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SAFETY AND EFFECTIVENESS OF NIMOTUZUMAB IN HIGH GRADE GLIOMA PATIENTS. PHASE IV STUDY RESULTS

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ARTICLE INFO ABSTRACT Purpose: A multicentric, Phase IV clinical trial to evaluate safety and effectiveness of nimotuzumab, a monoclonal antibody against epidermal growth factor receptor added to standard therapy for newly diagnosed high grade glioma. Methods: Patients were recluted after surgery to receive nimotuzumab 200 mg weekly in combination with radiotherapy (RT) or chemoradiation (CRT), followed by the same doses biweekly until clinical worsening or intolerance toxicity. Safety profile, Progression-free survival (PFS) and overall survival (OS) were main endpoints based in Common Toxicity Criteria, Macdonald criteria and time to death since inclusion date. Results: 127 patients were treated, 93 glioblastoma, 25 anaplastic astrocytoma and 9 anaplastic oligoastrocytoma. Mostly patients received nimotuzumab in combination with radiation: concurrently 54.3 %, sequentially to RT 15.7 % and 6.3 % in combination to RT and Temozolomide; however 23.6 % received nimotuzumab as monotherapy. Completed induction phase 87.4% of patients and continued in maintenance beyond 2 years 11.1 %. Only 10.5 % of adverse events were related to nimotuzumab. Headache, transaminase increased, fever and skin rash, were the most frequents as mild intensity. Median PFS time was 8.97 and 21.77 months and OS was 10.57 and 28.27 months for glioblastoma and anaplastic astrocytoma patients respectively. Conclusions: This study was consistent to safety and adherence as continues maintenance treatment, prior described in controlled trials. Nimotuzumab in combination with RT might improve survival over RT alone, but it was marginal with respect to chemoradiation. For enhance the clinical benefit patients would be select according predictor biomarkers unknown yet.
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International Journal of Current
Medical and Pharmaceutical
Research
Available Online at http://www.journalcmpr.com
RESEARCH ARTICLE
SAFETY AND EFFECTIVENESS OF NIMOTUZUMAB IN HIGH GRADE GLIOMA PATIENTS.
PHASE IV STUDY RESULTS
Giselle Saurez1., Silvia Noema Salva2., Rolando Uranga3., Patricia Piedra4., Jorge Abel Anoceto5.,
Bárbara Iglesias6., Yanet González7., Rafael Dominguez8., Carolina Toledo9., María Teresa
Solomón10., Hector Gómez11., Julio Selva12., Daysi Chi13., María Acelia Marrero14.,
Lisett Palomino15 and Agustin Lage16
1,4Medical Division, Center of Molecular Immunology, La Habana, Cuba
2Department, “Hermanos Ameijeiras” Hospital, La Habana, Cuba
3National Coordinating Center of Clinical Trials, La Habana, Cuba
5Neurosurgery Department, “Arnaldo Milian” Castro Hospital, Villa Clara, Cuba
6,7Oncology Department, “III Congreso” Hospital, Pinar del Río, Cuba
8Neurosurgery Department, “Saturnino Lora” Hospital, Santiago de Cuba, Cuba
9Oncology department, “Maria Curie” Oncology Hospital, Camagüey, Cuba
10Neurosurgery Department, “Calixto García” University Hospital, La Habana, Cuba
11Morphophysiology Laboratory. National Institute of Neurology and Neurosurgery, La Habana, Cuba
12Neurosurgery Department. Lucia Iñiguez Hospital, Holguín, Cuba
13Oncology Department. National Institute of Oncology and Radiobiology, La HabanaCuba
14,15National Coordinating Center of Clinical Trials, La Habana, Cuba
16General Direction. Centre of Molecular Immunology, La Habana, Cuba
ARTICLE INFO ABSTRACT
Purpose: A multicentric, Phase IV clinical trial to evaluate safety and effectiveness of nimotuzumab,
a monoclonal antibody against epidermal growth factor receptor added to standard therapy for newly
diagnosed high grade glioma.
Methods: Patients were recluted after surgery to receive nimotuzumab 200 mg weekly in
combination with radiotherapy (RT) or chemoradiation (CRT), followed by the same doses biweekly
until clinical worsening or intolerance toxicity. Safety profile, Progression-free survival (PFS) and
overall survival (OS) were main endpoints based in Common Toxicity Criteria, Macdonald criteria
and time to death since inclusion date.
