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Noninfectious Pneumonitis after Everolimus Therapy for Advanced Renal Cell Carcinoma


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Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. Objectives: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with (NCT 00410124).
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Noninfectious Pneumonitis after Everolimus Therapy
for Advanced Renal Cell Carcinoma
Dorothy A. White
, Philippe Camus
, Masahiro Endo
, Bernard Escudier
, Emiliano Calvo
, Hideyuki Akaza
Hirotsugu Uemura
, Euloge Kpamegan
, Andrea Kay
, Matthew Robson
, Alain Ravaud
, and Robert J. Motzer
Pulmonary Section, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York;
Department of Pulmonary
Medicine, Ho
ˆpital Le Bocage and PneumotoxÒ, Dijon, France;
Division of Diagnostic Radiology, Shizuoka Cancer Center, Shizuoka, Japan;
Gustave Roussy, Villejuif, France;
Centro Integral Oncologico Clara Campal, Madrid, Spain;
University of Tsukuba, Tsukuba, and
Kinki University,
Osaka, Japan;
Novartis Oncology, Florham Park, New Jersey; and
ˆpital Saint Andre
´, Centre Hospitalier Universitaire, Bordeaux, France
Rationale: Noninfectious pneumonitis is a known class effect of
mammalian target of rapamycin (mTOR) inhibitors.
Objectives: To assess the incidence, radiographic patterns, manage-
ment, and outcome of pneumonitis in patients with advanced renal
cell carcinoma receiving everolimus.
Methods: Clinical study data from 416 patients, randomized to re-
ceive everolimus versus placebo, were analyzed for adverse events
of pneumonitis. Radiographic studies performed every 8 weeks
were subject to a prospective, independent, blinded central review
for the presence of findings indicative of pneumonitis.
Measurements and Main Results: Of 274 patients receiving everolimus,
clinical pneumonitis was suspected for 37 patients (13.5%) (none
with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18
(6.6%) were grade 2 (not interfering with daily living), and 10
(3.6%) were grade 3 (interfering with daily living or oxygen indi-
cated). No grade 4 (life-threatening) pneumonitis was observed. Of
the 10 patients with grade 3 pneumonitis, 5 had baseline radiologi-
cal evidence of pneumonitis before everolimus therapy. Twenty of
the 37 cases (54.0%) were reversible within the follow-up period;
resolution followed dose reduction for 20 patients and treatment
discontinuation in 10 patients. Corticosteroid therapy was initiated
in 16 cases. Dedicated radiological review of available serial radio-
graphic studies (245 patients receiving everolimus and 132 receiving
placebo) found a higher percentage of new radiographic findings
even in patients without a diagnosis of clinical pneumonitis who
were receiving everolimus versus placebo (38.9 vs. 15.2%).
Conclusions: Early recognition, prompt intervention, and a conserva-
tive approach are important in managing the risk associated with
noninfectious pneumonitis in association with everolimus.
Clinical trial registered with (NCT 00410124).
Keywords: mTOR (mammalian target of rapamycin) inhibitors; lung
toxicity; RAD001
Everolimus (formerly RAD001; Novartis Pharmaceuticals, East
Hanover, NJ) is a selective inhibitor of the mammalian target of
rapamycin (mTOR), a central regulator of intracellular signal-
ing pathways involved in cell growth and proliferation, cellular
metabolism, and angiogenesis. This drug is currently in use to
prevent allograft rejection after solid organ transplantation
(Certican) (1) and in the treatment of advanced renal cell
carcinoma (RCC) (Afinitor) (2). Everolimus and other rapa-
mycin derivatives generally are well tolerated. Noninfectious
pneumonitis, stomatitis/oral mucositis, and an increased risk of
infection, including opportunistic infections, represent the most
important toxicities seen with everolimus (2, 3).
Noninfectious pneumonitis, apparently a class effect of
mTOR inhibitors, is characterized by noninfectious, non-
malignant infiltrates and will be referred to as ‘‘pneumonitis’’
throughout this report. It has been described with sirolimus
(rapamycin), temsirolimus, and everolimus in isolated case
reports or retrospective series with a small number of patients
(4–11). An incidence of 5–15% of clinical pneumonitis has been
reported in transplant recipients receiving sirolimus (8, 12–14).
Published reports suggest that it is relatively unaggressive and
reversible on discontinuation of therapy in many cases, but
there can be significant toxicity (9, 10). A similar experience
with clinical pneumonitis has been noted with temsirolimus (15,
16). However, a radiological review of routine serial chest
computed tomography (CT) scans during treatment showed
a higher incidence (36%) of new radiographic abnormalities (5).
Many patients were asymptomatic and continued treatment
without progressing to more severe stages.
Pneumonitis was initially reported in association with ever-
olimus therapy in two investigator-initiated phase II trials in
small numbers of patients with breast cancer and renal cancer
Scientific Knowledge on the Subject
Inhibitors of the mammalian target of rapamycin (mTOR),
including everolimus, are used for the prevention of solid
organ transplant rejection and the treatment of cancer.
This class of drugs has been associated with the develop-
ment of pneumonitis. Little information is currently avail-
able on the incidence and outcome of pneumonitis in
patients with advanced cancer receiving mTOR inhibitors.
What This Study Adds to the Field
Everolimus is associated with a 13.5% incidence of clini-
cally identified pneumonitis in patients with renal carci-
noma. Dedicated radiological review of serial computed
tomography scans during treatment showed new radio-
graphic findings in a higher percentage of patients without
clinical evidence of pneumonitis. Radiographic findings, out-
comes, and a management strategy are described. Adoption
of a conservative approach (in the absence of infection) of
dose reduction or discontinuation with corticosteroid ad-
ministration as needed in those with clinical pneumonitis is
associated with manageable risk.
(Received in original form November 16, 2009; accepted in final form February 24, 2010)
Supported by Novartis Oncology (Florham Park, NJ). The sponsor was respon-
sible for the collection and analysis of the data. The authors and sponsor were
involved in the study design, data interpretation, manuscript preparation, and
the decision to publish.
Correspondence and requests for reprints should be addressed to Dorothy A.
White, M.D., Memorial Sloan-Kettering Cancer Center, Pulmonary Medicine,
1275 York Avenue, New York, NY 10021. E-mail:
This article has an online supplement, which is accessible from this issue’s table of
contents at
Am J Respir Crit Care Med Vol 182. pp 396–403, 2010
Originally Published in Press as DOI: 10.1164/rccm.200911-1720OC on March 1, 2010
Internet address:
(17, 18). An incidence of 18.7–49% was noted. Many of the
cases were grade 1/2 in severity (79 and 63% of affected
patients, respectively, in these studies), and pneumonitis re-
solved after treatment suspension, dose reduction, or cortico-
steroid treatment. A retrospective independent radiological
review of everolimus use in a phase II study of patients with
advanced lung cancer found a 25% incidence of new radio-
graphic findings consistent with pneumonitis with a probable or
possible relationship to the study drug (19).
Herein, we describe those patients who experienced pneu-
monitis during the course of the RECORD-1 (Renal Cell
Cancer Treatment with Oral RAD001 Given Daily) study of
the efficacy of everolimus in RCC and report their management
and outcomes. In addition, to address the issue of a higher
incidence of radiographic findings while on treatment with
everolimus without clinically recognized pneumonitis (as was
noted with temsirolimus), we report the results of a dedicated
radiographic review of all available serial CT scans.
