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International Lung Cancer Consortium
Information Research
SoDr 1667 Roche Pharma_Layout 1 28.08.13 14:48 Seite 1
Volume 90, November 2015, Pages 267–273
e-print
Anti-angiogenic-specific adverse events in patients with non-small cell lung cancer treated with nintedanib and docetaxel
Martin Reck, Anders Mellemgaard, Joachim von Pawel, Maya Gottfried, Igor Bondarenko, Ying Cheng, Kostas Zarogoulidis, Alexander Luft, Jaafar Bennouna, José Barrueco, Hesham Aboshady, Julia Hocke, Rolf Kaiser, Jean-Yves Douillard, for the LUME-Lung 1 Study Group
http://dx.doi.org/10.1016/j.lungcan.2015.08.003
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Lung Cancer 90 (2015) 267–273
Contents lists available at ScienceDirect
Lung Cancer
jou rn al hom epage: www.elsev ier .com/ locate / lungcan
nti-angiogenic-specific adverse events in patients with non-smallell lung cancer treated with nintedanib and docetaxel
artin Recka,∗, Anders Mellemgaardb, Joachim von Pawelc, Maya Gottfriedd,gor Bondarenkoe, Ying Chengf, Kostas Zarogoulidisg, Alexander Lufth, Jaafar Bennounai,osé Barruecoj, Hesham Aboshadyj, Julia Hockek, Rolf Kaiserk,ean-Yves Douillard i, for the LUME-Lung 1 Study GroupDepartment of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung ResearchDZL), Grosshansdorf, GermanyDepartment of Oncology, Herlev University Hospital, Herlev, DenmarkPneumology Clinic, Asklepios Fachkliniken, Gauting, GermanyLung Cancer Unit, Meir Medical Center, Kfar Saba, IsraelClinical Facility, Dnepropetrovsk Medical Academy, Clinical Hospital #4, Dnepropetrovsk, UkraineDivision of Thoracic Oncology, Jilin Province Cancer Hospital, Changchun, ChinaPulmonary Department-Oncology Unit, General Hospital of Thessaloniki, Thessaloniki, GreeceDepartment of Thoracic Surgery, Leningrad Regional Clinical Hospital, St. Petersburg, RussiaDepartment of Medical Oncology, Centre René Gauducheau, Nantes, FranceBoehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USABoehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
r t i c l e i n f o
rticle history:eceived 11 June 2015eceived in revised form 4 August 2015ccepted 8 August 2015
eywords:on-small cell lung cancerngiogenesis inhibitorsrug-related side effects and adverse
eactions
a b s t r a c t
Objectives: LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigatingnintedanib + docetaxel versus placebo + docetaxel in patients with advanced NSCLC progres-sing after first-line chemotherapy. Progression-free survival was significantly improved withnintedanib + docetaxel in the overall population and overall survival was significantly improved in thepre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristicadverse events (AEs) commonly seen with existing anti-angiogenic agents.Materials and methods: The incidence and intensity of AEs were evaluated in all patients who received atleast one dose of study medication (N = 1307) and for the two main histologies: adenocarcinoma (n = 653)and squamous cell carcinoma (SCC; n = 553). AEs of special interest were analyzed by category, preferredterm, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events,and skin disorders.Results and conclusion: The incidence of patients with all-grade gastrointestinal (GI) perforations waslow and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perfora-tions was 1.2% with nintedanib + docetaxel versus 0.2% with placebo + docetaxel. The incidence of someevents was higher with nintedanib + docetaxel versus placebo + docetaxel; hypertension (3.5% vs 0.9%),rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reac-tions were predominantly Grade 1–2 with both treatments. The incidence of all-grade bleeding was alsoslightly higher in nintedanib + docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatmentdifferences in the SCC subpopulation; most events were Grade 1–2. The proportion of patients with a
thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3(2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib + docetaxel. Survival benefits from addition of nintedanib toachieved alongside a managea∗ Corresponding author at: Department of Thoracic Oncology, Lung Clinic GrosshansdoE-mail address: [email protected] (M. Reck).
ttp://dx.doi.org/10.1016/j.lungcan.2015.08.003169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.
docetaxel in patients with adenocarcinoma after first-line therapy can beble safety profile.