Results: 127 patients were treated, 93 glioblastoma, 25 anaplastic astrocytoma and 9 anaplastic
oligoastrocytoma. Mostly patients received nimotuzumab in combination with radiation: concurrently
54.3 %, sequentially to RT 15.7 % and 6.3 % in combination to RT and Temozolomide; however 23.6
% received nimotuzumab as monotherapy. Completed induction phase 87.4% of patients and
continued in maintenance beyond 2 years 11.1 %. Only 10.5 % of adverse events were related to
nimotuzumab. Headache, transaminase increased, fever and skin rash, were the most frequents as
mild intensity. Median PFS time was 8.97 and 21.77 months and OS was 10.57 and 28.27 months for
glioblastoma and anaplastic astrocytoma patients respectively.
Conclusions: This study was consistent to safety and adherence as continues maintenance treatment,
prior described in controlled trials. Nimotuzumab in combination with RT might improve survival
over RT alone, but it was marginal with respect to chemoradiation. For enhance the clinical benefit
patients would be select according predictor biomarkers unknown yet.
Copyright © 2016 Giselle Saurez et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
INTRODUCTION
Glioblastoma (GBM) and Anaplastic Astrocytoma (AA),
commonly considered as High Grade Glioma (HGG), are the
most frequent primary brain tumors in adults, and despite
decades of research, continue to be aggressive diseases which
invariable cause the patient´s death. Standard treatment
Key words:
Monoclonal antibodies, clinical trials,
post-marketing studies, High Grade
Glioma, targeted therapies,
nimotuzumab.
Article History:
Received 28th June, 2016
Received in revised form 6th
July, 2016 Accepted 14th August, 2016
Published online 24th September, 2016
International Journal Of Current Medical And Pharmaceutical Research, Vol. 2, Issue, 9, pp.657-664, September, 2016
658
approaches for GBM and AA result in median survivals of 9-
12 months and 2-5 years respectively(1).
Therefore this is unmet medical need and novel therapeutics is
urgently required and could be targeted therapies change the
natural course of this lethal disease.
Nowadays two monoclonal antibodies(MoAb) are already
approved in different countries for recurrent GBM and newly
diagnosed HGG patients: Bevacizumab, targeting Vascular
Endothelial Growth Factor (VEGF) and nimotuzumab aiming
Epidermal Growth Factor Receptor (EGFR)respectively(2,
3).Nimotuzumab is a MoAb binds EGFR, interferes the
interaction of EGFR with its ligand (EGF), inhibits
EGF/EGFR signaling cascade, and has anti-proliferative, anti-
angiogenic and pro-apoptotic effects in malignant epithelial
cells(4, 5). This MoAb passes the blood-brain barrier and
sensitizes tumor cells to radiation (6-8).
Based on these previous finding, nimotuzumab has been
evaluated in randomized clinical trials (RCT), in combination
with radiotherapy (RT)(9)or chemoradiation (CRT) in
HGG(10). Survival advantage was revealed in both
combination modalities, however, reached statistically
significance when nimotuzumab was added to RT, but did not
in combination of CRT(9, 10).The results of RCT with
nimotuzumab plus RT in newly diagnosed HGG patients
granted the approval as a front-line therapy.
After launch, a post-marketing surveillance studies is relevant
for the identification, assessment and management of risks
when a new drug is approved. Therefore, a Phase-IV study
was launched in agreement with the national regulatory
authority for evaluate safety, effectiveness in terms of
progression-free survival (PFS) and overall survival (OS) in
an open population. Final data is reported.
MATERIAL AND METHODS
A multicentric, open label, Phase IV clinical trial was
conducted in newly diagnosed HGG patients, who received
nimotuzumab added to RT or CRT and were followed during 2
years.
Patients had a diagnosis of HGG according to a local
pathologist´s report, which was confirmed by a centralized
second pathologist, blinded to clinical data.
Other eligibility criteria were age older than 18 years,
Karnofsky performance status (KPS) ≥ 50 %, adequate bone
marrow, liver and renal function; a negative pregnancy test
(effective contraceptive methods were used in those patients in
fertile age).
Surgical resection was attempted in all patients and performed
as total or partial resection or just biopsy. Tumor samples were
available for EGFR expression assessment through
immunohistochemistry performed in agreement with the
indirect enzyme immunoassay, previously described(11).