Between November 2006 and October 2007, 416 patients with metastatic
RCC after failure of treatment with sunitinib, sorafenib, or both sunitinib
and sorafenib were randomly assigned at a 2:1 ratio to receive treatment
with everolimus 10 mg once daily or placebo as part of the RECORD-1
study ( identifier, NCT00410124) (2, 3). To help
formulate a definitive approach to address pneumonitis occurring in this
study, an advisory board consisting of several leading pulmonologists was
convened by Novartis Pharmaceuticals Corporation. Routine screening
of all patients via chest X-ray (CXR) and CT scan was proposed. Advice
on the management of pneumonitis was provided in the form of
a treatment algorithm (Table 1). CT scans and CXRs were performed
on all patients on a routine basis (at 8-wk intervals). Pulmonary function
tests (PFTs) were performed at baseline.
Pneumonitis was considered to have occurred if the investigator
coded for the adverse event of pneumonitis during the trial. These cases
were assessed by review of the trial clinical database for the presence
of this adverse event, associated symptoms, severity, treatment, and
outcome. Decisions on the need for additional procedures, such as
bronchoscopy to exclude infectious etiologies or other causes, were made
by investigators during the study. In addition, a Medical Dictionary for
Regulatory Activities (MedDRA) search strategy of the clinical database
was followed to check for coding for other pulmonary events that could
indicate pneumonitis or pneumonitis-like cases. These included terms
such as alveolitis, interstitial lung disease, pneumopathy, and pulmonary
toxicity. Pulmonary adverse events forming the basis for this search
strategy are listed in the online supplement.
All events were graded in accordance with the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI
CTCAE), version 3.0 (20). For pneumonitis, this corresponds to the
following: grade 1 (mild)—asymptomatic, radiographic findings only;
grade 2 (moderate)—symptomatic, not interfering with activities of
daily living; grade 3 (severe)—symptomatic, interfering with activ-
ities of daily living or oxygen indicated; grade 4 (life-threatening or
disabling)—life-threatening or ventilatory support indicated.
Advice on management was provided to investigators in the form of
a treatment algorithm developed by a pulmonary advisory panel and
incorporated into the study protocol as detailed in Table 1.
Serial routine CXRs and CT scans were subsequently subjected to
an independent, blinded (with treatment and safety results unknown)
central review for the presence or absence of new radiographic findings
that could be pneumonitis; categorization of the findings if present; and
details of its distribution, severity, incidence of associated pleural
effusions, and evidence of progression. An incidence rate was calcu-
lated for newly occurring or worsening radiological evidence of
pneumonitis that was confirmed on a CT scan.
Imaging findings on chest CT scan were classified into four distinct
patterns, consistent with the approach proposed by Endo and col-
leagues (21): pattern A—nonspecific areas of ground-glass attenuation,
corresponding to diffuse and faint opacity without loss of lung volume
on chest radiography; pattern B—multifocal areas of airspace con-
solidation (as in, but not diagnostic of, cryptogenic organizing pneu-
monia or bronchiolitis obliterans organizing pneumonia), corresponding
primarily to peripheral consolidation on chest radiography; pattern
C—patchy distribution of ground-glass attenuation accompanied by
interlobular septal thickening (as in, but not diagnostic of, acute eosin-
ophilic pneumonia), corresponding to patchy or diffuse faint, linear
opacities on chest radiography; and pattern D—extensive bilateral
ground-glass attenuation or airspace consolidation with traction bron-
chiectasis (as in, but not diagnostic of, acute interstitial pneumonia),
corresponding to diffuse faint opacities or consolidation with lung vol-
ume loss on chest radiography.
Progression-free survival curves based on the absence/presence of
clinical pneumonitis were estimated by Kaplan-Meier methodology;
cohorts of patients with radiographic findings consistent with pneumo-
nitis versus those with no new findings were compared by log-rank test.
The percentage of predicted absolute values for PFTs was calculated
using the equations of Crapo (22, 23).
A total of 274 patients received treatment with everolimus and
137 received placebo. Demographic characteristics are summa-
rized in Table 2. Close to 80% of patients were male, and
approximately one-third had a history of one or more re-
spiratory disorders and/or symptoms at the start of treatment.
This included patients with a wide range of pulmonary diseases
including chronic obstructive pulmonary disease, asthma, res-
trictive pulmonary disease, and/or symptoms of dyspnea and
cough, among others. Lung metastases were present in approx-
imately three-fourths of the patients. Previous treatment with
interferon had been received by 51 and 52% of patients in the
everolimus and placebo groups, respectively. Treatment with
interleukin-2 had been received by 22 and 24% of these
Grade Intervention Investigations Everolimus Dose Adjustment
1 No specific therapy required CT scan and PFTs.* Repeat chest X-ray/CT scan
every two cycles until return to baseline
No change
2 Symptomatic only. Prescribe
corticosteroids if cough is
CT scan and PFTs.* Repeat each cycle until return
to baseline. Consider bronchoscopy
Reduce dose until improvement to grade <1; consider
interruption if symptoms are troublesome. Discontinue
treatment if recovery to grade <1 is not evident within 3 wk
3 Prescribe corticosteroids if infectious
etiology is ruled out. Taper as
clinically indicated
CT scan and PFTs.* Repeat each cycle until return
to baseline. Bronchoscopy required
Interrupt treatment until improvement to grade <1. Restart
therapy within 2 wk at a reduced dose if clinical benefit
is evident
4 Prescribe corticosteroids if infectious
etiology is ruled out. Taper as
clinically indicated
CT scan and PFTs.* Repeat each cycle until return
to baseline. Bronchoscopy required
Discontinue treatment
Definition of abbreviations: CT 5computed tomography; PFT 5pulmonary function test.
* PFTs include spirometry diffusion capacity of carbon monoxide and room air oxygen saturation at rest tests.
White, Camus, Endo, et al.: Pneumonitis and Everolimus Therapy 397
patients, respectively. In more than 90% of patients, these drugs
had been given several months before the start of treatment
with everolimus.
Clinical Pneumonitis
Pneumonitis was diagnosed by the investigators in 36 patients
(13.1%) who received everolimus therapy. No cases of clinical
pneumonitis were reported in patients receiving placebo. After
a systematic review of all respiratory events reported by the
investigators using other search terms for pulmonary toxicity,
three additional cases were considered to be representative of
pneumonitis but had been identified as pneumopathy (n 52)
and noninfectious pneumopathy (n 51). In addition, two cases
that had been coded as pneumonitis were noted to be of
infectious origin and were therefore discounted. This provided
a group of 37 patients (13.5%) with clinical pneumonitis—34
patients as per the study coding and three additional patients by
this expanded search.
Of the 37 patients with clinical pneumonitis, a total of 19
(51.4%) patients had cough, with grade 3 cough in one (2.7%)
patient (Table 3). Dyspnea was present in 16 (43.2%) patients,
with 6 (16.2%) having grade 3 symptoms. A total of 12 (32.4%)
patients had both cough and dyspnea.
Time to onset for these pulmonary events ranged over
several months. Descriptive statistics for the 37 patients with
pneumonitis showed a median time to occurrence of 108 days
(range, 24–257 d).
For the 37 patients with a clinical diagnosis of pneumonitis
by investigators, radiographic findings were independently
reviewed to confirm the presence of new pneumonitis on
radiographic study and to assess the nature of the abnormalities.
