Journal of Cancer Therapy, 2013, 4, 59-75
http://dx.doi.org/10.4236/jct.2013.48A010 Published Online September 2013 (http://www.scirp.org/journal/jct)
Current Algorithm for Treatment of Advanced NSCLC
Patients: How to Include Active Immunotherapy?*
Gisela Gonzalez1#, Arlhee Diaz-Miqueli1, Tania Crombet1, Luis E. Raez2, Agustin Lage1
1Center of Molecular Immunology, Havana, Cuba; 2Memorial Cancer Institute, Memorial Health Care System, Florida International
University, Miami, USA.
Received July 19th, 2013; revised August 18th, 2013; accepted August 26th, 2013
Copyright © 2013 Gisela Gonzalez 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.
ABSTRACT
Despite the availability of different treatments for advanced NSCLC, all of them have a palliative intention and a cure
for the disease is unlikely. Thus, advanced lung cancer remains as an unmet medical need. Chemotherapy has been used
as the therapy of choice for advanced NSCLC patients, but it is mainly limited by the patient’s performance status.
More recently, targeted therapies have introduced more specific treatment options that show efficacy in specific niche
of patients, but precisely due to their target specificity, they usually provoke early resistance. In addition to these limita-
tions, most of the best drugs currently used for treatment of advanced NSCLC show small increases in patient survival
with severe associated toxicity. Novel drugs with low toxicity that could be given chronically to control the advanced
disease can make a difference. They could allow the management of advanced cancer as a chronic disease that, even
when not cured, it can be controlled for long periods of time offering patients a good quality of life. Active-specific
immunotherapy is an area of oncology that is rapidly expanding with encouraging results. Cancer vaccines against
many potential targets have shown to increase patient survival in clinical trials at all stages NSCLC, when included as
first-line, maintenance, or second-line therapy. Safety of cancer vaccines supposes a new hope for cancer therapy, and
this unique characteristic makes it possible to be used in sub-sets of patients that cannot receive other approved treat-
ments because of their high toxicity. In this paper, authors propose how active immunotherapy could be included in the
current algorithm for treatment of advanced NSCLC patients.
Keywords: Lung Cancer Therapy; Active Immunotherapy; Cancer Vaccines
1. Introduction
Lung cancer has been the most common cancer in the
world for several decades, and by 2008, there were an
estimated 1.61 million new cases, representing 12.7% of
all new cancers. Lung cancer is the leading cause of can-
cer mortality in the US and worldwide, accounting for
1.38 million deaths (18.2% of the total) [1]. Lung cancer
figures show a close similarity between incidence and
mortality, demonstrating that almost all patients diag-
nosed with lung cancer died from the disease. Approxi-
mately 85% of newly diagnosed lung cancers are catego-
rized as non-small cell lung cancers (NSCLC) [2]. NSCLC
includes squamous cell carcinoma, adenocarcinoma, and
large cell carcinoma. Unlike other common types of solid
tumors, such as breast cancer and colon cancer, there are
no approved screening modalities for early detection of
lung cancer in the general population [3]. As a result,
many of these patients have locally advanced or metas-
tatic disease by the time they become symptomatic and
present for care. Patients with stage IIIb or IV NSCLC
are deemed to have unresectable tumors and, while they
may benefit from palliative chemotherapy, radiation or
both, a cure is unlikely. Even if the tumor can be com-
pletely resected, the 5-year mortality is 40% in stage I
disease, 66% in stage II disease, and 75% in stage IIIa
loco-regional disease. Micrometastases are commonly
left behind after surgical resection, resulting in eventual
relapse. As such, a diagnosis of NSCLC carries a poor
prognosis under all circumstances [4].
Lung cancer is usually diagnosed at advanced stages,
when the disease is not curable, and available therapies
are mainly palliatives. Several drugs are available for treat-
ment of advanced NSCLC, some of them are limited to a
*Dr Luis E. Raez has received research support from Glaxo-Smith
Kline and Merck Serono.
#Corresponding author.

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 60
specific niche of patients, showing only a marginal im-
provement in patient survival (real clinical impact) with
high or moderate associated toxicity. For those reasons,
advanced lung cancer remains as an unmet medical need.
Advanced NSCLC patients are not always amenable to
receive the existing onco-specific therapies. Chemother-
apies are very toxic and tolerated only by patients with
an acceptable performance status (PS). Other biologic
drugs have demonstrated effect only in small group of
patients with specific genetic characteristics; but given its
high specificity, these drugs usually develop resistance.