© 2015 Elsevier Ireland Ltd. All rights reserved.
rf, 22927 Grosshansdorf, Germany.
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68 M. Reck et al. / Lung
. Introduction
Vascular endothelial growth factor (VEGF) plays the mostmportant role in regulating tumor-related angiogenesis and isften highly expressed in human cancers making it a preferredarget for antitumor therapy [1,2]. With the introduction of VEGFnhibitors for cancer treatment, new class-specific adverse eventsAEs) for these drugs have been observed, including perforations,leeding, thromboembolic events, hypertension, and proteinuria3,4]. Skin-related AEs are also often associated with the anti-VEGFmall-molecule tyrosine kinase inhibitors sorafenib and sunitiniblthough these effects are not related directly to VEGF inhibition3,5].
In addition to VEGF, various other signaling pathways mediateumor angiogenesis, growth, and metastasis (e.g., platelet-erived growth factor [PDGF], fibroblast growth factor [FGF]) [6].intedanib is an oral, twice-daily, triple angiokinase inhibitor tar-eting VEGF receptors 1–3 (VEGFR-1 to -3), PDGF receptors �/�PDGFR-� and -�), and FGF receptors 1–3 (FGFR-1 to -3), as wells rearranged during transfection (RET) receptor tyrosine kinasend fms-like tyrosine kinase receptor-3 (FLT3) [7,8]. Nintedanib hasegligible drug–drug interactions via cytochrome P450 (CYP450)9], and a manageable safety profile in combination with docetaxel,emetrexed, carboplatin/paclitaxel, and afatinib [8,10–12]. LUME-ung 1 (NCT00805194;1199.13), a randomized, placebo-controlled,hase III trial that investigated nintedanib plus docetaxel in patientsith advanced non-small cell lung cancer (NSCLC) progressing
fter first-line chemotherapy, demonstrated that nintedanib plusocetaxel significantly improved median progression-free survivalegardless of histology (median 3.4 vs 2.7 months; hazard ratioHR] = 0.79 [95% confidence interval [CI]: 0.68–0.92], p = 0.0019) [8].he addition of nintedanib to docetaxel also significantly improvededian overall survival in the pre-specified population of patientsith adenocarcinoma histology (12.6 vs 10.3 months; HR = 0.83
95% CI: 0.70–0.99], p = 0.0359). AEs with nintedanib plus docetaxelere manageable with adequate treatment, dose interruptions, andose reductions, and the most frequently reported Grade ≥3 AEsere diarrhea and reversible increases in alanine and aspartate
minotransferase levels. The outcomes of the LUME-Lung 1 studyontributed to nintedanib in combination with docetaxel beingpproved in the European Union for the treatment of patients withocally advanced, metastatic or locally recurrent NSCLC of adeno-arcinoma histology after first-line chemotherapy [13].
The current analysis extends our investigation of the LUME-ung 1 trial and evaluates the frequency of characteristic AEsommonly seen with existing agents that target angiogenesis. Inddition, the safety profile is further characterized in the two mainistologies in the LUME-Lung 1 trial – adenocarcinoma and squa-ous cell carcinoma (SCC).
. Materials and methods
.1. Study design
Complete details of the LUME-Lung 1 study design have beeneported previously [8]. All patients provided written informedonsent and the study protocol was approved by independentthics committees or institutional review boards at each center.atients with tumors of all histologies who had stable (≥4 weeks)symptomatic brain metastases were permitted. Key exclusionriteria included: radiographic evidence of cavitary or necrotic
umors; centrally located tumors with radiographic evidence (com-uted tomography [CT] or magnetic resonance imaging [MRI]) ofocal invasion of major blood vessels; history of clinically signif-cant hemoptysis within the past 3 months; use of therapeutic
90 (2015) 267–273
anticoagulation (except for low-dose heparin and/or heparin flushas needed for maintenance of indwelling intravenous device) orantiplatelet therapy (except for chronic low-dose therapy withacetylsalicylic acid ≤325 mg daily); history of major thrombotic orclinically relevant major bleeding event in the past 6 months; andknown inherited predisposition to bleeding or thrombosis.