In two cases, radiographs were not available for central review,
and 29 patients with CT scans and 6 patients with CXRs only
were reviewed. Findings consistent with pneumonitis were
confirmed in all but two patients. In one case, changes sugges-
tive of pneumonitis were seen on CXR at the time of diagnosis,
but a subsequent available CT scan for independent review by
the radiologist suggested that findings had likely been related to
progression of cancer. In another case, there were baseline
radiographic findings; the local investigators noted a worsening
of findings at the time of suspected pneumonitis, but the
independent radiologist did not concur with the difference.
For analysis of radiographic patterns, only those with serial
CTs throughout the course of study were analyzed. In this
subgroup of 25 patients, various radiographic patterns were
seen. Furthermore, the presentation changed over time, with
46.7% of patients exhibiting pattern A, 33.3% pattern B, 36.7%
pattern C, and 36.7% pattern D (at any time). When reanalyzed
in terms of the last pattern retained during the observation
period, pattern A was evident for 36.7% of patients, pattern B
for 26.7%, pattern C for 10.0%, and pattern D for 26.7%.
Diagnoses of pneumonitis were associated with pleural effusion
in only two cases—a mild, unilateral effusion was seen in one
patient with a grade 2 event and mild, bilateral effusions in one
patient with grade 3 pneumonitis.
An exploratory analysis was conducted to determine
whether any correlation was evident between CT and CXR
data in diagnosing pulmonary events. In 22 patients, both
a CXR and CT were available at the same time period during
pneumonitis. Positive confirmation was obtained on both CT
and CXR for 14 patients but by CT only in 8 patients. The
degree of correlation improved with increasing severity (grad-
ing) of pneumonitis (50.0% for grade 1 [mild]; 66.7% for grade
2 [moderate]; and 71.4% for grade 3 [severe]).
Management and Outcome
The maximal NCI CTCAE grading (severity) of pneumonitis
and related events is presented in Table 4 for all cases identified
as pneumonitis. Grade 1 and 2 cases were present in 3.3 and
6.6% of patients, respectively, with 3.6% having grade 3. There
were two deaths in patients with grade 3 toxicity. One patient
had alveolar hemorrhage and lung infiltration, and eventually
died of acute respiratory distress syndrome (ARDS). This
patient had initially presented with an infiltrate on chest CT
scan with dyspnea and fever. Blood cultures were positive for
Candida; initial bronchoalveolar lavage was negative, but
a follow-up was positive for Candida. A diagnosis of candidal
sepsis and pneumonia was made. Another patient died of
progressive metastatic disease and ARDS. This was not con-
sidered to be related to everolimus although ARDS per se
cannot be ruled out as being related to the drug. No grade 4
cases were seen.
Treatment of the 37 patients with clinical suspicion of
pneumonitis was as follows (see Table 4). Dose adjustments of
everolimus were made for 20 patients, and everolimus was
permanently discontinued for 10 patients (including 1 patient
with previous dose adjustments). Corticosteroid therapy was
Everolimus, 10 mg Placebo
(n5274)* (n5137)*
Median age, yr (range) 61.0 (27–85) 60.0 (29–79)
Sex, n (%)
Male 215 (78.5) 105 (76.6)
Female 59 (21.5) 32 (23.4)
Underlying respiratory disorders/
symptoms, n (%)
97 (35.4) 45 (32.8)
Respiratory disorders
Pleural effusion 12 (4.4) 4 (2.9)
Chronic obstructive pulmonary disease 8 (2.9) 0
Pulmonary embolism 3 (1.1) 0
Site of most recent metastases, n (%)
Lung 214 (78.1) 108 (78.8)
Lymph node 153 (55.8) 82 (59.9)
Bone 104 (38.0) 46 (33.6)
Liver 99 (36.1) 48 (35.0)
* Safety population (excludes five patients who did not receive study drug).
No Clinical Pneumonitis
Clinical Pneumonitis*
New Radiographic
Findings (n5107)
No New
Findings (n592)
Cough, n (%)
Total 19 (51.4) 31 (29.0) 23 (25.0)
Grade 1 10 (27.0) 22 (20.6) 17 (18.5)
Grade 2 8 (21.6) 9 (8.4) 5 (5.4)
Grade 3 1 (2.7) 0 (0.0) 1 (1.1)
Dyspnea, n (%)
Total 16 (43.2) 22 (20.6) 15 (16.3)
Grade 1 6 (16.2) 7 (6.5) 5 (5.4)
Grade 2 4 (10.8) 8 (7.5) 6 (6.5)
Grade 3 6 (16.2) 7 (6.5) 3 (3.3)
Grade 4 0 (0.0) 0 (0.0) 1 (1.1)
Cough and dyspnea, n (%)
Total 12 (32.4) 5 (4.7) 10 (10.9)
* All patients identified by investigators.
Only patients with computed tomographic findings.
initiated in 16 patients, including 14 patients with either dose
reductions or discontinuation of everolimus.
Complete resolution was evident for 11 of 18 patients with
grade 2 events (with partial reversibility in an additional 2
patients) and for 6 of 10 patients with grade 3 events (with
partial reversibility in 1 additional patient). Representative CT
scans showing presentation at baseline and subsequent time
points for two patients for whom the pulmonary event resolved
are shown in Figure 1.
Regarding the 10 patients with grade 3 events, 3 patients
continued treatment with everolimus. One had a dose reduction
and all received corticosteroids. Resolution was evident in 1
patient after 2 days, a second patient showed signs of improve-
ment (at the time of data cutoff), and the third died of
respiratory failure believed to be due to progression of disease.
Of the seven patients who discontinued treatment, complete
resolution/reversibility was documented in five cases, and the
event was ongoing in one patient at the time of data cutoff. The
final patient died with candidal sepsis and pneumonia. (Details
of the presentation and management of these patients are given
in the online supplement.)
Diagnostic Evaluation
Diagnosis was made clinically in most cases. Bronchoscopy was
performed in only 6 of 274 patients (2.2%) receiving everolimus
therapy, with lung biopsies performed in 4 (1.5%) patients.
Transbronchial biopsy in one patient with grade 3 pneumonitis
showed severe acute lung injury with features suggestive of
organizing diffuse alveolar damage and rare giant cells. The
second patient had grade 2 pneumonitis, and biopsy showed
acute fibrinous and organizing pneumonia with rare, poorly
formed granuloma. Other detailed reports are not available.
Radiological Review
Blinded central radiological review was performed on all avail-
able chest CT scans to determine whether new radiographic
findings occurred during treatment in patients even without
a diagnosis of clinical pneumonitis. Changes consistent with
pneumonitis were evident in approximately 20% of baseline CT
scans for both treatment groups. Postbaseline review was
available for 245 (89.4%) and 132 (96.4%) of patients receiving
everolimus and placebo, respectively. New or worsening radio-
graphic changes of pneumonitis were subsequently observed in
53.9% (n 5132) and 15.2% (n 520) of everolimus- and
placebo-treated patients, respectively, for whom scans were
available (Table 5). In those without a diagnosis of pneumonitis,
38.9% of patients taking everolimus developed new un-
explained radiographic abnormalities compared with 15.2% of
patients taking placebo. Symptoms of cough and dyspnea were
compared in patients with the presence of new imaging findings
confirmed on chest CT scans versus those without new findings
(Table 4). Dyspnea was reported in 29.0 versus 25.0%, cough in
20.6 versus 16.2%, and cough and dyspnea in 4.7 versus 10.9%,
Results from an exploratory analysis assessing whether the
presence of new radiographic findings were correlated with
improved efficacy (as determined by progression-free survival,
the primary end point of the RECORD-1 trial) indicated that
no relationship was present (Figure 2).