Compliant with the statement on the package insert,
nimotuzumab was administered by six weekly intravenous
infusions at 200 mg, as induction phase, followed by every two
weeks infusions as maintenance, until worsening performance
status (KPS < 40 %) or unacceptable toxicity(12).
Nimotuzumab was combined with external beam radiotherapy.
Fractionated, conformal RT or intensity-modulated
radiotherapy (IMRT) was given within protocol-defined
guidelines at institutions, at a daily dose of 2 Gy, delivered 5
days a week for 6 weeks, for a total dose of 60 Gy.
Addition of Temozolomide (TMZ) chemotherapy was
allowed, as standard scheme (13).
Full patient evaluation included complete physical
examination, laboratory tests (blood cell counts and blood
chemistry), and CT-scan or Nuclear Magnetic Resonance
images, at inclusion and every three months.
Adverse events (AEs) were classified according to the
Common Terminology Criteria for Adverse Events version 3.0
(14). Serious adverse events as death, life-threatening,
hospitalization, disability or permanent damage, congenital
anomaly, required intervention or any other important medical
event to prevent permanent impairment or damage were also
recorded and analyzed separately. Adverse events considered
as related to nimotuzumab use were classified as adverse drug
reaction (ADR).
For assessment clinical response, was used Macdonald criteria
(15).
Statistical Analysis
The statistical significance of the possible association among
ADR and dosage, exposure time and treatment schedule was
assessed using the X2test.
For patients who achieved objective response (either complete
or partial) or stable disease, progression- free survival (PFS)
was calculated as time from inclusion to progression or death.
Overall survival (OS) was defined as time from inclusion until
death or last news alive.
The relationship between either PFS or OS and treatment was
assessed in all patients, by intent to treat, using the Kaplan-
Meier test. Univariate and multivariate Cox proportional
hazards models were also used. Data were processed using the
software: SAS for Windows, release 9.3, x 64-7pro platform.
This trial was performed in compliance with the Helsinki
Declaration. Institutional Review Boards from 11 hospitals
approved the protocol and National Regulatory Authority
(CECMED) was notified for this postmarketing study.
All patients included signed the informed consent. The
protocol was submitted on the National Register for clinical
trials (RPCEC00000087) which is a primary register, approved
by the World Health Organization (WHO)
(http://registroclinico.sld.cu/ensayos).
http://registroclinico.sld.cu/en/trials/RPCEC00000087-En
RESULTS
Patient’s characteristics
Between September 2008 and September 2011, 241 patients
were screened, 127 of them were included in the study (52.7
%), and 114 (47.3 %) excluded because of diverse causes (Fig.
1). The cut-off date for evaluation was set at September 2013.
Average age was 49.5 years, with rate1:1.5 between male and
female and skin color as Caucasian prevailed. Most patients
(96%) had a good performance status, but in 39.4 % of cases
some co-morbidities were presented, mainly cardiovascular
(23%) metabolic (6.3%) and neurologic disorders (6.2%).
Glioblastoma histology was the most common (73.2%),
followed by Anaplastic Astrocytoma (19.7%) and Anaplastic
Oligoastrocytoma (7.1%). Frontal and Parietal tumor
International Journal of Current Medical And Pharmaceutical Research, Vol. 2, Issue, 9, pp.657-664, September, 2016
659
localizations were more frequent, however one fourth of
patients had tumor lesion in more than one site.
All patients underwent surgery as initial treatment, although
complete tumor resection was possible only in 7.9 % of
patients, the rest received either partial resection (57.5%) or
just biopsy (34.7%).
Immunohistochemistry staining (IHC) was performed in 50
patients, showing that most of tumors over express EGFR
(Table 1).
Treatment and compliance
Nimotuzumab was used in all patients. In most of them
(54.3%) the MoAb was given concurrently with RT. In 15.7%
following the criteria of the treating physician, the MoAb
treatment was given sequentially after completion of
radiotherapy. A small group of 8 patients (6.3%) received
TMZ chemotherapy concurrently with radiation. In 30 cases
(23.6%) RT or chemotherapy was not possible and these
received only nimotuzumab as monotherapy after surgery.
Maintenance antibody treatment was given used biweekly in
most patients (more than 6 doses, 87.4%), although a small
group of 16 patients (12.6%) received less than 6 doses.
