Christine Longvert

Claire Danel

Philippe Camus

Philippe Saiag

Solène Houlle-Crepin

Sylvie Labrune

Thierry Chinet

Violaine Giraud

BMC Cancer

Springer - Publisher Connector

CASE REPORT Open Access
Relapsing pneumonitis due to two distinct
inhibitors of the MAPK/ERK pathway: report
of a case
Violaine Giraud1,6*, Christine Longvert2, Solène Houlle-Crepin3, Claire Danel4, Sylvie Labrune1, Philippe Camus5,
Philippe Saiag2 and Thierry Chinet1
Abstract
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.
Case presentation: 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.
Conclusion: 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.
Keywords: Trametinib, Vemurafenib, Drug-induced pneumonitis, Granuloma, Metastatic melanoma
Background
The novel BRAFV600 (vemurafenib, dabrafenib) and MEK
(trametinib) inhibitor are structurally-unrelated small mole-
cules targeting two critical proteins which belong to the
MAPK/ERK pathway. These drugs have transformed the
prognosis of metastatic melanoma harboring BRAFV600
mutation improving both disease-free and overall survival
[1–3]. We report a patient who developed trametinib and
vemurafenib induced reversible pneumonitis.
Case presentation
Case
A 50 year-old non-smoking man was diagnosed with
BRAFV600E mutation-positive metastatic melanoma in
2010. Evaluation following two courses of a dacarbazine-
based regimen showed progression of the cutaneous lesions
and new metastases in both the lung parenchyma and me-
diastinal lymph nodes. After informed consent, he entered
clinicaltrial.gov NCT01245062 phase III study and received
trametinib 2 mg daily. Pretherapy high resolution com-
puted tomography (HRCT) showed no evidence of intersti-
tial lung disease (ILD). Five months into treatment, he
complained of dyspnea and mild hemoptysis. There was no
fever. Progressive dyspnea led to admission. Clinical exam-
ination showed bilateral crackles. Arterial blood gases
results (room air) were PaO2 58 mmHg, PaCO2 40 mmHg,
pH 7.47. On HRCT, melanoma metastases were no longer
* Correspondence: violaine.giraud@aphp.fr
1AP-HP, Department of Pulmonary Medicine and Thoracic Oncology, Hôpital
A. Paré, Boulogne, & université de Versailles SQY, Boulogne, France
6Service de Pneumologie et d’Oncologie Thoracique, Hôpital Ambroise Paré,
9, avenue Charles de Gaulle, Boulogne 92 104, France
Full list of author information is available at the end of the article
© 2015 Giraud et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Giraud et al. BMC Cancer  (2015) 15:732 
DOI 10.1186/s12885-015-1754-3
present. There were bilateral ground glass shadowing and
subpleural reticulations (Fig. 1a). Blood eosinophils were
640 × 106 × L−1. Bronchoalveolar lavage (BAL) fluid yielded
20 × 106 cells.mL−1, of which 87 % were lymphocytes (CD4
+/CD8+ ratio: 0.4) and 1 % of all cells were eosinophils. No
Pneumocystis jiroveci (PJ) cysts were visualized. Trametinib
was discontinued, while the remainder of drugs (bisoprolol,
valsartan, rosuvastatin, allopurinol, paracetamol, oxazepam)
was kept unchanged. Corticosteroids were not given.
Patient improved clinically and radiologically (Fig. 1b).
Vemurafenib (1920 mg/d) was started 2 months later.
Three months into treatment, patient reported recurrence
of hemoptysis and dyspnea. Although HRCT revealed new
ground-glass opacities in both lungs, vemurafenib was con-
tinued. Respiratory status and HRCT slowly worsened
(Fig. 1c). Fifteen months into treatment with vemurafenib,
a new BAL disclosed lymphocytic alveolitis (730 × 103
cells.mL−1, 68 % lymphocytes, CD4/CD8 ratio: 0.4, eosino-
phils were 3 %). There was no peripheral eosinophilia. A
CT-guided transthoracic lung biopsy disclosed an intersti-
tial and alveolar lymphocytic infiltrate, scattered eosinophils
associated with poorly-formed epithelioid granulomas and
multinucleated giant cells (Fig. 2). Necrosis, vasculitis, ma-
lignant cells or refractive foreign body under polarized light
were absent. Special stains for PJ were negative. Polymerase
chain reaction on BAL for PJ was nondiagnostic with 33.5
replication cycles indicating colonization or low burden. No
anti-Pneumocystis drugs were given. Vemurafenib-induced
pneumonitis was suspected and the drug was withheld. Re-
spiratory symptoms progressively waned. Six months later,
infiltrates and reticulations had cleared but metastatic dis-
ease progression was noted (Fig. 1d). The patient currently
is on dabrafenib a BRAF inhibitor and is monitored serially
and carefully as regards pulmonary signs and symptoms.
Discussion
We report here two episodes of subacute pneumonitis
that are chronologically compatible with a drug etiology.
BAL findings and pathology, although not entirely specific,