Baseline Radiographic Changes
Baseline radiographic changes were present in 46 patients (17.2%
of all patients taking everolimus) and 9 of 37 patients (24.3%)
identified as having clinical pneumonitis. In patients with grade 3
Grade 1 Grade 2 Grade 3 Grade 4 All Grades
Clinical suspicion of
pneumonitis, n (%)
9 (3.3) 18 (6.6) 10 (3.6) 0 37 (13.5)
Management, n
Steroid administration 0 10 6 0 16
Dose adjustment 2 12 6 0 20
Discontinuation of
Reversibility 3 11* 6
* Plus an additional two patients with partial reversibility.
Plus an additional patient with partial reversibility.
Plus an additional three patients with partial reversibility.
Figure 1. Computed tomography (CT) scan series of representative
cases showing resolution of noninfectious pneumonitis. (A) A 74-year-
old man with metastatic renal cancer developed a cough approxi-
mately 4 months after starting everolimus. Top left: Chest radiograph
showed a slight increase in markings in addition to metastases. Top
right: Subsequent chest CT scan showed stable metastatic nodules but
increased interstitial markings with septal thickening. Bottom left:
Improving infiltrates after holding everolimus and a 2-week course of
steroids. Bottom right: Resolved infiltrates being maintained on a re-
duced dose of everolimus. (B) Approximately 3 months after starting
everolimus, a 63-year-old man with metastatic renal cancer developed
cough and dyspnea with a need for supplemental oxygen. Left: Bilateral
ground-glass opacities with mild reticular interstitial disease, predom-
inantly in the lower lobes. Right: After discontinuation of everolimus
and high-dose corticosteroids, symptoms and infiltrates cleared.
White, Camus, Endo, et al.: Pneumonitis and Everolimus Therapy 399
toxicity, however, baseline radiographic changes were found in 5
of 10 patients (50%).
Pulmonary Function Tests
Results of baseline PFTs in patients with and without clinical
pneumonitis are shown in Table 6, with a separate analysis of
patients with grade 3 pneumonitis. The development of pneu-
monitis was not found to be associated with more impaired
baseline PFTs. In the group without clinical pneumonitis,
baseline PFTs in those with and without new radiographic
infiltrates on CT showed that the mean percentage (standard
deviation [SD]) of predicted forced vital capacity was 83.6
(16.8) versus 83.3 (19.9), respectively; the mean percentage
(SD) of predicted diffusing capacity for carbon monoxide was
43.9 (24.6) versus 44.0 (25.4), respectively.
The mTOR inhibitors are a class of drugs used in the prevention
of solid organ transplant rejection and for the treatment of
advanced RCC. They are under study for use in other cancers
and for treating complications of tuberous sclerosis complex,
including lymphangioleiomyomatosis (24). These drugs have
been associated with a 5–15% incidence of pneumonitis in solid
organ transplant recipients with a wide spectrum of disease
severity, varying from subclinical to fulminant (8, 12–14). Dose
reduction or interruption has been shown to be helpful in some
cases, and corticosteroids have been found to be efficacious in
other cases (5, 8, 10, 25, 26). Similar findings have been found
with the use of temsirolimus and everolimus in the treatment of
cancer, although in this setting, the availability and analysis of
serial CT scans during treatment have suggested the occurrence
of a higher incidence of asymptomatic radiographic abnormal-
ities (5, 15, 17–19). This may be related to the frequency of CT
scans during cancer studies leading to increased detection, use
of different dosing regimens, or the routine use of other im-
munosuppressive agents (including corticosteroids) to prevent
rejection in the lung or other solid organ transplant setting.
The presentation of mTOR inhibitor–related pneumonitis is
usually with cough and dyspnea, although systemic symptoms of
fever and fatigue have been reported in some cases (5, 6, 10, 25,
26). Radiographs have shown areas of ground-glass attenuation
and patchy consolidation, and pulmonary function tests have
shown either a restrictive pattern or an isolated reduction in
diffusing capacity (5, 10, 25, 26).
The etiology of the pneumonitis related to mTOR inhibitors
remains speculative. Clinicopathological patterns include in-
terstitial pneumonitis with or without fibrosis, bronchiolitis
obliterans organizing pneumonia (8, 10, 12, 27, 28), alveolar
hemorrhage (10, 29, 30), and lymphocytic interstitial pneumonia
(9). Limited evidence also exists for granulomatous interstitial
lung disease, a desquamative interstitial pneumonia or pulmo-
nary alveolar proteinosis pattern, pulmonary vasculitis, and
necrosis (29, 31). Helper T-cell lymphocytosis has been reported
in bronchoalveolar lavage (10, 32). Although it is not fully
understood, hypersensitivity mechanisms are supported by lung
biopsies, bronchoalveolar lavage findings, and the observed
clinical response to corticosteroids. It has been hypothesized
that a cell-mediated autoimmune response may occur if siroli-
mus exposes cryptic antigens that continue to induce an immune
response and subsequent pneumonitis (26). In addition, it is
speculated that the high affinity of sirolimus for plasma proteins
may render it immunogenic as a hapten with ongoing T-cell
recognition of the processed antigen complex (10). Pneumonitis
appears be dose dependent in some individuals who tolerate
lower doses or in whom the disease abates on reduction in drug
dosage. Although there are clinical and pathological similarities
of pneumonitis with all mTOR inhibitors, relapse does not
always occur after switching to another agent (33).
The rate of investigator-reported pneumonitis in patients
with advanced RCC, based on data obtained in the RECORD-1
study in which everolimus therapy was compared with placebo,
was 13.5% with everolimus. There were no reports in the
placebo group. This rate of clinical pneumonitis is consistent
with the literature for temsirolimus, with symptomatic rates of
18% in patients with cancer (5). Drug-induced lung disease can
be difficult to establish, as there are no pathognomonic findings.
In this study, the diagnosis was made clinically in most cases,
Everolimus 10 mg Placebo
Radiographic studies available for review, n (%) 245 (89.4) 132 (96.4)
Radiographic findings consistent with
noninfectious pneumonitis, n (%)
At baseline 47 (17.2) 26 (19.0)
Postbaseline 144 (52.6) 36 (26.3)
Newly occurring or worsened change, n (%) 132 (53.9) 20 (15.2)
No clinical pneumonitis 95 (38.9) 20 (15.2)
Figure 2. Kaplan-Meier probability curve of progression-free survival
based on the absence/presence of new radiographic findings consistent
with pneumonitis.
Grade 3
n 237 37 10
n 226 34 9
Mean, L (SD) 3.5 (1.0) 3.8 (0.8) 3.4 (0.9)
Mean % predicted (SD) 83.1 (19.0) 88.5 (18.6) 77.0 (20.0)
Median % predicted 83.8 88.1 75.7
n 227 34 9
Mean, L (SD) 2.6 (0.8) 2.7 (0.6) 2.6 (0.6)
Mean % predicted (SD) 79.0 (20.1) 82.7 (18.2) 74.1 (19.8)
Median % predicted 80.8 80.1 72.8
n 175 27 6
Mean, ml/min/mm Hg (SD) 13.2 (7.9) 17.5 (10.0) 19.3 (6.8)
Mean % predicted (SD) 42.7 (24.7) 55.7 (26.4) 59.4 (22.1)
Median % predicted 34.3 56.8 58.4
Definition of abbreviation:D
5diffusing capacity for carbon monoxide.
with bronchoscopy only occasionally used. This approach is
common in patients with advanced cancer and was successful in
managing the patients in this study.