2.2. Assessment
The incidence and intensity of AEs according to the Com-mon Terminology Criteria for Adverse Events (CTCAE) version 3.0were evaluated in all patients who received at least one dose ofstudy medication: nintedanib/placebo or docetaxel. AEs were cat-egorized by pooling Medical Dictionary for Regulatory Activities(MedDRA) terms and by using standardized MedDRA queries ortailored special search categories, and were tabulated by the AE ofspecial interest (AESI) category, preferred term, and worst CTCAEgrade. AESIs that were analyzed included perforation (i.e., gas-trointestinal [GI] and non-GI), hypertension, bleeding (includingrespiratory bleeding), thromboembolic events (in particular, arte-rial and venous thromboembolisms), and skin reactions (includingrash, cutaneous adverse reactions [Standardized MedDRA Queriesterm: severe cutaneous adverse reactions), and hand–foot syn-drome [HFS]).
In addition to an analysis of the overall population, patientswith adenocarcinoma and SCC were analyzed to determine thepresence of histology-specific AEs. Safety analyses compared thenintedanib arm to the placebo arm, and were based on the con-cept of treatment-emergent AEs. AEs with onset between the firstadministration of the study drug (docetaxel or nintedanib/placebo)until 28 days after the last administration were considered to be‘on-treatment’ AEs.
3. Results
3.1. Patient population
Baseline demographics and disease characteristics for the over-all population (N = 1314) have been reported previously and werebalanced between the two treatment groups. Of the overall popu-lation, 658 patients had tumors of adenocarcinoma histology and555 had tumors of SCC histology; demographics and baseline char-acteristics, including predefined stratification factors, were alsobalanced across treatment groups (Table A.1). On the randomizedpopulation, 1307 patients went on to receive at least one dose ofstudy drug, and comprised the safety population (adenocarcinoman = 653; SCC n = 553).
3.2. Perforation
GI perforations were infrequent, and were balanced betweenboth treatment arms and across histologies (Table 1). In the overallpopulation, a total of six patients had GI perforations (any grade)(nintedanib n = 3 and placebo n = 3); of these, one patient in thenintedanib group and three patients in the placebo group expe-rienced an intestinal or gastric perforation, while the remainingtwo nintedanib-treated patients experienced an anal or perirectalabscess. Grade ≥3 GI perforations were infrequent in both treat-ment arms and across histologies, and lower in the nintedanibarm.
The incidence of non-GI perforations was also low overall buthigher in nintedanib-treated patients (1.2% vs 0.2%; see Table 1).
The non-GI perforations in the nintedanib arm were due to bladderperforation (one patient), laryngeal fistula (one patient), periproc-titic abscess (one patient), and lung or chest wall abscess (fivepatients). Four of the five patients who reported lung or chest wall
M. Reck et al. / Lung Cancer
Tab
le
1Fr
equ
ency
of
sele
cted
adve
rse
even
ts
of
spec
ial i
nte
rest
by
his
tolo
gy.
Ad
vers
e
even
t
Ove
rall
, n
(%)
Ad
enoc
arci
nom
a,
n
(%)
Squ
amou
s
cell
carc
inom
a,
n
(%)
Nin
ted
anib
+
doc
etax
el(N
=
652)
Plac
ebo
+
doc
etax
el(N
=
655)
Nin
ted
anib
+
doc
etax
el(n
=
320)
Plac
ebo
+
doc
etax
el(n
=
333)
Nin
ted
anib
+
doc
etax
el(n
=
275)
Plac
ebo
+ d
ocet
axel
(n
= 27
8)
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3Pe
rfor
atio
ns
GI
3
(0.5
)
1
(0.2
)
3
(0.5
)
3
(0.5
)
1
(0.3
)
1
(0.4
)
1
(0.3
)
2
(0.7
)
1
(0.4
)
0
2
(0.7
)
2
(0.7
)N
on-G
I
8
(1.2
)
2
(0.3
)
1
(0.2
)
1
(0.2
)
4
(1.3
)
1
(0.3
)
1
(0.3
)
1
(0.3
)
3
(1.1
)
1 (0
.4)
0
0H
yper
ten
sion
23
(3.5
)
4
(0.6
)
6
(0.9
)
1
(0.2
)
11
(3.4
)
1
(0.3
)
2
(0.6
)
1
(0.3
)
9
(3.3
)
2 (0
.7)
2
(0.7
)
0B
leed
ing
All
92
(14.