Average number of nimotuzumab doses was 28.6 implying a
median duration of 9 months of antibody treatment. In 14
patients biweekly nimotuzumab treatment continued beyond 2
years. The extension of treatment was not different between
patients receiving the concurrent or the sequential schedule
(Table2).
Progressive disease (38.5%), worsening KPS (15%) and death
by progression (7.8%) were the most common causes of
interruption of nimotuzumab treatment, over the 2 years of
follow-up.
In no case treatment had to be stopped as a consequence of
antibody toxicity.
Safety
The majority of patients presented some adverse events
(92/127 patients, 72.4 %). In total were 749 events, classified
as mild (47.5%) and moderate (34.6%).
Only 79 events (10.5 %) were classified as ADR to
nimotuzumab. These were mainly headache (16.5 %),
transaminase increased (11.4 %), fever (10.1%) and skin rash
(6.3%). Adverse events related to the drug were also mild
(65%) and moderate (29%), (Table 3).Among ADR, four were
recognized as Serious Adverse Events (SAEs); three of them
in the same patient who suffered fever, chills and tremors,
summarized as anaphylactic reaction; the second, presented
severe seizures. Both patients required hospitalization and had
complete resolution.
Figure 1 Diagram of patients
Legend: CRT: Chemoradiation; HGG: High Grade Glioma; KPS: Karnofsky
Performance Status; RT: Radiotherapy.
Table 1 Baseline patient characteristics of full population
included
Variables Patients
N= 127/%
Age (mean, min- max) 49. 5 (17-82)
< 50 years 67/52.8
≥ 50 years 60/47.2
Gender
Male 76/ 59.8
Female 51/40.1
Skin color
Caucasian 86/67.7
Black 14/11.0
Mestizo 27/21.3
KPS (mean, min-max) 90.1 (50-100)
KPS grouped
≥ 70 % 122 /96.1
< 70 % 5/3.9
Comorbidities 50/39.4
Histology
GBM 93/73.2
AA 25/19.7
AOA 9/7.1
Tumor localization
Frontal 46/36.2
Parietal 20/15.8
Temporal 16/12.6
Occipital 8/6.3
Corpus Callosum 2/1.6
III Ventricle 1/0.8
Protuberance 1/0.8
Other (more than 1 localization) 33/26.0
Prior Surgery
Biopsy 44/34.7
Partial resection 73/57.5
Total resection 10/7.9
EGFR expression (N = 50 pts/%) **
0 7/14.0
1+ 5/10.0
2+ 12/24.0
3+ 26/52.0
Legend: AA: Anaplastic Astrocytoma; AOA: Anaplastic Oligoastrocytoma, GBM
Glioblastoma multiforme. ** Only 50 patients were available for outcome EGFR
Table 2 Nimotuzumab treatment and compliance
Modality N= 127/%
nimo + RT concurrently 69/54.3
nimo + RT sequentially 20/15.7
CRT+ nimo concurrently 8/6.3
nimotuzumab
(monotherapy) 30/23.6
nimotuzumab doses received
Mean doses
(SD; min. -max.)
28.6
(2.26; 1-119)
Less than 6 doses 16/12.6
Between 6 to 30 doses 67/52.8
More than 31 to 60 doses 30/23.6
More than 60 doses 14/11.0
SD: standard deviation
International Journal Of Current Medical And Pharmaceutical Research
Legend: Others ADR were notified one each: Anorexia,
Appetite augmentation, Asthenia, Bleeding uterine, Blurred
vision, Dermatitis, Dizziness, Eosinophilia, Hyperglycemia,
Hypertension, Insomnia, Lactate desgydrogenase
augmentation(LDH), Pruritus and Pyrosis.
There was no association between incidence of adverse events
and treatment modality, neither nimotuzumab do
(Figure 2a, 2b).
Survival Analysis
The median progression-
free survival (PFS) for the all patients
was 10.05 months (95% confidence interval, 8.40 to 14.27).
Overall survival (SV) showed a median of 12.23 months (95%
Table 3
Most common adverse drug reactions to
nimotuzumab
ADR No.
Headache 13
Transaminase alterations (ALAT) 9
Fever 8
Rash 5
Alkaline phosphatase alteration 4
Pain (chest/ limbs) 4
Tremors 4
Chills 3
Thrombocytosis 3
Arthralgia 2
Hypotension 2
Infection (respiratory/other) 2
Nauseas 2
Seizures 2
Vomiting 2
Others 14
Total 79
Figure 2a
Figure 2b
Adverse events according number doses received
Legend: ADR:
Adverse drug reactions to nimotuzumab; AEs: Adverse
events.