Pulmonary toxicity developed from 3.4 to 36.7 weeks (me-
dian, 15.4 wk) after starting treatment, similar to other mTOR
inhibitors. We found radiographic patterns to be quite variable,
from ground-glass infiltrates to more diffuse infiltrates, with the
patterns frequently changing over time. As anticipated, chest
CT had a higher sensitivity than CXR for the detection of
pneumonitis, although the latter improved in sensitivity as the
grade of toxicity increased.
Baseline radiographic abnormalities were present in 17% of
all of those receiving everolimus and in 24% of those with
clinical pneumonitis, but were noted in 50% of patients with
grade 3 toxicity. The presence of baseline radiographic abnor-
malities contributing to an increased risk of serious toxicity
previously has been noted for other drugs, notably gefitinib,
erlotinib, methotrexate, leflunomide, and temsirolimus as well
as with everolimus (19, 34–39). Baseline PFTs did not identify
patients with an increased risk of pneumonitis or predict its
Patients identified as having pneumonitis during the study
were managed on the basis of suggested guidelines according to
severity (Table 1). In our study, 8 of the 10 patients with grade 3
toxicity had a favorable outcome subsequent to treatment
according to the management suggestions; of the other 2
patients, 1 died of candidal pneumonia and sepsis, and the
other died as a result of progressive RCC and ARDS.
As previously noted with temsirolimus, we found a high
frequency of new radiographic findings during everolimus
treatment on dedicated CT scan review without a suspected
diagnosis of pneumonitis. These were found in 38.9% of
patients taking everolimus compared with 15.2% taking pla-
cebo. In those patients, no interruption of therapy occurred, and
higher-grade toxicity did not develop during the period of
observation. The nature and significance of these radiographic
findings are not completely known. Transitory radiographic
abnormalities are common in those with advanced cancer and
multiple comorbidities on surveillance scans. The higher fre-
quency with everolimus may represent a low grade of drug
toxicity not clinically detected, but also may reflect other
changes occurring in the lungs during cancer therapy, such as
capillary leak or an alteration of normal immune responses to
inhaled antigens. Knowledge of the occurrence of new radio-
graphic findings that may be transitory during treatment is
important clinically to help determine appropriate interven-
On the basis of our data, we recommend the following
essentially noninvasive management for pneumonitis occurring
during everolimus treatment, particularly in the context of
cancer or RCC:
dGrade 1: For patients with radiological changes suggestive
of pneumonitis but with few or no symptoms, everolimus
therapy may be continued without dose adjustment in
most cases. Follow-up with careful clinical assessment
should be performed at each visit, with routine radio-
graphic follow-up if asymptomatic. Exceptions should be
considered if there is baseline pneumonitis or if the
infiltrates are extensive, and these patients could be
managed more aggressively. Patients should be specifically
cautioned to report respiratory symptoms immediately.
Those with baseline radiographic findings should have
close interval assessment with chest CT and/or be man-
aged as having grade 2 toxicity.
dGrade 2: Patients with moderate symptoms may be man-
aged by temporary interruption or a decrease in dose to
5 mg daily with close observation for resolution of symp-
toms. Corticosteroids may be helpful for troublesome
symptoms if dose alteration is not effective. Diagnostic or
therapeutic measures to exclude an infectious origin or
other causes of radiographic infiltrates/respiratory symp-
toms, such as fluid overload or pulmonary embolus, should
be performed, preferably before starting corticosteroids.
With improvement to an asymptomatic status, everolimus
may be reintroduced, if interrupted, at a reduced dose of
5 mg daily with close observation.
dGrade 3: For patients whose symptoms are severe, ever-
olimus should be discontinued and the use of corticoste-
roids may be indicated until clinical symptoms resolve.
Therapy with high-dose methylprednisolone in patients
with respiratory distress is recommended; lower doses of
corticosteroids may be used in less severe cases. It is
essential that an appropriate work-up, including bronchos-
copy and other diagnostic tests as indicated, be done to
exclude any infectious etiology, particularly given the risk
of opportunistic infection with the mTOR inhibitors.
Other causes such as pulmonary emboli or progressive
metastatic disease also should be considered. In general,
for any patient with significant respiratory compromise,
corticosteroids should be given urgently while the evalu-
ation is proceeding. With resolution of evidence of toxic-
ity, everolimus should be reinitiated at a reduced dose of
5 mg daily in select clinical circumstances with proven
advantage and close follow-up.
dGrade 4: For patients with life-threatening complications,
everolimus should be permanently discontinued. Cortico-
steroids should be given and an appropriate evaluation to
exclude other possible etiologies performed. Everolimus
should not be reinstituted even with resolution of pneu-
Both CXRs and CTs are used for monitoring during cancer
treatment. The CXR was less sensitive in detecting asymptom-
atic radiographic findings and also clinical pneumonitis. Sensi-
tivity for detection of pneumonitis did improve with increasing
grade of toxicity. CTs have the benefit of earlier detection of all
grades of pneumonia and are often helpful in determining the
extent of abnormalities and the differential diagnosis. If CXR
rather than CT is used for monitoring during treatment, it is
essential that a CT be performed for any patient with new
respiratory symptoms and a negative CXR and for evaluation
of more severe cases of toxicity. A cost–benefit analysis is not
Some issues were not addressed in this study. One is the
possibility of reescalation of dose with resolution of toxicity on
a reduced dose with or without the use of chronic corticoste-
roids. The role of PFTs in managing toxicity was also not
addressed; however, the authors suggest they may be useful in
some patients to determine the level of physiological impair-
ment. This would include patients with baseline radiographic
changes with the potential for higher level toxicity to help
determine the level of impairment in those with extensive
radiographic findings and few or no symptoms, and to monitor
the effect of interventions such as dose reduction/discontinua-
tion and corticosteroids, in conjunction with imaging. Specific
management of patients with baseline radiographic findings was
not addressed, but it may be prudent to use closer interval
radiographic assessment for this group.
White, Camus, Endo, et al.: Pneumonitis and Everolimus Therapy 401
Everolimus has been shown to prolong progression-free sur-
vival in patients with advanced RCC (2). Drug-related toxicity
can occur during treatment with everolimus and should be
considered in patients presenting with nonspecific respiratory
signs and symptoms (including hypoxia, cough, or dyspnea) or
unexplained radiographic findings and in whom infectious,
neoplastic, and other noniatrogenic, causes have been excluded
by appropriate investigation. A relatively high incidence of low-
grade radiographic abnormalities may be anticipated during
treatment. It is important to recognize possible pneumonitis
to avoid considering this pulmonary event as progression of
disease or infection, and because early recognition and prompt
intervention are important in managing the risk associated
with pneumonitis. Guidelines are given for this cancer setting;
however, this general approach may also be useful for pneu-
monitis occurring with mTOR inhibitors in other settings.