1)
15
(2.3
)
76
(11.
6)
12
(1.8
)
35
(10.
9)
4
(1.3
)
37
(11.
1)
5
(1.5
)
47
(17.
1)
8
(2.9
)
30
(10.
8)
7
(2.5
)R
esp
irat
ory
blee
din
g
52
(8.0
)
10
(1.5
)
46
(7.0
)
7
(1.1
)
15
(4.7
)
2
(0.6
)
20
(6.0
)
3
(0.9
)
30
(10.
9)
6
(2.2
)
24
(8.6
)
4
(1.4
)Th
rom
bo-e
mbo
lism
All
33
(5.1
)
14
(2.1
)
30
(4.6
)
20
(3.1
)
17
(5.3
)
8
(2.5
)
18
(5.4
)
11
(3.3
)
12
(4.4
) 4
(1.5
)
11
(4.0
)
9
(3.2
)A
rter
ial
4
(0.6
)
3
(0.5
)
9
(1.4
)
4
(0.6
)
3
(0.9
)
3
(0.9
)
7
(2.1
)
3
(0.9
)
1 (0
.4)
0
1
(0.4
)
1
(0.4
)V
enou
s
18
(2.8
)
8
(1.2
)
10
(1.5
)
7
(1.1
)
9
(2.8
)
3
(0.9
)
4
(1.2
)
2
(0.6
)
6 (2
.2)
3
(1.1
)
6
(2.2
)
5
(1.8
)
GI =
gast
roin
test
inal
.
90 (2015) 267–273 269
abscess had tumors of adenocarcinoma histology. The patient inthe placebo arm experienced a skin abscess (percutaneous abscessdrainage) associated with a fistula at the site of a previous inter-costal drain. Most patients (six out of nine) had non-GI perforationsof Grade 1 or 2.
3.3. Hypertension
The percentage of patients with hypertension (all grades) waslow in both treatment arms for all patients and independent ofhistology, albeit higher in patients receiving nintedanib treatment(3.5% vs 0.9%; Table 1). The majority (24 of 29) of patients withhypertension had Grade 1 or 2 events; no patients had hyperten-sion of Grade 4 or 5, and there were no cases of posterior reversibleencephalopathy syndrome/reversible posterior leukoencephalopa-thy syndrome.
Blood pressure remained stable during treatment in both treat-ment arms. Median systolic blood pressure was 125 mmHg atscreening and 120 mmHg at the end of treatment in both treat-ment arms. Median diastolic blood pressure was 80 mmHg in bothtreatment arms at screening and 70 mmHg in the nintedanib groupand 76 mmHg in the placebo group at the end of treatment. Similarresults were observed in patients with adenocarcinoma and SCC.
3.4. Bleeding
The percentage of patients with bleeding (all grades) wasslightly higher in the nintedanib arm than in the placebo arm (14.1%vs 11.6%; Table 1). The difference between treatments in the over-all study population was driven by patients with SCC (nintedanib17.1% vs placebo 10.8%). The frequency of bleeding was similar inthe two treatment groups in patients with adenocarcinoma histol-ogy (nintedanib 10.9% vs placebo 11.1%). The majority of cases ofbleeding were Grade 1 or 2 with few patients experiencing Grade≥3 bleeding events. The number of patients with Grade ≥3 bleedingevents was similar between treatment arms in all study populations(see Table 1). There were no imbalances in the number of patientswith respiratory bleeding (all grades and Grade ≥3) events betweenthe treatment arms for the overall study population and for patientswith adenocarcinoma. In patients with SCC, respiratory bleedingwas more frequent in the nintedanib arm than in the placebo arm(10.9% vs 8.6%).
As shown in Table 2, the most common bleeding events in theoverall population were epistaxis and respiratory bleeding. Therewas no clustering of bleeding events in any organ system otherthan the respiratory tract. No AEs indicating intracerebral bleedingwere reported. Similar results were seen in patients with adeno-carcinoma and SCC.