International Journal Of Current Medical And Pharmaceutical Research
, Vol. 2, Issue, 9, pp.657-
664
660
Legend: Others ADR were notified one each: Anorexia,
Appetite augmentation, Asthenia, Bleeding uterine, Blurred
vision, Dermatitis, Dizziness, Eosinophilia, Hyperglycemia,
Hypertension, Insomnia, Lactate desgydrogenase
There was no association between incidence of adverse events
and treatment modality, neither nimotuzumab do
ses received
free survival (PFS) for the all patients
was 10.05 months (95% confidence interval, 8.40 to 14.27).
Overall survival (SV) showed a median of 12.23 months (95%
CI, 9.87 to 15.80). At the time of analysis, after 2 years of
follow-up,
30 of the 127 patients (23.6%) were still alive.
According histology grade, the median PFS in GBM stratum
patients was 8.97 months (95% CI, 7.83
of 10.57 months (95% CI, 8.43
was 17.39% and SV rate was
18.57%.
In patients with AA histology, the median PFS was 21.77
months (95% CI; 10.20 -
45.83) and SV of 28.27 months (95%
CI, 8.87 -
.). Two year PFS rate was 43.64 % and SV rate was
52%.
The small group of 9 patients classified as Anaplastic
Oligoast
rocytoma (AOA), only 2 deaths occurred. Therefore
median PFS and SV data could not be calculated. Two year
PFS and SV rates were respectively 57.14 % and 77.78%
(Figure 3a, 3b).
Subgroup analysis showed survival advantage for patients
younger than 50 years old as compared with older patients and
also for patients who have non GBM diagnosis. Additionally
patients receiving any combined modality (nimo plus
radiotherapy or chemotherapy or both) performed better than
patients receiving only antibody as monotherapy (Table 4).
In this series 96% of patients were included with good
performance status and therefore the influence of this factor
Most common adverse drug reactions to
%
16.5
11.4
10.1
6.3
5.1
5.1
5.1
3.8
3.8
2.5
2.5
2.5
2.5
2.5
2.5
17.8
100
Adverse events according treatment modality.
Legend: ADR: Adverse drug reactions to nimot uzumab; AEs: Adverse events.
Adverse events according number doses received
Adverse drug reactions to nimotuzumab; AEs: Adverse
Figure 3a Kaplan–
Meier Estimates of progression
Legend:
AA: Anaplastic Astrocytoma; AOA: Anaplastic Oligoastrocyto ma; GBM:
Glioblastoma multiforme; PFS: Progression
Figure 3b Kaplan–
Meier Estimates of overall survival.
Legend: AA: Anaplastic Astrocytoma; AOA: Anaplastic
Oligoastrocytoma;
GBM: Glioblastoma multiforme.
664
, September, 2016
CI, 9.87 to 15.80). At the time of analysis, after 2 years of
30 of the 127 patients (23.6%) were still alive.
According histology grade, the median PFS in GBM stratum
patients was 8.97 months (95% CI, 7.83
- 10.87) and survival
of 10.57 months (95% CI, 8.43
- 13.50). The two year PFS rate
18.57%.
In patients with AA histology, the median PFS was 21.77
45.83) and SV of 28.27 months (95%
.). Two year PFS rate was 43.64 % and SV rate was
The small group of 9 patients classified as Anaplastic
rocytoma (AOA), only 2 deaths occurred. Therefore
median PFS and SV data could not be calculated. Two year
PFS and SV rates were respectively 57.14 % and 77.78%
Subgroup analysis showed survival advantage for patients
younger than 50 years old as compared with older patients and
also for patients who have non GBM diagnosis. Additionally
patients receiving any combined modality (nimo plus
radiotherapy or chemotherapy or both) performed better than
patients receiving only antibody as monotherapy (Table 4).
In this series 96% of patients were included with good
performance status and therefore the influence of this factor
Meier Estimates of progression
-free survival
AA: Anaplastic Astrocytoma; AOA: Anaplastic Oligoastrocyto ma; GBM:
Glioblastoma multiforme; PFS: Progression
-free survival.
Meier Estimates of overall survival.