Additionally, when patients receive all possible onco-
specific treatments and have disease progression, they
are considered “terminal patients” that will only receive
best supportive care to enhance as much as possible their
quality of life. But at this stage, even with tumor pro-
gression, patients can live with a quality of life that will
depend on the management of their disease. Another
group of patients, who are unfit for available treatments
are amenable to receive non-toxic treatments that might
help increase overall survival with a good quality of life,
such as immunetherapies. This is the case of cancer vac-
cines that can be given chronically due to its low toxicity,
even in advanced stages of disease [5,6]. That means a
major change in advanced cancer treatment: the possibil-
ity of a chronic treatment that converts advanced cancer
into a controlled chronic disease, offering patients a good
quality of life.
In this scenario, biotechnology has become an impor-
tant source of new products for cancer treatment. Ac-
cording to the 2011 Pharma Report, from 900 biotech-
nological products under development, 352 are devoted
to cancer treatment: 170 are monoclonal antibodies and
90 are cancer vaccines. That means 40% of worldwide
biotechnology now is devoted to cancer immunotherapy.
Biotechnology gives technological tools for obtaining
products that can be designed and produced to target
specifically tumor cells. Their specificity gives them a
precious advantage translated in a better toxicity profile
when compared with current onco-specific therapies (i.e.
chemotherapy) that provoke systemic toxicity due to
their lack of specificity for tumor cells. In this paper we
review the state of the art in NSCLC therapy; the algo-
rithm of existing treatments for advanced (stages IIIb and
IV) NSCLC patients; and how non-toxic therapies (i.e.
cancer vaccines) can be inserted in such algorithm for
patient’s benefit.
2. Which Is the Current Algorithm for
Treatment of Advanced NSCLC?
The current algorithm for therapy of advanced NSCLC,
takes into account the patients characteristics; basically:
PS, tumor histology and the presence of “driver muta-
tions” (Figure 1). Once diagnosed, a patient with ad-
vanced NSCLC must be characterized according these
PS 0-1 PS 0-3
Non-squamous NSCLC
EGFR
squamous NSCLC
EGFR
∆EGFR EML4/MK
Taxane doublet/Bevacizumab
Pemetrexed/Bevacizumab
Gemcitabine or taxane doublet Erlotinib/gefitinib
(10% Caucasian
population)
Crizotinib
(5% advanced NSCLC)
1st line therapy
Maintenance
Crizotinib
CR, PR, SD
Erlotinib CR, PR, SD
Erlotinib/gefitinib
CR, PR, SD
Bevacizumab or erlotinib
Pemetre xe
d
(50% elegible for
bevacizumab)
PD
Docetaxel or erlotinib
or pemetrexed PD
Chemotherapy
PD
Docetaxel or Erlotinib
2nd line therapy
Clinical
characterization
Histological
characterization
Figure 1. Current algorithm of treatment of advanced NSCLC patients.

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 61
to decide the most appropriated treatment to be as-
signed. According to this algorithm, available therapies
can be used in first-line, maintenance and second-line
therapy in patients, depending of their clinical, histologi-
cal and molecular tumor characteristics. However, cur-
rently approved therapies have a limited potential to in-
crease patient survival and a high or moderate toxicity
(Table 1).
Chemotherapy, as first-line treatment for advanced
NSCLC (PS 0-1) offers a median OS of approximately
10 months, with associated hematologic toxicity, nephro-
toxicity, nausea and vomiting [7]. The addition of bevaci-
zumab to the first-line therapy in non-squamous NSCLC
(PS 0-1), increased in 2 months the median OS of che-
motherapy, but added new severe adverse events such as
hypertension, proteinuria, bleeding, febrile neutropenia,
thrombocytopenia, hyponatremia, rash, and headache [8].
The use of tyrosine kinase inhibitors (TKI) gefitinib
Table 1. How the currently available therapies for advanced NSCLC patients have been approved.