Fatal bleeding events were balanced between the arms forthe overall population (nintedanib 1.4% vs placebo 1.1%), theadenocarcinoma population (nintedanib 0.9% [n = 3] vs placebo0.6% [n = 2]), and the SCC population (nintedanib 1.8% [n = 5] vsplacebo 1.8% [n = 5]). Fatal bleeding in patients with adenocarci-noma resulted from hemoptysis (nintedanib n = 1 vs placebo n = 1),pulmonary hemorrhage (nintedanib n = 1 vs placebo n = 1), and dis-seminated intravascular coagulation (nintedanib n = 1 vs placebon = 0). Fatal bleeding in patients with SCC resulted from hemop-tysis (nintedanib n = 3 vs placebo n = 1), pulmonary hemorrhage(nintedanib n = 2 vs placebo n = 2), and hemorrhage (nintedanibn = 0 vs placebo n = 2). One additional nintedanib-treated patient of
unknown tumor histology suffered a fatal hemorrhage. The major-ity of fatal bleeding events were tumor-associated and no deathsin the nintedanib arm were considered related to nintedanib treat-ment.
270 M. Reck et al. / Lung Cancer
Tab
le
2Fr
equ
ency
of
blee
din
g
even
ts
of
spec
ial i
nte
rest
by
his
tolo
gy, a
nd
mos
t
com
mon
ly
rep
orte
d
(>1%
of
pat
ien
ts
in
any
trea
tmen
t
grou
p)
pre
ferr
ed
term
s.
Ad
vers
e
even
t
Ove
rall
, n
(%)
Ad
enoc
arci
nom
a,
n
(%)
Squ
amou
s
cell
carc
inom
a,
n
(%)
Nin
ted
anib
+
doc
etax
el(N
=
652)
Plac
ebo
+
doc
etax
el(N
=
655)
Nin
ted
anib
+
doc
etax
el(n
=
320)
Plac
ebo
+
doc
etax
el(n
=
333)
Nin
ted
anib
+
doc
etax
el(n
=
275)
Plac
ebo
+
doc
etax
el(n
=
278)
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3
All
grad
es
Gra
de
≥3A
ll
blee
din
g
even
ts
92
(14.
1)
15
(2.3
)
76
(11.
6)
12
(1.8
)
35
(10.
9)
4
(1.3
)
37
(11.
1)
5
(1.5
)
47
(17.
1)
8
(2.9
) 30
(10.
8)
7
(2.5
)Ep
ista
xis
32
(4.9
)
0
18
(2.7
)
0
16
(5.0
)
0
12
(3.6
)
0
13
(4.7
)
0 4
(1.4
)
0H
emop
tysi
sa31
(4.8
)
5
(0.8
)
31
(4.7
)
3
(0.5
)
8
(2.5
)
1
(0.3
)
14
(4.2
)
1
(0.3
)
19
(6.9
)
3 (1
.1)
16
(5.8
)
2
(0.7
)Pu
lmon
ary
hem
orrh
agea
14
(2.1
)
5
(0.8
)
12
(1.8
)
3
(0.5
)
3
(0.9
)
1
(0.3
)
4
(1.2
)
1
(0.3
)
8
(2.9
)
3
(1.1
)
7
(2.5
)
2
(0.7
)R
esp
irat
ory
trac
t
hem
orrh
agea
5
(0.8
)
0
4
(0.6
)
0
1
(0.3
)
0
1
(0.3
)
0
4
(1.5
) 0
3
(1.1
)
0
aR
esp
irat
ory
blee
din
g
even
ts.
90 (2015) 267–273
3.5. Thromboembolic events
The overall percentage of patients with thromboembolic eventswas low and comparable across all main study populations(Table 1). The incidence of Grade ≥3 thromboembolic events wasalso comparable in both treatment arms across all main study popu-lations. As shown in Table 1, the number of patients with arterialthromboembolism was lower in the nintedanib group than in theplacebo group in the overall population and the adenocarcinomapopulation, but did not differ between these groups in the SCCpopulation. The number of patients with venous thromboembolismwas higher in the nintedanib group than in the placebo group in theoverall population and the adenocarcinoma population, but did notdiffer between these groups in the SCC population. Reported ratesof Grade ≥3 arterial and venous thromboembolism were compara-ble across study populations.
