hôpital Ambroise Paré, 9, avenue Charles de Gaulle, Boulogne, 92 104, France. violaine.giraud@aphp.fr.
Violaine
V
Giraud
AP-HP, Department of Dermatology, Hôpital A. Paré, Boulogne, France. christine.longvert@aphp.fr.
Christine
C
Longvert
AP-HP, Department of Pathology, Hôpital A. Paré, Boulogne, France. solenehoulle@hotmail.com.
Solène
S
Houlle-Crepin
AP-HP, Department of Pathology, Hôpital Bichat Claude Bernard, Paris, France. claire.danel@aphp.fr.
Claire
C
Danel
AP-HP, Department of Pulmonary Medicine and Thoracic Oncology, Hôpital A. Paré, Boulogne, & université de Versailles SQY, Boulogne, France. sylvie.labrune@aphp.fr.
Sylvie
S
Labrune
Department of Pulmonary Medicine, CHU Le Bocage and www.pneumotox.com, Dijon, 21079, France. philippecamus1@gmail.com.
Philippe
P
Camus
AP-HP, Department of Dermatology, Hôpital A. Paré, Boulogne, France. philippe.saiag@uvsq.fr.
Philippe
P
Saiag
AP-HP, Department of Pulmonary Medicine and Thoracic Oncology, Hôpital A. Paré, Boulogne, & université de Versailles SQY, Boulogne, France. thierry.chinet@aphp.fr.
Thierry
T
Chinet
D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D006801:Humans; D007211:Indoles / Q000009:adverse effects*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D011014:Pneumonia / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011728:Pyridones / Q000009:adverse effects*; D011744:Pyrimidinones / Q000009:adverse effects*; D012008:Recurrence; D013449:Sulfonamides / Q000009:adverse effects*; D014057:Tomography, X-Ray Computed; D000077484:Vemurafenib
D007211:Indoles; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; D000077484:Vemurafenib; C560077:trametinib; D048369:MAP Kinase Kinase 1