Drug/combination Patients Treatment line Safety Efficacy Ref
Platinum-based Advanced NSCLC First Line
PS 0-1
Hematologic toxicity,
nephrotoxicity, and nausea
and vomiting
RR 34 %
OS 10 months [7]
Carboplatin+ paclitaxel
+ bevacizumab
Non squamous
NSCLC
First Line
PS 0-1
Hypertension, proteinuria,
bleeding, neutropenia, febrile
neutropenia, thrombocytopenia,
hyponatremia, rash, and
headache
OS (CP - bev vs. CP):
12.3 vs. 10.3 months
PFS (CP - bev vs. CP):
6.2 vs. 4.5 months
[8]
Gefitinib EGFR mutant First line
PS 0-3
Rash and diarrhea with
gefitinib, and appetite loss,
sensory neuropathy, and
myelotoxicities
PFS (gefitinib vs. CTP):
10.8 vs 5.4 months
OS (gefitinib vs. CTP):
27.7 vs. 26.6 months
[10]
Erlotinib EGFR mutant First line
PS 0-3
Rash and increased
aminotransferase
concentrations
ORR (erlotinib vs. CTP):
58 % vs. 15 %
PFS: 13.1 vs. 4.6 months
[9]
Crizotininb ALK-EML4 m
Fusion protein
First line
PS 0-3
Visual effects, nausea,
diarrhea, constipation,
vomiting, and peripheral
oedema
OR: 60.8 %
Median PFS was
9.7 months
[11]
Pemetrexed Non squamous
NSCLC
Continuation
maintenance
PS 0-1
Anaemia, neutropenia,
and fatigue
PFS (pemetrexed vs.
placebo): 4.1 vs 2.8
months
[12]
Pemetrexed Non squamous
NSCLC
Switch maintenance
PS 0-1 Neutropenia and fatigue
PFS (pemetrexed vs.
placebo): 4.3 vs 2.6
months
OS (pemetrexed vs.
placebo): 13.4 vs 10.6
months
[13]
Docetaxel NSCLC Switch maintenance
PS 0-1
Neutropenia, thrombocytopenia,
anemia, fatigue, dyspnea
PFS (immediate vs.
delayed): 5.7 vs 2.7
months
[14]
Erlotinib NSCLC Switch maintenance
PS 0-3 Rash
PFS (pemetrexed vs.
observation):
2.9 vs 1.9 months
[15]
Docetaxel NSCLC Second line
PS 0-1
Neutropenia and febrile
neutropenia
OS (docetaxel vs. BSC):
7.5 vs 4.6 months [16]
Pemetrexed Non squamous
NSCLC
Second line
PS 0-1
Neutropenia and febrile
neutropenia
OS (pemetrexed vs.
docetaxel): 8.3 vs 7.5
months
[17]
Erlotinib NSCLC Second line
PS 0-3
Diarrhea, rash, anorexia,
nausea
OS (erlotinib vs.
docetaxel):
6.7 vs 4.7 months
[18]
Abbreviations: BSC, best supportive care; bev, bevacizumab; CP, carboplatin; CPT, cisplatin; NSCLC, non-small cell lung cancer; OS, overall survival; ORR,
verall response rates; PFS, progression-free survival; PS, performance status; RR, response rates. o

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 62
and erlotinib as first-line in patients with mutated forms
of the epidermal growth factor receptor (EGFR) NSCLC
(PS 0-3) (10% of advanced NSCLC patients among
Caucasian population), increased in 5.4 months the PFS
without modifying the OS as compared to chemotherapy
alone for this small number of patients, with adverse
events typical of TKIs, including cutaneous rash and di-
arrhea [9,10]. More recently, crizotinib was approved for
using in NSCLC patients, PS 0-3, that present the ALK-
EML4 fusion protein (only 5% of advanced NSCLC pa-
tients) as first-line therapy because its ability to increase
PFS—but not OS—in advanced NSCLC patients [11].
Adverse events associated to the administration of crizo-
tinib include visual effects, nausea, diarrhea, constipation,
vomiting, and peripheral edema.
In maintenance therapy, pemetrexed was approved as
continuation maintenance in PS 0-1 non-squamous
NSCLC patients [12]. In this setting, pemetrexed added
1.3 months in PFS, despite this increase was not trans-
lated into a better OS. It has also been used as switch
maintenance therapy in this group of patients showing an
increase of 2.8 months in OS [13]. Pemetrexed-related
adverse events include anemia, neutropenia, and fatigue.
Docetaxel it is also used as switch maintenance therapy
resulting in a 3-month increase PFS, despite this is not
translated into a better OS [14]. Most frequent docetaxel-
associated adverse events are neutropenia, thrombocy-
topenia, anemia, fatigue and dyspnea. Erlotinib as switch
maintenance therapy has shown to increase progression
free survival, but not OS, of treated patients [15].