Author Disclosure:D.A.W. received $10,001–$50,000 from Novartis Pharmaceu-
tical in consultancy fees (Safety Committee for study; reviewing data), $1,001–
$5,000 from Novartis Pharmaceutical for serving on the Pulmonary Advisory
Board, and $1,001–$5,000 from Novartis Pharmaceutical for lectures at in-
vestigator meetings. P.C. received $1,001–$5,000 from Merck, Pierre Fabre,
Pfizer, and Novartis in advisory board fees, and up to $1,000 from Roche in
lecture fees. M.E. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. B.E. received $1,001–
$5,000 from Roche, Bayer, and Novartis in consultancy fees and $5,001–$10,000
from Bayer, Roche, Pfizer, and Novartis in advisory board fees. E.C. received
$50,001–$100,000 from Pfizer in consultancy fees, $1,001–$5,000 from Novar-
tis, Pfizer, and Roche and up to $1,000 from Bayer in advisory board fees,
$5,001–$10,000 from Novartis, and $1,001–$5,000 from Pfizer, Roche, and
Bayer in lecture fees, $100,001 or more from Wyeth for investigator-initiated
research, $100,001 or more from Roche, Novartis and Bayer for contracted
research, and $100,001 or more from Pfizer for contracted research and IIR in
industry-sponsored grants. H.A. received $1,001–$5,000 from Novartis Pharma
KK for serving as a medical advisor of everolimus (RAD001) and $1,001–$5,000
from Novartis Pharma KK for (promotional) presentation in seminar. H.U.
received $1,001–$5,000 from Novartis Pharma KK for serving as a medical
advisor of everolimus (RAD001), $1,001–$5,000 from Novartis Pharma KK for
(promotional) presentation in seminar, and up to $1,000 from Novartis Pharma
KK in compensation for participation in an investigator meeting. E.K. is a full-time
employee of Novartis Pharmaceuticals Corp. A.K. is an employee of Novartis,
holds a patent from Novartis (Serum LDH Predicts Response to VEGF Inhibitors in
Cancer), and holds more than $100,001 in stock ownership or options in
Novartis. M.R. is a full-time employee of Novartis Pharmaceuticals Corp. and
has stock ownership or options in the company. A.R. received $1,001–$5,000
from Pfizer, Bayer Schering, Roche, Novartis, and GlaxoSmithKline in advisory
board fees, $1,001–$5,000 from Pfizer, $1,001–$5,000 from Roche, Pfizer, and
Novartis in lecture fees, up to $1,000 from AFSSAPS for serving as an expert
witness, and up to $1,000 from INCa in advisory board fees. A.R.’s dependent
received more than $100,001 from Pfizer and $10,001–$50,000 from Novartis,
Roche, and GlaxoSmithKline in institutional grants. R.J.M. received $1,001–
$5,000 from Novartis in advisory board fees, $50,001–$100,000 from Novartis,
Pfizer, and GlaxoSmithKline in industry-sponsored grants.
Acknowledgment: The following investigators recruited patients to RECORD-1
(listed in alphabetical order by country): Australia—I. Davis, D. Goldstein,
H. Gurney, P. Mainwaring, K. Pittman; Canada—S. Ades, T. Cheng, S. Hotte,
J. Knox, Y.-J. Ko, M. MacKenzie, S. North; France—A. Caty, C. Chevreau, B.
Duclos, B. Escudier, S. Negrier, S. Oudard, A. Ravaud, F. Rolland; Germany
P. Albers, J. Beck, L. Bergmann, V. Gru
¨nwald, J. Gschwend; Italy
E. Bajetta, F. Boccardo, S. Bracarda, G. Carteni, P.F. Conte, R. Passalacqua,
C. Porta, C. Sternberg; Japan—H. Akaza, M. Eto, H. Fujimoto, Y. Hamamoto, H.
Kanayama, M. Maruoka, M. Niwakawa, N. Shinohara, Y. Sumiyoshi, A. Terai, N.
Tsuchiya, T. Tsukamoto, H. Uemura, M. Usami; The Netherlands
G. Groenewegen, S. Osanto, F. Van Den Eertwegh, C. Van Herpen; Poland
J. Pikiel, A. Pluzanska, C. Szczylik, R. Zdrojowy; Spain—E. Calvo, D.
Castellano, M. Climent, F. del Muro, P. Maroto; United States—C. Alemany,
T. Anderson, L. Appleman, J. Beck, W. Berry, M. Danso, A. Dudek, R. Figlin, N.
Gabrail, D. George, R. Gersh, M. Gordon, G. Guzley, J. Hajdenberg, J. Hamm,
A. Hussain, T. Hutson, P. Lara, D. Loesch, T. Logan, R. Motzer, K. Rathmell, D.
Schlossman, D. Smith, J. Thompson, U. Vaishampayan, N. Vogelzang. The
authors thank the patients and their families for their participation in the study
and Peter Berry (Novartis Oncology) and Victoria A. Robb, Ph.D. (Scientific
Connexions), for assistance in the preparation of this manuscript.
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White, Camus, Endo, et al.: Pneumonitis and Everolimus Therapy 403
... Hypersensitivity pneumonitis (HP) is a rare adverse effect, initially described in patients under SRL, probably because this was the first approved mTORi, but more recently recognized as a class side effect 11,12 . The lack of uniform diagnostic criteria led to wide reported incidence rates 13 . ...
... The exact pathophysiology is unknown, with both immune-mediated and direct toxicity mechanisms already described. A dose-dependent mechanism is suspected, because HP rates are higher in the oncology setting, as higher doses are used when compared to solid organ transplantation 12,13 . An immunological mechanism was suggested because of the lymphocytosis and eosinophilia is detected on bronchoalveolar lavage (BAL) (see ahead). ...
... MTORi-induced HP is mainly asymptomatic, or just mildly symptomatic with dry cough, dyspnea, hypoxia, occasionally with hemoptysis and systemic symptoms, such as fever and fatigue. Rarely, symptoms are severe and may progress to potentially life-threatening disease requiring mechanical ventilation 1,12,13,16,17 . The reported time for HP onset is wide, from months to years 12,13 . ...
Objective: The purpose of this report was to describe the clinical features of mammalian target of rapamycin inhibitors (mTORi) pulmonary toxicity in kidney recipients. Material and methods: We analyzed clinical, analytical, and image data of all kidney recipients who were immunosuppressed with everolimus or sirolimus, between 2013 and 2018. Results: From a pool of 379 recipients, 12 presented evidence of mTORi-induced hypersensitivity pneumonitis. The median age at onset of pneumonitis was 62.8 years. The majority had chronic graft dysfunction, with a median serum creatinine of 1.9 mg/dL. All patients were under mTORi for at least 2 years. The most common symptoms were cough and fever. Chest computerized tomography documented ground-glass opacities and lower lobe involvement in all patients. Two required mechanical ventilation, one of which died (the only dead in this series). Conclusions: The size of this sample does not allow inferring about risk factors or prognosis predictors. However, most patients were male, with chronic graft dysfunction and exposure to mTORi for at least 2 years. MTORi-induced pneumonitis is rare but potentially fatal. It should be included in the differential diagnosis of pulmonary conditions in these patients.
... Pneumonia is an immune-related adverse event defined as focal or diffuse inflammation of the lung parenchyma, and its incidence in studies with anti-PD-1/PD-L1 mAbs ranges from 0% to 10% [104]. Drug-related pneumonia can also occur with chemotherapy (docetaxel [105], gemcitabine [106], bleomycin [107]), targeted therapy (epidermal growth factor receptor inhibitors [108,109], mammalian target of rapamycin inhibitors [110]), and radiotherapy [111,112]. ...