Legend: AA: Anaplastic Astrocytoma; AOA: Anaplastic
GBM: Glioblastoma multiforme.
International Journal of Current Medical And Pharmaceutical Research, Vol. 2, Issue, 9, pp.657-664, September, 2016
661
was not considered. Other factors as surgery extension and
EGFR expression no shown effect over survival.
DISCUSION
The results presented here reinforces the safety profile of good
tolerability for nimotuzumab, even in long term use and also
reproduce the survival data of the preceding clinical trials, this
time in an open patient population, closely to the real world
context.
Despite treatment compliance was coherent to indication and
posology recommended in package insert, nimotuzumab
combined to RT concurrently, a notable proportion of them
received nimotuzumab after ended RT as sequential, even as
monotherapy. This deviation treatment also was described in
prior observational study (16) and could be as consequence of
organizational issues as distance from radiotherapy department
and department destined to receive nimotuzumab or
chemotherapy, waiting time of radiotherapy or just preference
of parents and patients.
With independence of treatment combination modality, the
majority of patients received maintenance with nimotuzumab
even as long lasting 2 years or more. Actually the
maintenance treatment specifically with biological becomes as
usual practice in the oncology attributable to more clinical
benefit (17-22); but many patients withdrawal treatment and
fails as consequence of intolerance and deleterious effects (23-
25).
Remarkably none patients discontinued treatment as
consequence of toxicity directly related to nimotuzumab
treatment, even there were no cases of infusion-related
toxicities, skin rash, diarrhea, electrolyte of magnesium and
potassium imbalances, substantial cause of interruptions of
treatment, and therefore limited in maintenance with others
anti EGFR drugs(26).
Many experimental assays explain how this MoAb has optimal
affinity to tumor cell specifically with high EGFR expression
and can discriminate tumor cell between normal cells to
focuses antitumor effect, with a minimum of adverse
events(11, 27). To differences of those anti EGFR MoAb,
nimotuzumab has an intermediate affinity, which facilitates
binding to cells with high density of EGFR as tumor cells, to
those of lower density of EGFR as normal epithelial cells
located primarily in skin epithelial and mucosae.
This distinctive mechanism, explains their differentiation from
the point of view of safety without detriment to the efficacy.
Likewise, nimotuzumab safety profile allows to use in
vulnerable population as child and elderly patients, even with
comorbidities to require concomitant medication for other
disease and also, to continuing immunotherapy for long
exposition time (28-32). All of them are advantages for a good
adherence treatment to warranty efficacy.
Consequently, this report provides reliable evidence to safety
profile described in prior studies (6, 7, 9, 10); albeit the
majority of patients included had several comorbidities as
representative of patients of real word, in contrast to restrictive
inclusion criteria of patients who participated from RCT(9,
10).
Other interesting finding related to nimotuzumab safety is how
the combination therapy with RT even CRT, no exacerbate the
toxicities for this conventional therapy, either not found
evidence of cumulative toxicity by a treatment continued
beyond of the year, even at 2 years.
As far as effectiveness, PFS and SV reported for all patients
treated in this study (median 10.05 and 12.23 months) were
lower to describe in RCT, which evaluated nimotuzumab +
RT, (median 15.73 and 17.76 months) and some differences
data from control arms (median PFS 6.5 and SV 12.63
months)(9).
However, survival analyses by histology strata separately
could be better illustrated the benefit of nimotuzumab in
addition to irradiation. Here, outcome to median survival was
remarkable for GBM patients (10.57 months), in contrast to all
GBM patients treated in RCT refereed above (8.40
nimotuzumab arms vs. 8.36 months in control arm)(9).
Additional postmarketing studies (PMS) which assessed
nimotuzumab describe similar results for GBM patients with a
median SV between 14.8 and 12.4 months (16, 33) . For AA
patients results were not reproducing to data from RCT
(median SV 28.3 and median SV 44.56 month respectively);
however it was improved than control arm from same RCT
(17.57 months)(9). Similarly, in AA patients from others PMS
with nimotuzumab, results were wide different, median
survival 27 and 45 months (16, 33).
Many factors could be explained the dispersal of data. In our
opinion, besides of heterogeneity of HGG, it was also
important therapeutic schedule received. Nimotuzumab with
RT, concurrently as sequentially, absolutely was better than
monotherapy, even some patients received CRT based TMZ,
exhibited a longer lasting survival.