supported a drug reaction. Pathology findings were com-
patible with hypersensitivity pneumonitis to inhaled anti-
gens, but there was no exposure to organic environmental
sources. The drug etiology was also supported by improve-
ment following drug discontinuation while corticosteroids
Fig. 1 Chest CT scan (a): during the episode of acute respiratory failure after 5 months of treatment with trametinib, (b): 7 months after trametinib
discontinuation and 5 months after vemurafenib initiation, (c): 15 months after vemurafenib initiation, (d): 6 months after vemurafenib discontinuation
Giraud et al. BMC Cancer  (2015) 15:732 Page 2 of 4
were not given [4, 5]. Cardiogenic, infectious and neoplastic
causes were considered unlikely on the basis of clinical, im-
aging, BAL and pathology data and because our patient’s
condition improved upon drug stoppage.
Several pathological patterns have been described in pa-
tients with drug-induced pneumonitis [6]. A lymphocytic
interstitial infiltrate with poorly-formed granulomas and
giant cells has been described in patients with methotrex-
ate, nitrofurantoin, BCG therapy, anti-TNF agents and
mTOR inhibitor-induced lung reactions [6–8]. However,
in patients with drug-induced pneumonitis, changes on
pathology are rarely specific and correlate poorly with
findings on imaging [9].
The present case is one of five trametinib-induced pneu-
monitis cases mentioned to date in the US marketing
authorization file (www.accessdata.fda.gov/drugsatfdadocs/
label/2014/204114s001lbl.pdf). There is no report in the
literature yet. As of vemurafenib, our case is the second
one described [10] but it is the first one with histological
documentation. Our patient is also unique in that ILD
developed while he was being treated with either one agent.
Both trametinib and vemurafenib target effectors of
the MAPK/ERK pathway. Other drugs targeting up-
stream proteins involved in this pathway such as the
tyrosine kinase inhibitors erlotinib, gefitinib, cetuximab
and sorafenib may also cause pulmonary toxicity [11].
The pathophysiology of these disorders is currently un-
clear, but involvement of the MAPK/ERK pathway itself
is one hypothesis [11].
Conclusion
The dual inhibition of BRAF and MEK is currently one
of the most promising therapeutic options to improve
survival in melanoma patients [12]. Moreover, these
drugs are under development for the treatment of sev-
eral other solid tumors. We feel it is important to alert
clinicians to the potential severe pulmonary toxicity of
these two drugs targeting the MAPK/ERK pathway and
to their possible class effect.
Consent
Written informed consent was obtained from the patient
for publication of this case report and any accompanying
images. A copy of the written consent is available for review
by the Editor of this journal.
Abbreviations
HRCT: High Resolution Computed Tomography; ILD: Interstitial Lung Disease;
BAL: Bronchoalveolar Lavage; PJ: Pneumocystis jiroveci.
Competing interests
V. Giraud, C. Longvert, S. Houlle-Crepin, C. Danel, S. Labrune, Ph. Camus and Th.
Chinet have no competing interests. Ph. Saiag received research grants and
clinical research or consultancy fees from GSK, Roche-Genentech, BMS and
Novartis. None of the authors have any non-financial competing interests.
Authors’ contributions
VG and CL wrote the manuscript, SL, PC, PS and TC revisited it critically for
important intellectual content, SHC and CD did the pathologic interpretation.
All authors read and approved the final manuscript.
Fig. 2 Lung biopsy. a: epithelioid granulomas with giant cells associated with interstitial and alveolar lymphocytic infiltrate (M: X100). b: inflammatory
infiltrate with lymphocytes and scattered eosinophils (M: X400)
Giraud et al. BMC Cancer  (2015) 15:732 Page 3 of 4
Author details
1AP-HP, Department of Pulmonary Medicine and Thoracic Oncology, Hôpital
A. Paré, Boulogne, & université de Versailles SQY, Boulogne, France. 2AP-HP,
Department of Dermatology, Hôpital A. Paré, Boulogne, France. 3AP-HP,
Department of Pathology, Hôpital A. Paré, Boulogne, France. 4AP-HP,
Department of Pathology, Hôpital Bichat Claude Bernard, Paris, France.
5Department of Pulmonary Medicine, CHU Le Bocage and
www.pneumotox.com, Dijon 21079, France. 6Service de Pneumologie et
d’Oncologie Thoracique, Hôpital Ambroise Paré, 9, avenue Charles de Gaulle,
Boulogne 92 104, France.
Received: 8 December 2014 Accepted: 9 October 2015
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Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case

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Relapsing pneumonitis due to two distinct inhibitors of the MAPK/ERK pathway: report of a case

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