In the scenario of second-line therapy, docetaxel was
approved for treating patients with PS 0-1, increasing OS
in 2.9 months as compared with best supportive care, but
adding the previously described adverse events associ-
ated to the use of this drug [16,17]. Erlotinib was also
approved in this setting, but in patients with PS 0-3, with
a two-month increased OS compared with docetaxel, and
associated-adverse events (diarrhea, cutaneous rash, anor-
exia and nausea) [18].
Looking at these figures, the approved drugs for ad-
vanced NSCLC therapies have still a limited impact in
patient OS (maximum of 3 months), and its use is fre-
quently associated with the occurrence of severe averse
events that affect patient’s quality of life. Therefore, new
approaches are needed to improve current outcomes [19].
3. What Is Coming as Second-Generation
Agents for Treatment of Advanced
NSCLC Patients?
As has been previously described, erlotinib and gefitinib
are currently used in the first-line treatment of patients
with advanced NSCLC and EGFR-activating mutations,
as well as second- and third-line settings in unselected
patients, regardless of EGFR mutations status [20]. How-
ever, patients that initially respond to this treatment, usu-
ally develops acquired resistance after a median of 12 -
16 months [21]. Once progression occurs, further treat-
ment options are very limited due to the performance
status of patients who are unable to tolerate toxicities
associated to cytotoxic chemotherapy. Thus, new therapy
options are urgently needed after the progression to first-
generation anti-EGFR agents. Molecularly targeted ther-
apies under investigation in NSCLC include ErbB family
blockers, multityrosine kinase inhibitors, c-Met inhibi-
tors and antiangiogenic agents. Table 2 summarizes the
phase II and phase III clinical trials of investigational
new drugs for the treatment of advanced NSCLC pa-
tients.
Most of the second generation of TKI acts through an
irreversible, covalent binding to ATP-binding site in the
kinase domains of the EGFR [22]. This covalent binding
leads to longer suppression of tyrosine kinase activity, as
it is suppressed until the synthesis of new receptors.
Among the second generation of TKIs afatinib has
shown thus far the most extensive evaluation with prom-
ising results, being recently approved in July 2013 as first-
line therapy for patients with EGFR mutations [23-26].
However, the general consensus for using afatinib as a
second- or third-line treatment in patients with EGFR
activating mutations is that the drug does not differs from
current approved first-generation TKIs gefitinib and er-
lotinib in terms of OS or PFS when used for unselected
patients and does not have FDA approval for that.
The amplification of the Met gene is another mecha-
nism of resistance to currently available targeted treat-
ments for NSCLC [27]. Tivatinib is a non-ATP-com-
petitive inhibitor of the Met signaling pathway, which
has been extensively tested as a second-line therapy, in
combination with TKI erlotinib in patients with or with-
out EGFR-activating mutations. However, a phase II trial
initially conducted with tivantinib failed to increase OS
and PFS compared with erlotinib plus placebo [28].
Moreover, a subsequent phase III trial was recently
stopped early after an interim analysis that showed the
study would not meet its primary endpoint of OS [29].
In 2006, the US Food and Drug Administration ap-
proved bevacizumab for the first-line treatment of pa-
tients with advanced non-squamous NSCLC in combina-
tion with cytotoxic drugs carboplatin and paclitaxel [30].
However, the develop of tumor resistance frequently
occurs, permitting only the half of the patients being eli-
gible for bevacizumab therapy [31]. For such reason, a
considerable number of new antiangiogenic agents are
currently being evaluated for the treatment of patients
with NSCLC in combination with cytotoxic drugs, in-
cluding sorafenib and sunitinib. Nevertheless, sorafenib
did not meet its primary endoint in two separate large p

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 63
Table 2. Phase II and phase III clinical trials of investigational new drugs for the treatment of advanced NSCLC patients.