As mentioned above, this outcome is in line with Westphal´s
Phase III trial that compared nimotuzumab in combination
Table 4 Regression analysis
Univariate Multivariate
Subgroup No.
pts
Median Overall
Survival
(mo.)
HR
(95% CI) p
HR
(95%
CI)
p
Age ( years)
Younger than
50
67 22.33 2.79
(1.85 to 4.22)
< 0.0001
2.25
(1.47 to
3.44)
0.0002
Equal or older
than 50 60 8.16
Surgery extension
Complete
resection 10 18.61
1.18
(0.54 to
2.54)
0.6796
-
-
Residual
tumor
(biopsy and
partial
resection)
117
12.10
Histology
No GBM
(AA and
AOA)
34 31.57
2.78
(1.63 to
4.72)
0.0002
2.32
(1.35 to
3.99)
0.0022
GBM 93 10.57
EGFR expression
**
2-3+ 38 9.93
0.78
(0.37 to
1.65)
0.5217
-
-
0-1 12 8.30
Modality of treatment
Combination
therapy 97 14.50
2.04
(1.29 to
3.23)
0.0024
1.73
(1.09 to
2.76)
0.0211
Monotherapy
30 5.63
** Only patients available for EGFR by IHC.
International Journal Of Current Medical And Pharmaceutical Research, Vol. 2, Issue, 9, pp.657-664, September, 2016
662
with CRT (TMZ+RT) vs. CRT where the differences on
survival was in more than 3 months in favor to nimotuzumab
arm; however did not reach statistical significance(10). It is not
doubt the benefit to CRT based TMZ, however the
combination with nimotuzumab could provide a greater
benefit, but we need explore in a major sample. Specifically in
Cuba is not possible evaluate the ample use of TMZ due to
restrictions imposed by the United States.
To best understanding regards sensible factors to improve
survival, regression analyses discriminated those patients who
have younger 50 years and histology grade non GBM were the
subgroup more beneficed to this drug refers with multimodal
treatment added nimotuzumab. This find is rational to describe
as the most important prognosis factors for HGG with
independent to treatment (34, 35). Even so, it is well known as
a poor KPS and incomplete surgical resection or only biopsy,
impedes the survival improvement (35-38). In this study those
variables have a similar behavior to literature ready described
on.
Moreover EGFR status was not correlated with nimotuzumab
response. Same notice is described byYang et al., in GBM
patients treated with CRT and nimotuzumab (39). We consider
it could be influenced for the very limited sample tested or due
to heterogeneity of HGG tumor patients. On the other hand,
Westphal´s study evaluated EGFR amplified and do not found
differences with regard to this marker expression and response
to this MoAb in GBM patients. Nevertheless, authors noted a
subset of patients characterized by residual tumor and non-
methylated MGMT promoter with greatest benefit to
nimotuzumab (19.0 vs. 13.8 months, P = 0.3648)(10). The
biology of responsiveness is still unclear for nimotuzumab, so
those finds suggest a differentiate evaluation of efficacy-
predicting tumor parameters for nimotuzumab in the treatment
of GBM.
CONCLUSION
Results of this Phase IV trial is consistent to safety profile and
adherence as maintenance prolonged treatment, in HGG
patients treated with nimotuzumab below RCT. Although
survival benefit could be marginal with respect to CRT based
TMZ, it is no doubt that nimotuzumab might improve survival
time over RT alone and may have promising value in the
combination treatment. Furthermore those approaches must be
evaluated in patients selected on the basis of having predictor
biomarkers.
The results of this PMS provide further information about
drugs´ s safety, efficacy or optimal use to take account for
multimodal treatment in HGG patients.
Nimotuzumab treatment can be currently recommended as
standard treatment for adults newly diagnosis with HGG, in
combination with radiotherapy, including maintenance long
term treatment. The combination with chemo-radiotherapy
could be also beneficial. On the other hand, this MoAb as
monotherapy produced poor results and is not to be
recommended.
Funding
This Phase IV trial was funded and undertaken by Center of
Molecular Immunology (CIM) and Cuban government in
accordance with the conditions for approval. CIM was
responsible for design, development of the protocol and for the
analysis of the data in contract agreement with CENCEC who
was responsible for monitoring, data management and
statically analysis for this trial mostly.