Full-text available
Due to the increasing number of COVID-19-infected and vaccinated individuals, radiologists continue to see patients with COVID-19 pneumonitis and recall pneumonitis, which could result in additional workups and false-positive results. Moreover, cancer patients undergoing immunotherapy may show therapy-related pneumonitis during imaging management. This is otherwise known as immune checkpoint inhibitor-related pneumonitis. Following on from this background, radiologists should seek to know their patients’ COVID-19 infection and vaccination history. Knowing the imaging features related to COVID-19 infection and vaccination is critical to avoiding misleading results and alarmism in patients and clinicians.
... Everolimus is a mammalian target of rapamycin (mTOR) inhibitor. Everolimus-related pneumonitis has relatively higher incidence rates (of 13.5%)compared to other chemotherapeutic drugs, as White et al. indicated [18]. The incidence rate of everolimus-related pneumonitis, with CTCAE grade 3 or 4 was 0-9% [19]; however, OP and NSIP patterns are common and the HP pattern is rare [20]. ...
Full-text available
Novel therapies have recently emerged for various diseases, and the management of drug-related pneumonitis (DRP) has become increasingly important. In particular, the hypersensitivity pneumonitis (HP) pattern of DRP has been increasingly recognized due to development of new therapeutic strategies, such as immunotherapy. However, literature describing detailed clinical cases is still lacking. Herein, we report three cases of DRP with typical HP radiographic pattern. These patients were treated with different drugs, namely nano albumin-bound (nab)-paclitaxel, everolimus, or nivolumab, but had common clinical features, including a good prognosis.
... Even in case of neuropsychiatric disorders in TSC patient, rapalogs failed to demonstrate effectiveness (98). In addition, clinicians are reluctant to use rapalogs stemming from concern about severe side effects (originally rapalogs developed as an immunosuppressant drug) including developmental delay and infection (96,(99)(100)(101). In previous clinical trials, mTOR inhibitors resulted in severe side effects of grade 3 or 4 (102). ...
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Brain somatic mutations confer genomic diversity in the human brain and cause neurodevelopmental disorders. Dysregulation of eukaryotic initiation factor 4E (eIF4E), which is a core translational regulator, is a common molecular hallmark in various neurological disorders. Individuals carrying inherited mutations in the mechanistic target of rapamycin (mTOR) or Ras/mitogen-activated protein kinase (MAPK) pathway, upstream activators of eIF4E, have abnormalities in translation and are prone to developing epilepsy, megalencephaly, autism spectrum disorder (ASD), brain tumor, and neuropshychiatric disorder. It has been hypothesized that brain somatic mutation that activates eIF4E is a potential culprit of neurological disorders. Here we report for the first time a mouse model with behavioral abnormalities including anxiety, defective sociability, deficits in repetitive behavior, and anhedonia caused by brain somatic mutation in MTOR. Recently, brain somatic activating mutations in MTOR have been identified as a major etiology of intractable epilepsy in patients with cortical malformations. However, the molecular genetic mechanism of how brain somatic mutations in MTOR cause intractable epilepsy has remained elusive. In this study, translational profiling of intractable epilepsy mouse models with brain somatic mutations and genome-edited cells revealed a novel translational dysregulation mechanism and mTOR activation–sensitive targets mediated by human MTOR mutations that lead to intractable epilepsy with cortical malformation. These mTOR targets were found to be regulated by novel mTOR-responsive 5′-UTR motifs, distinct from known mTOR inhibition–sensitive targets regulated by 5′ terminal oligopyrimidine motifs. Novel mTOR target genes were validated in patient brain tissues, and the mTOR downstream effector eIF4E was identified as a new therapeutic target in intractable epilepsy via pharmacological or genetic inhibition. We show that metformin, an FDA-approved eIF4E inhibitor, suppresses intractable epilepsy. However, there is no clinically relevant drug which specifically inhibits eIF4E in the brain. We found that antisense oligonucleotides (ASO) directed at eIF4E in the brain downregulated eIF4E and reversed the behavioral, neurophysiological, and bio-chemical abnormalities in mouse model with brain somatic mutation in MTOR. Altogether, the present study describes behavioral, neurophysiological, and biochemical abnormalities resulting from eIF4E dysregulation by mTOR pathway activation, and its therapeutic reduction could represent a promising and broadly effective translational therapy for neurological disorders where eIF4E is dysregulated. Altogether, the present study describes translational dysregulation resulting from brain somatic mutations in MTOR, as well as the pathogenesis and potential therapeutic targets of intractable epilepsy.
Introduction Les inhibiteurs de mTOR (mammalian target of rapamycin), initialement utilisés comme immunosuppresseurs en transplantation d’organe solide, ont vu leurs indications s’étendre au domaine de l’oncologie médicale en raison de leurs propriétés antitumorales. La toxicité pulmonaire des inhibiteurs de mTOR est rapportée dans les deux indications [1], [2], mais peu d’études ont exploré les différences entre les pneumopathies aux inhibiteurs de mTOR (mTOR-PI) en transplantation (T) et en oncologie (K). L’objectif de notre étude est de comparer les mTOR-PI dans ces deux populations. Méthodes Notre étude rétrospective monocentrique a été réalisée dans un centre expert en pneumopathies interstitielles, en transplantation et en oncologie (Hôpital Européen Georges Pompidou). Quatre bases de données ont été utilisées afin d’assurer la collecte exhaustive de tous les cas de mTOR-PI entre 2001 et 2020. Toutes les données cliniques, biologiques, radiologiques et pathologiques ainsi que les résultats ont été collectés et analysés. Résultats Trente-neuf patients atteints de mTOR-PI ont été diagnostiqués pendant cette période, 24 en transplantation et 15 en oncologie. La posologie moyenne de l’inhibiteur de mTOR était respectivement de 2,7 mg (±1,7) et 8,8 mg (±2,3). La prévalence globale de mTOR-PI était de 6,4 % avec un délai médian de survenue de 7 mois [IQR 3–35 mois]. Les mTOR-PI étaient significativement plus fréquentes (p < 0,001) et survenaient plus précocement (p < 0,001) chez les patients K. Aucune autre différence clinique, fonctionnelle, radiologique, pathologique ou de sévérité n’a été observée entre les deux groupes. Au moment du diagnostic de mTOR-PI, 14/18 (78 %) des patients transplantés avaient un taux résiduel d’éverolimus dans les normes des valeurs thérapeutiques recommandées. Conclusion Les pneumopathies aux inhibiteurs de mTOR sont comparables en termes de présentation chez les patients T et K, mais elles surviennent significativement plus tôt après l’introduction du médicament chez ces derniers. Cela pourrait être en partie lié aux différences de posologie utilisées dans ces deux populations.