Trial design Patients Drug/
combination
Treatment
line
Most common
grade ≥3 AEs (%)
Efficacy
(primary endpoint)
Trial
success Ref
Afatinib
LUX-Lung2;
phase II;
(N = 129)
Ongoing/not
recruiting
∆EGFR Afa vs Placebo
First- and
second-line
PS: 0-2
Diarrhea 22;
rash 28 at 50 mg
Diarrhea 7;
rash 7 at 40 mg
(RR: 61%) Met primary
endpoint [24]
LUX-Lung1;
phase IIb/III;
(N = 585)
Completed
Advanced/
metastatic NSCLCAfa vs Placebo
Second- or
third-line
PS: 0-2
Diarrhea 17; rash 14
(OS: 10.8 vs
12.0 months)
PFS: 3.3 vs
1.1 months
Did not met
primary
endpoint
[26]
LUX-Lung3;
phase III;
(N = 345)
Ongoing/not
recruiting
∆EGFR Afa vs Cis/Pem First-line
PS: 0-2 Diarrhea; Rash (PFS: 11.1 vs
6.9 months)
Met primary
endpoint [25]
LUX-Lung6;
phase III;
(N = 364)
Ongoing/not
recruiting
∆EGFR Afa vs Gem/Cis First-line
PS: 0-2 NR (PFS) NR NR None
Tivantinib
Phase II
(N = 167)
Completed
Advanced NSCLCErlotinib/Tiv vs
Erlotinib/Placebo Second-line (PFS: 3.8 vs 2.3 months) OS: 8.5 vs 6.9 months
Did not met
primary
endpoint
[28]
MARQUEE
Phase III
(N = 988)
Ongoing/not
recruiting
∆EGFR/
∆K-ras/
Met amplif
Erlotinib/Tiv
vs Erlotinib/
Placebo
Second-lineNR (PFS) NR [29]
Sorafenib
ESCAPE;
phase III;
(N = 926);
Halted
Advanced
NSCLC
Car/Pac/Sor vs
Car/Pac/Plac First-line Rash (9), hand-foot disease (8)
(OS: 10.7 vs
10.6 months) PFS:
4.6 vs 5.4 months
Did not met
primary
endpoint
[32]
NExUS;
Phase III;
(N = 904);
Completed
Advanced
NSCLC
Gem/Cis/Pla vs
Gem/Cis/Sor First-line
Thrombocytopenia (9.9)
Hand-foot skin
reaction (8.6)
Fatigue (7.3)
(OS: 376 vs
379 days)
PFS: 183 vs
168 days
Did not met
primary
endpoint
[33]
Sunitinib
SABRE-L;
phase II;
(N = 56);
Terminated
Advanced
NSCLC Car/Pac/Bev/Sun First-line
Neutropenia (65.5)
Thrombocytopenia (37.9)
Leukopenia (27.6)
Febrile neutropenia (13.8)
Hypertension (10.3)
(Best tumor response):
PR (8% vs 26%)
PFS: 3.8 vs 4.5 months
OS: 6.6 months vs NR
Did not met
primary
endpoint
[44]
CALGB30704;
phase II;
(N = 225);
Ongoing/not
recruiting
Advanced
NSCLC
A: Sun
B:Pem
C:Sun + Pem
Second-lineNR (PFS) NR NR None
phase II;
(N = 16);
Unknown
Advanced
NSCLC Sun/Doc/Cis Salvage NR (RR) NR NR None
phase III;
(N = 244);
Recruiting
Advanced
NSCLC
Chemo + Sun
maintenance vs
Chemo +
maitenance
MaintenanceNR (PFS) NR NR None

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 64
Continued
Aflibercept
VITAL;
phase III;
(N = 913);
Active
Advanced
NSCLC
Afli + Doc vs
Placebo+Doc Second-lineNR (OS) NR
Did not met
primary
endpoint
[35]
Vandetanib
ZEAL;
phase III;
(N = 510);
Completed
Advanced
NSCLC
Van + Pem vs
Placebo + Pem Second-line Rash (6) Diarrhea (4)
(PFS 17.6 vs
11.9 weeks)
OS 10.5 vs
9.2 weeks
Met primary
endpoint [36]
ZEST;
phase III;
(N = 1240);
Completed
Advanced
NSCLC
Van vs
Erlotinib Second-line
Rash (3)
Diarrhea (5)
Fatigue (4)
Dyspnea (4)
(PFS 2.6 vs
2.0 months)
OS 6.9 vs
7.8 months
Did not met
primary
endpoint
[43]
ZODIAC;
phase III;
(N = 1391);
Completed
Advanced
NSCLC
Van + Doc vs
Placebo + Doc Second-line
Rash (9)
Neutropenia (29)
Leukopenia (14)
Febrile
neutropenia (9)
(PFS 4.0
vs 3.2 months)
OS 10.6 vs
10.0 months
Did not met
primary
endpoint
[42]
ZEPHYR;
phase III;
(N = 924);
Completed
Advanced
NSCLC
Van vs
Placebo
Second- or
third-line NR
(OS 8.5 vs
7.8 months)
PFS: NR
Did not met
primary
endpoint
[40]
Cediranib
BR24;
phase II/III;
(N = 296);
Completed
Advanced
NSCLC
Ced/Car/Pac
vs Placebo/Car/Pac First-line
Hypertension (19)
Diarrhea (15)