Conflict of Interest
GS, PP, and ALare employees of the Center of Molecular
Immunology (CIM), the research institution that patented and
manufactures nimotuzumab. RU, MAM, and LP are
employees of the National Coordinating Center of Clinical
Trials, clinical research coordinator (CRO) who was hired by
CIM.
Rests of authors have no competing interests.
Acknowledgements
We are grateful to all medical team, patients and family for
their special cooperation.
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f f f f f f f
... Además, pudieran estar asociados a morbilidades propias de la enfermedad de base, de la cirugía previa incluso a enfermedades cardiovasculares y metabólicas. 2,11,12 En referencia a la histología la población de pacientes con Glioblastoma multiforme en los EPA fue mayoritariamente signi cativa en contraste con la de los estudios pre registro de igual diagnóstico. Esto es de esperar dado que en una población real el GBM es más frecuente que el AA. 1 Por otro lado, en relación con los tratamientos recibidos, la mayoría de los pacientes se expusieron a la combinación del nimotuzumab y radioterapia; sin embargo, en la práctica (EPA) aunque en una frecuencia menor, se identi caron otras modalidades terapéuticas como la combinación con quimio-radioterapia y como simple terapia. ...
... Ciertamente la quimioradioterapia basada en temozolamida es el estándar internacional para los gliomas malignos de alto grado, 15 pero no es la generalidad en nuestro medio por res- Table 2. Características demográficas y clínicas entre los estudios pre-registro y pos-registro tricciones internacionales para acceder a la temozolamida. 11,12 La combinación de nimotuzumab y quimio-radioterapia se ha evaluado en estudios controlados, pero no tenemos estudios pos autorización para compararlos, 10 pero no tenemos estudios pos autorización para compararlos en nuestro medio. Los pacientes que recibieron nimotuzumab como simple terapia, suceden como consecuencia de asuntos organizativos de la práctica habitual, tales como distanciamiento del local de la radioterapia y del destinado para recibir nimotuzumab, el tiempo de espera para recibir radioterapia, entre otras. ...
... Los pacientes que recibieron nimotuzumab como simple terapia, suceden como consecuencia de asuntos organizativos de la práctica habitual, tales como distanciamiento del local de la radioterapia y del destinado para recibir nimotuzumab, el tiempo de espera para recibir radioterapia, entre otras. 11,12 Toda vez identi cada esta desviación se propusieron estrategias administrativas para minimizarla. ...
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... Además, pudieran estar asociados a morbilidades propias de la enfermedad de base, de la cirugía previa incluso a enfermedades cardiovasculares y metabólicas. 2, 11,12 En referencia a la histología la población de pacientes con Glioblastoma multiforme en los EPA fue mayoritariamente significativa en contraste con la de los estudios pre registro de igual diagnóstico. Esto es de esperar dado que en una población real el GBM es más frecuente que el AA. 1 Por otro lado, en relación con los tratamientos recibidos, la mayoría de los pacientes se expusieron a la combinación del nimotuzumab y radioterapia; sin embargo, en la práctica (EPA) aunque en una frecuencia menor, se identificaron otras modalidades terapéuticas como la combinación con quimio-radioterapia y como simple terapia. ...
... Ciertamente la quimioradioterapia basada en temozolamida es el estándar internacional para los gliomas malignos de alto grado, 15 pero no es la generalidad en nuestro medio por restricciones internacionales para acceder a la temozolamida. 11,12 La combinación de nimotuzumab y quimio-radioterapia se ha evaluado en estudios controlados, pero no tenemos estudios pos autorización para compararlos, 10 pero no tenemos estudios pos autorización para compararlos en nuestro medio. Los pacientes que recibieron nimotuzumab como simple terapia, suceden como consecuencia de asuntos organizativos de la práctica habitual, tales como distanciamiento del local de la radioterapia y del desti- Table 2. Características demográficas y clínicas entre los estudios pre-registro y pos-registro nado para recibir nimotuzumab, el tiempo de espera para recibir radioterapia, entre otras. ...
... Los pacientes que recibieron nimotuzumab como simple terapia, suceden como consecuencia de asuntos organizativos de la práctica habitual, tales como distanciamiento del local de la radioterapia y del desti- Table 2. Características demográficas y clínicas entre los estudios pre-registro y pos-registro nado para recibir nimotuzumab, el tiempo de espera para recibir radioterapia, entre otras. 11,12 Toda vez identificada esta desviación se propusieron estrategias administrativas para minimizarla. ...
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