There was no pattern in the type of arterial thromboem-bolism events between treatment groups although, for venousthromboembolism events, deep vein thrombosis was slightly morecommon in the nintedanib (0.6% [n = 4]) than the placebo treatmentarm (0.2% [n = 1]). There was no difference in the rate of pulmonaryembolism between the treatment arms (0.8% [n = 5] vs 0.9% [n = 6]).
Fatal thromboembolic events were balanced between the arms(nintedanib 0.8% [n = 5] vs placebo 0.6 [n = 4]). Fatal thromboem-bolic events in patients with adenocarcinoma resulted fromcerebrovascular accident (placebo n = 1), myocardial infarction(nintedanib n = 1), ischemic stroke (nintedanib n = 1), and dis-seminated intravascular coagulation (nintedanib n = 1), while fatalthromboembolic events in patients with SCC resulted from pul-monary embolism (placebo n = 3), superior vena caval occlusion(nintedanib n = 1), and venous thrombosis (nintedanib n = 1).
3.6. Skin toxicity
The percentages of patients with rash and cutaneous adversereactions were slightly higher with nintedanib than with placeboin all populations (although most events were Grades 1−2). The fre-quency of patients with cutaneous adverse reactions was slightlyhigher in the nintedanib arm compared with the placebo armof the adenocarcinoma population (15.6% vs 10.5%), whereas nodifferences were observed between treatment arms in the SCCpopulation (9.5% vs 9.0%; Table 3). The most common events bypreferred term contributing to the grouped terms of rash were rash(2.9% vs 2.7% in the overall population) and dermatitis acneiform(2.5% vs 2.1%), and stomatitis (9.7% vs 8.7%) was the most commoncutaneous adverse reaction (Table 3). The percentages of patientswith HFS were low (<1%) and similar in the two treatment armsacross populations. No patients experienced Stevens–Johnson syn-drome or toxic epidermal necrolysis.
4. Discussion
VEGF-targeted therapies have demonstrated significant efficacyacross a range of tumor types; however, there are concerns abouttreatment-related toxicity when using antibodies targeted to VEGFsignaling, such as monoclonal antibodies (e.g., bevacizumab, ramu-cirumab) or VEGFR tyrosine kinase inhibitors (TKIs; e.g., sunitinib,sorafenib) [14]. As expected, there is overlap in the safety pro-files associated with agents that inhibit one or more steps in theangiogenesis signaling pathway; however, there are also differ-
ences, which give each compound a characteristic safety profile.We evaluated the anti-angiogenic AEs associated with the angioki-nase inhibitor nintedanib, and found differences compared to otherinhibitors of angiogenesis.
M. Reck et al. / Lung Cancer
Tab
le
3Fr
equ
ency
of
skin
-rel
ated
adve
rse
even
ts
of
spec
ial i
nte
rest
by
his
tolo
gy
(gro
up
ed
term
),
and
mos
t
com
mon
ly
rep
orte
d
(>2%
of
pat
ien
ts
in
any
trea
tmen
t
grou
p)
pre
ferr
ed
term
s.