Fatigue (29)
Dyspnea (10)
(PFS) NR
OS: 10.5
vs. 10.1 months
NR [37]
BR29;
phase III;
(N = 306);
Closed
Advanced
NSCLC
Ced/Car/Pac
vs Placebo/Car/Pac First-line NR (OS) NR NR None
Nintedanib
LUME-Lung1
phase III;
(N = 1300);
Ongoing/not
recruiting
Advanced
NSCLC
Nin/Doc vs
Placebo/Doc Second-lineNR (PFS) NR NR None
LUME-Lung2
phase III;
(N = 1302);
Ongoing/not recruiting
Advanced
NSCLC
Nin/Pem vs
Placebo/Pem Second-line NR (PFS) NR NR None
Motesanib
phase II;
(N = 186);
Terminated
Advanced
NSCLC
A:
Mot 125 mg once/
daily/Pac/Car
B:
Mot 75 mg twice/
daily/Placebo/Pac/
Car
C: Car/Pac/Ava
First-line
Diarrhea (19 and 11)
Fatigue (17)
Dehydration
(17 and 11)
Anorexia (12)
(RR)
A: 30%; B: 23%;
C: 37%
PFS 7.7 vs 5.8
vs 8.3 months
OS: 14.0 vs 12.8
vs 14.0 months
Did not met
primary
endpoint
[38]
MONET1
phase III;
(N = 1090);
Terminated
Advanced
NSCLC
Pac/Car/Placebo
vs Pac/Car/Mot First-line Neutropenia (22), Diarrhea (9)
(OS: 13.0
vs 11.0 months)
PFS: 5.6 vs
5.4 months
Did not met
primary
endpoint
[39]
Abbreviations: ΔEGFR, mutated epidermal growth factor receptor; Afa, afatinib; Afli, aflibercept; Amplif, amplification; Bev, bevacizumab; Car, carboplatin;
Cer, cediranib; Chemo, chemotherapy; Cis, cisplatin; Doc, docetaxel; Gem, gemcitabine; Mot, motesanib; Nin, nintedanib; NR, not reported; NSCLC,
non-small cell lung cancer; OS, overall survival; Pac, paclitaxel; PR, partial response, Pem, pemetrexed; PS, performance status; PFS, progression-free survival;
R, response rates; Sor, sorafenib; Sun, sunitinib; Tiv, tivantinib; Van, vandetanib. R

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 65
phase III studies that evaluated the drug as a first-line
treatment [32,33] while further results are awaited for
sunitinib from ongoing trials conducting in a different
setting of patients [34].
Other investigational new drugs for the treatment of
advanced NCSLC patients are at different stages of de-
velopment (Table 2). However, most of them have
shown controversial results or still have a low level of
evidence for efficacy [35-39]. An illustrative example is
vandetanib, a multitargeted TKI, which failed to improve
OS or PFS in a series of four phase III clinical trials as
monotherapy [40] or combined to chemotherapy [36,41,
42] or erlotinib [43]. Based on these negative results, the
FDA withdrew its approval in NSCLC. In addition, the
administration of most of these drugs has been associated
with the occurrence of severe (grade ≥ 3) adverse events.
For example, the randomized phase II study that evalu-
ated untreated NSCLC patients receiving either car-
boplatin/paclitaxel/bevacizumab with or without sunit-
inib, was not completed due to the poor tolerability of
patients to receive the drug (of patients receiving sunit-
inib, 52% required treatment interruption and 59% dis-
continued the treatment because of adverse events) [44].
4. New Paradigm for the Treatment of
Patients with Advanced NSCLC: The
Transition to a Chronic Disease
Up to date, advanced cancer cannot be cured. However,
therapeutic progress is opening the possibility of trans-
forming cancer into a chronic disease compatible with
years of good quality of life. This trend is clearly identi-
fiable in lymphoma, prostate, breast and ovarian tumors,
where a 5-year survival rates for the advanced disease is
moving near 30% and beyond [45]. Could this be also an
attainable goal for advanced NSCLC?