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Gaetano Pezzicoli,1,2 Elisabetta Filoni,1,2 Angela Gernone,2 Laura Cosmai,3 Mimma Rizzo,4 Camillo Porta2,5 1Department of Biomedical Sciences and Human Oncology, Post-Graduate School of Specialization in Medical Oncology, University of Bari ‘A. Moro’, Bari, Italy; 2Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy; 3Onconephrology Outpatient Clinic, Division of Nephrology and Dialysis, A.S.S.T. Fatebenefratelli-Sacco, Fatebenefratelli Hospital, Milan, Italy; 4Division of Translational Oncology, I.R.C.C.S. Istituti Clinici Scientifici Maugeri, Pavia, Italy; 5Chair of Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari ‘A. Moro’, Bari, ItalyCorrespondence: Camillo PortaDivision of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Piazza Giulio Cesare, 11, Bari, 70124, ItalyTel +39-080-5594167Fax +39-080-5593477Email; camillo.porta@uniba.itAbstract: In the last decade, the inhibition of the mechanistic target of Rapamycin (mTOR) in renal clear cell carcinoma (RCC) has disappointed the clinician’s expectations. Many clinical trials highlighted the low efficacy and unmanageable safety profile of first-generation mTOR inhibitors (Rapalogs), thus limiting their use in the clinical practice only to those patients who already failed several therapy lines. In this review, we analyze the major resistance mechanisms that undermine the efficacy of this class of drugs. Moreover, we describe some of the possible strategies to overcome the mechanisms of resistance and their clinical experimentation, with particular focus on novel mTOR inhibitors and the combinations of mTOR inhibitors and other anti-cancer drugs.Keywords: everolimus, temsirolimus, Rapa-Link, anti-angiogenics, autophagy
Interstitial lesion is one of the causes of respiratory failure. Drugs are a modifiable etiological factor of lung damage. Medications most commonly associated with drug-induced interstitial lung disease include antineoplastic drugs, disease-modifying anti-rheumatic drugs and amiodarone. According to the latest literature data, the previously described link between anti-rheumatic drugs and interstitial lung diseases is very inconsistent. It may even be a protective effect of this group of drugs on the lung tissue. The relationship between statin use and interstitial lesions is also complex and not fully understood. It is necessary to carefully assess the appearance of respiratory tract complaints in patients taking statins as in other groups of patients. Prescription of additional diagnostic methods is necessary to close monitoring and prevention the toxic effect of these drugs. These actions, as well as the potential prescription of steroid therapy and change in the underlying disease treatment approaches, are an important factor in reducing the incidence of respiratory failure in the population.
A 27-year-old man, with a history of renal transplantation, presented with acute kidney failure and Pneumocystis jirovecii pneumonia. The patient developed severe acute respiratory failure and required support by veno-venous extracorporeal membrane oxygenation for a total of 59 days. During this period, the patient had extremely low tidal volumes using a lung protective ventilation strategy and intermittent prone positioning was used to optimise oxygenation. There was full recovery of pulmonary and partial recovery of renal function.
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To assess the incidence and radiographic and clinical presentation of pneumonitis associated with the mammalian target of rapamycin inhibitor everolimus in patients with advanced non-small cell lung cancer. A retrospective, centralized review of serial computed tomography scans and corresponding clinical data from patients with advanced non-small cell lung cancer treated with 10-mg oral once daily everolimus monotherapy in a phase II clinical study was conducted. Serial chest CT scans underwent a consensus read by two radiologists for presence of pneumonitis. These cases were then reviewed with corresponding clinical data by a pulmonologist to assess the suspected causality to everolimus and outcome. Twenty-four of 64 patients reviewed were found to have radiographic evidence of pneumonitis. In 16 of these 24 patients, pneumonitis was suspected as either possibly (12) or probably (4) related to everolimus. The most common radiographic manifestations were focal areas of consolidation at the lung bases or ground-glass opacities. Pneumonitis evaluated with Common Terminology Criteria for Adverse Events (version 3) was grade 1 or 2 in 12 of 16 suspected cases, with 4 patients experiencing higher grades. In most of the patients, pneumonitis remained at the same or lower grade without discontinuation of therapy. Patients with evidence of interstitial lung disease at baseline had an increased risk of Common Terminology Criteria for Adverse Events grade more than or equal to 3 pneumonitis. Within the limitation of this retrospective study, results suggest that a mostly low-grade pneumonitis with a possible or probable relationship to everolimus was relatively frequent, occurring in 25% of evaluated patients. These results suggest a need for monitoring of pulmonary adverse events and the development of guidelines for managing pneumonitis in future studies with everolimus.
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To evaluate the safety and efficacy of oral everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in two different schedules in minimally pretreated patients with metastatic breast cancer and to explore for possible biologic correlates of response. Patients who received no or one prior chemotherapy regimen for metastatic breast cancer were entered onto this multicenter, noncomparative, randomized phase II study of everolimus 10 mg daily versus 70 mg weekly; the multinomial end points of response and progression were evaluated at 8 weeks. A two-stage accrual design was used, with 15 evaluable patients in each schedule in stage 1. Only daily therapy met criteria for continuing, and another 15 patients were added. pAKT, PTEN, carbonic anhydrase 9, estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were evaluated for possible correlation with response. The most common drug-related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough, and pneumonitis. Pneumonitis occurred at higher than expected rates and seemed to be schedule dependent, with the highest incidence on the daily schedule. Response rate with daily therapy was 12% (95% CI, 3.4% to 28.2%) compared with 0% (95% CI, 0.0% to 20.6%) for weekly therapy. Twenty-seven percent of patients on daily therapy discontinued treatment compared with 13% on weekly therapy (16% v 6% with pneumonitis, respectively). No biologic correlates of response could be identified, although there were trends favoring benefit in ER-positive and HER2-negative metastatic breast cancer. Oral everolimus has activity in metastatic breast cancer that is schedule dependent. Daily therapy with 10 mg is worthy of further study in this patient population.
Inhibitors of mTOR (mammalian target of rapamycin) are immunosuppressants with less nephrotoxic potential than calcineurin inhibitors and antiproliferative effects, which are advantageous in the case of malignancy. However, a series of adverse events has been reported with the first-generation mTOR inhibitor sirolimus that includes hypersensitivity-like interstitial pneumonitis. To our knowledge, only one case of a pneumonitis associated with everolimus in a heart transplant patient has been reported, and it was related to elevated trough blood levels. We report herein the first case of a kidney graft recipient who developed everolimus-associated pneumonitis with normal trough blood levels that was completely reversed after drug withdrawal.
Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy. Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with, number NCT00410124. All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0.30, 95% CI 0.22-0.40, p<0.0001; median progression-free survival 4.0 [95% CI 3.7-5.5] vs 1.9 [1.8-1.9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity. Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies.
To review all the current evidence of LEF-induced pneumonitis (LEIP) which will help rheumatologists recognize suspected cases of LEIP and to influence clinical guidelines. Thirty-two reported cases of LEIP (13 males and 19 females) were identified from a literature search and classified using Searles and McKendry's classification criteria. Their clinical characteristics were reviewed. All patients had a history of either exposure to MTX or interstitial lung disease (ILD) or both and all patients had RA. Most patients (82%) had LEIP within the first 20 weeks of initiation of LEF. All patients who had a loading dose LEF and most patients with ILD developed LEIP early (within 12 weeks of exposure). Case mortality was 19%. Two patients had previous MTX-induced pneumonitis (MTX-P) prior to initiation of LEF; both died from LEIP. There was a high mortality in the following groups of patients: diffuse alveolar damage (DAD) on histological examination, pre-existing ILD and ground glass shadowing on high resolution computerised tomography (HRCT). Treatment with cholestyramine did not appear to alter clinical outcome. LEIP usually occurs within the first 20 weeks of initiation of LEF. Clinical features of patients who died were pre-existing ILD, ground glass shadowing on HRCT and DAD on histological examination, and these could be poor prognostic indicators. Patients need to be made aware of this rare complication. LEF should not be used in patients with previous MTX-P and should be used with caution in patients with ILD.