Ad
vers
e
even
t
Ove
rall
, n
(%)
Ad
enoc
arci
nom
a,
n
(%)
Squ
amou
s
cell
carc
inom
a,
n
(%)
Nin
ted
anib
+
doc
etax
el(N
=
652)
Plac
ebo
+
doc
etax
el(N
=
655)
Nin
ted
anib
+
doc
etax
el(n
=
320)
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90 (2015) 267–273 271
Bevacizumab, which targets VEGF, was the first approved anti-angiogenic agent for the treatment of NSCLC, although it is notapproved for use in patients with SCC histology because of theincreased risk of pulmonary hemorrhage [15,16]. Indeed, bleedingis one of the most severe and potentially life-threatening toxicitiesof VEGF inhibitors, with a wide range of incidence and severityreported in different studies [17]. Although a pooled analysis ofthree randomized trials failed to demonstrate a significantly higherincidence of severe hemorrhages of CTCAE Grade 3 or 4 [16], theincidence of mild bleeding episodes was increased in the experi-mental arm of most trials using bevacizumab (up to 40%) [17]. Inboth the AVAiL (AVAstin in Lung cancer) and E4599 trials, patientswith advanced non-squamous NSCLC who received bevacizumab incombination with chemotherapy experienced significantly higherrates of Grade ≥3 bleeding (∼4%) compared to chemotherapy alone[18,19]. Bleeding or hemorrhage (all grades) has also been more fre-quently reported in patients treated with ramucirumab comparedto those treated with placebo in the REVEL study (29% vs 15%) [20].Life-threatening or fatal bleeding episodes have also been reportedwith bevacizumab [15]. Grade ≥3 bleeding events in the nintedanibarm of LUME-Lung 1 (2.3%) were comparable to ramucirumab inREVEL (2.4%) and lower than bevacizumab in the AVAiL study(4.2–4.3%) [18,20]. Bleeding events do not appear to be commonlyassociated with nintedanib treatment; although more nintedanibplus docetaxel-treated patients experienced bleeding compared toplacebo plus docetaxel-treated patients, the magnitude of the dif-ference between the nintedanib and placebo arms was lower thanwith bevacizumab or ramucirumab in NSCLC [18,20]. Moreover, thefrequency of fatal bleeding events was low (<1.5%) in the nintedanibarm and was balanced between the treatment arms for all his-tologies, suggesting a low risk of fatal bleeding with nintedanibin patients with NSCLC.
Hypertension is another frequently reported AE of VEGF inhi-bition. Thus far, the mechanisms by which VEGF inhibitors mayinduce hypertension have not been fully elucidated; however, it isspeculated that treatment-induced hypertension reflects the effectof anti-VEGF agents on multiple VEGFRs present on the vascula-ture throughout the body, and the affinity of an anti-VEGF agentfor specific VEGFR subtypes [17]. Despite the recognized associa-tion between anti-VEGF agents and hypertension, the frequencyand intensity of hypertension as an AE varies between studies,depending on the tumor type and other patient-related factors, andeven within the same indication with the same anti-angiogenicagent [17,21]. Meta-analyses have shown that the incidence ofhypertension (all grades) in patients receiving bevacizumab was24%, with 8% of events being Grades 3–4; rates significantly highercompared to controls [22]. Other angiogenesis inhibitors are alsoassociated with hypertension and meta-analyses have found simi-larly high rates of hypertension in patients treated with sorafenib(all grades, 19%; Grades ≥3, 4%) [23], sunitinib (all grades, 22%;Grades 3–4, 7%) [24], vandetanib (all grades, 24%; Grades 3–4, 6%)[25], pazopanib (all grades, 36%; Grades 3–4, 7%) [26], and axitinib(all grades, 40%; Grades 3–4, 13%) [27]. Treatment-related hyper-tension appears to be dose-dependent with some anti-angiogenicagents, e.g., sunitinib and axitinib [28,29], and a direct relation-ship between total drug dose and blood pressure has been reportedfor some agents (e.g., sunitinib) [28]. Consistent with findings forother VEGF inhibitors, a higher frequency of hypertension wasreported in LUME-Lung 1; however, the percentage of nintedanib-treated patients who experienced all-grades (3.5%) and Grade ≥3(0.6%) hypertension was relatively lower than would be commonlyexpected with VEGF inhibitors. Although nintedanib has not been
directly compared to an anti-angiogenic agent in NSCLC, a PhaseII study in previously untreated patients with renal cell carcinoma(RCC) compared nintedanib to sunitinib. In this study, 3% of patients
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72 M. Reck et al. / Lung
reated with nintedanib experienced any-grade hypertension com-ared to 16% in patients treated with sunitinib [30].
Although meta-analyses have shown that bevacizumab treat-ent is associated with a significantly increased risk of developingI perforation [31], a similar risk was not shown in a meta-analysisf Phase II and III studies in patients treated with VEGFR TKIs otherhan nintedanib [32]. Results from the LUME-Lung 1 study suggesthat this is also the case for nintedanib, as the rate of GI perforationsas not increased by the addition of nintedanib to chemotherapy.on-GI perforations did occur more commonly in the nintedanibrm than in the placebo arm, but the overall incidence was low.