In the last years, a trend to increased survival has been
observed in patients with advanced NSCLC with the in-
clusion of novel therapeutic approaches. From two-year
survival rates of 0% - 10% with single-agent chemother-
apy, the figure improves to 20% by using platinum dou-
blets. More recently, maintenance with pemetrexed in-
creased up to 25% [46], a data subsequently enhanced
with the use of angiogenesis and EGFR blocking agents
and small molecules TKIs. This trend of increased sur-
vival in advanced tumors, suggest the possibility to
transform advanced cancer into a chronic disease. How-
ever, the main drawback of existing drugs for advanced
NSCLC treatment is its high toxicity. Most of the ap-
proved drugs for advanced NSCLC treatment are highly
toxic.
Chemotherapies exert its cytotoxic effects un-specifi-
cally, affecting not only tumor cells, but also normal cells
and tissues. The up to date approved targeted therapies
provokes related adverse events, i.e. drugs targeting the
VEGF system like bevacizumab, are associated with
bleeding; and drugs targeting the EGFR system like
cetuximab, erlotinib and gefitinib, with skin rash and
others adverse events. The use of these drugs is then
subjected to patient’s tolerability; even when a minority
of patients that tolerate these adverse events can receive
it under long-term treatments. However, we still need
therapy options that can be used chronically in a wider
patient population.
The goal of transform advanced cancer into a chronic
disease, require therapeutic weapons with low toxicity
that could be used chronically. These weapons are pro-
vided by biotechnology, with the development of novel
specific immunotherapies approaches for cancer treat-
ment. With the availability of these target-specific, non-
toxic drugs, such as cancer vaccines, a major change in
the management of advanced cancer is foreseen.
Drugs with low toxicity and tolerable by the majority
of patients can be administered chronically, without risk
of accumulative toxicity, and advanced cancer could be
treated as a chronic disease that cannot be cured, but
controlled for long time periods, with a good quality of
life for the patients [5]. This is not the only case in the
history of medicine that a new drug could change the
curse of a disease. In fact, diabetes used to be a death
sentence until 1922, when the medical researcher Fre-
derick Banting and a colleague, Dr. John Macleod, dis-
covered the insulin [47]. Insulin allowed a therapeutic
management of diabetes that makes it a controllable,
chronic disease. Cancer vaccines could be thus the “insu-
lin” of cancer patients.
5. Developing Active Immunotherapy for
NSCLC Treatment
The immune system plays an important role in the inter-
action between a cancer and its host. Scientists have long
understood that tumors can be recognized by a patient’s
immune system. Rare reports dating back to the 1800s
have documented spontaneous tumor regression after
infectious events [48]. Such regressions, however, are
usually seen in only very immunogenic tumors, such as
renal cell carcinoma and melanoma [49,50]. NSCLC is a
notoriously non-immunogenic cancer, or a cancer in
which we have been unable to trigger an appropriate
immune response for multiple reasons; and this charac-
teristic has limited the development of immune therapies
for NSCLC [51]. If, however, the immune system can be
stimulated to recognize the tumor as an antigen, it can be
utilized to specifically attack the tumor. This strategy
allows the patient to avoid the toxicities, like myelosu-
pression, neutropenic fever, mucositis, hair loss and gas-
trointestinal disturbance that arise from indiscriminately
destroying all dividing cells with systemic chemotherapy.

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 66
Active-specific immunotherapy is an area of oncology
that is rapidly expanding and delivering promising results.
Therapeutic vaccines have been developed for the treat-
ment of different types of cancers. For example, Sipu-
leucel-T is a vaccine in phase III clinical trials that
modulates T cell activity in patients with metastatic me-
lanoma and castrate-resistant prostate cancer [52,53].
There is evidence to suggest that a similar approach
could be very beneficial to the survival and quality of life
of NSCLC patients [54], and has been proposed as a
novel method to palliate metastatic and non-operable
NSCLC patients and as an adjuvant therapy to surgical
resection.
A therapeutic vaccine is composed of one or more tu-
mor antigens, and sometimes with an adjuvant that the
immune system recognizes as foreign. Such a vaccine in-
duces a powerful and enduring immune response to the
specific tumor antigen(s). Vaccines can either be immune
system modulators directed to allow de novo generation
of antitumor activity or agents that elicit specific antitumor
activity, known as therapeutic cancer vaccines [55]. Ther-
apeutic cancer vaccines are classified in either whole-
cell vaccines or vaccines that target specific antigens.