Anti-angiogenic agents are also associated with an increasedisk of arterial and venous thromboembolism [33]. Meta-analysesave shown that bevacizumab is associated with an increasedisk of both arterial thromboembolism [34] and venous throm-oembolism in patients with solid tumors [35]. Generally, theisk of venous thromboembolism appears lower with VEGFRKIs, and is often comparable with that of patients treated withtandard chemotherapy. A meta-analysis evaluating US Food andrug Administration-approved VEGFR TKIs (pazopanib, sunitinib,
orafenib, and vandetanib) across different tumor types, found thathe incidence of venous thromboembolism events was 3% (95%I: 1.7–5.1%) and not significantly increased versus controls [26].onsistent with this, data from LUME-Lung 1 show a similar fre-uency of increased venous thromboembolisms in the nintedanibrm (2.8%) compared to the placebo arm (1.5%). The increasedrequency in the nintedanib arm occurred predominantly amongatients with adenocarcinoma histology. There was no increase inrterial thromboembolisms with nintedanib treatment relative tolacebo.
VEGFR- and multi-kinase inhibitors are also associated with skinoxicities, with hand–foot skin reaction (HFSR), a distinct variant ofFS, and rash being two of the more frequently reported AEs with
orafenib and sunitinib [36]. The exact mechanism of these sideffects is poorly understood but different mechanisms have beenroposed [37,38]. HFSR is considered one of the most clinically sig-ificant dermatologic side effects and can have a deleterious impactn quality of life [39]. Recent meta-analyses of Phase II and PhaseII studies in RCC have indicated that the Grade 1–3 HFSR incidenceate was 33.8% with single-agent sorafenib and 18.9% with single-gent sunitinib [38,40]. Although we found that the frequencies ofkin-related AEs in LUME-Lung 1 were higher in patients treatedith nintedanib than with placebo (cutaneous adverse reactions:
3.0% vs 10.7%; rash: 11.0% vs 8.1%), they were generally lower thaneported for other agents and HFS was rare (<1% in either treatmentrm). This observation is in line with data for nintedanib versusunitinib from a Phase II study in first-line RCC patients, where noatients on nintedanib had HFS compared to 31.3% of patients onunitinib [30].
. Conclusions
Extensive safety evaluation of the LUME-Lung 1 study showedhat the frequency of AEs commonly associated with anti-ngiogenic agents was lower with nintedanib plus docetaxel thanith other anti-angiogenic agents. The significant survival bene-ts demonstrated with the addition of nintedanib to docetaxel inUME-Lung 1 in patients with adenocarcinoma can be achievedlongside a manageable safety profile.
onflicts of interest
M. Reck has received honoraria for advice and lecturesrom Hoffmann-La Roche, Eli Lilly, Pfizer, Novartis, Merck Sharp
Dohme, Bristol-Myers Squibb, AstraZeneca and Boehringer
[
90 (2015) 267–273
Ingelheim. A Mellemgaard has participated in advisory boards,received honoraria for lectures and support for participation in con-gresses from Boehringer Ingelheim. J. von Pawel has participatedin advisory boards for Clovis Oncology, Novartis, Pfizer, AbbVie,Daiichi Sankyo and Bristol-Myers Squibb. J. Bennouna has partici-pated in advisory boards and received honoraria from BoehringerIngelheim, Hoffmann-La Roche and AstraZeneca. J.-Y. Douillard hasreceived honoraria for participating in advisory boards or lecturesin educational symposia from Boehringer Ingelheim, AstraZeneca,Hoffmann-La Roche and Novartis. J. Barrueco, H. Aboshady andJ. Hocke are employees of Boehringer Ingelheim. R. Kaiser is anemployee of and a patent holder with Boehringer Ingelheim. M.Gottfried, I. Bondarenko, Y. Cheng, K. Zarogoulidis and A. Luftdeclare no conflicts of interest.
Acknowledgments
Funding for this study was provided by Boehringer Ingelheim.Medical writing assistance was provided by Chris Ontiveros andSuzanne Patel (inVentiv Health, London, UK) during preparation ofthis report and was supported financially by Boehringer Ingelheim.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.lungcan.2015.08.003.
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