Different cancer vaccines has been developed for all
stages of NSCLC, being actually in phase III clinical
trials (Table 3 and Figure 2) [56,57]; among them, the
whole cell vaccine, Belagenpumatucel-L, targeting the
TGF-β2. There are other vaccines that target specific
antigens in cancer cells, including this targeting the me-
lanoma-associated antigen A3 (MAGE-A3), the L-BLP25
Table 3. Phase III clinical trials with therapeutic vaccines in NSCLC.
Trial design Target Stage Study design Primary end point Estimated completed date
Belagenpumatucel-L
STOP (N = 506)
Phase III
Completed
TGF-β2 IIIa, IIIb or IV
Vaccine + BSC vs placebo
+ BSC after response to
chemotherapy
OS October 2012
MAGE-A3 MAGRIT
(N = 2270) Phase III
Melanoma-associated
antigen M3 Ib, II or IIIa
Resection + chemotherapy
+ vaccine vs resection
+ vaccine in MAGE A 3
+ patients
DFS October 2016 [61]
L-BLP25 START
(N = 1476) Phase III MUC 1 protein IIIb
L-BLP25 + BSC vs BSC
alone after response to
chemotherapy
OS September 2014 [64]
TG4010 TIME
(N = 1000) Phase III MUC 1 protein IV Chemotherapy + TG4010
vs chemotherapy + placeboOS December 2016
CIMAvax-EGF (N = 579)
Phase III Completed EGF IIIb or IV
CIMAVAX + BSC vs
BSC alone after responding
to chemotherapy
OS Completed [83]
Abbreviations: BSC, best supportive care; DFS, disease-free survival; OS, overall survival; TGFβ2, transforming growth factor β2.
PS 0-1 PS 0-3
Non-squamous NSCLC
EGFR
squamous NSCLC
EGFR
∆EGFR EML4/MK
Taxane doublet/Bevacizumab
Pemetrexed/Bevacizumab
Gemcitabine or taxane doubletErlotinib/gefitinib
(10% Caucasian
population) Crizotinib
(5% advanced
NSCLC
)
1st line therapy
Maintenance
Crizotinib
CR, PR, SD
Erlotinib CR, PR, SD
Erlotinib/gefitinib
CR, PR, SD
Bevacizumab or erlotinib
Pemetre xe
d
(50% elegible for
bevacizumab)
PD
Docetaxel or erlotinib
or pemetrexed
PD
Chemotherapy
PD
Docetaxel or Erlotinib
2nd line therapy
Clinical
characterization
Histological
characterization
Cancer Vaccines
Cancer Vaccines
TG4010
CIMAvax EGF
Belagenpumatucel.L
L-BLP25
CIMAvax EGF
CIMAvax EGF
Figure 2. Inclusion of therapeutic cancer vaccines in the current algorithm of treatment of advanced NSCLC patients.

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 67
and TG4010 vaccines that target the Mucin-1 protein.
Finally, the CIMAvax EGF vaccine targets EGF and
prevents it from binding with its receptor, effectively
preventing tumor growth. Each of these vaccines has
shown promising results in clinical trials and offers many
potential targets for the directed treatment and improved
survival of NSCLC patients.
Belagenpumatucel-L is an allogeneic whole cell vac-
cine that was created from four different NSCLC cell
lines, genetically modified to elaborate an antisense oli-
gonucleotide to TGF-β2. Because this vaccine was cre-
ated from multiple cell lines, it has a wide array of anti-
gens and is thus potentially beneficial in most NSCLC
patients. In a phase II trial by Nemunaitis, et al, in 2006,
75 NSCLC patients with stage II-IV disease were ran-
domized to receive intradermal injections with one of
three different dosage levels of Belagenpumatucel-L [58].
The study revealed that patients who received one of the
two higher dosage levels had a significantly improved
OS rate relative to the low dosage level (p = 0.0069).
Moreover, the OS rate of 32.5 months among responders
was significantly higher compared to patients who did
not respond (OS of 11.6 months; p = 0.011). Belagen-
pumatucel-L demonstrated minor toxicity with only one
grade 3 adverse events [58]. Based on the promising re-
sults of the phase II trial, a phase III randomized pla-
cebo-controlled clinical trial was designed to assess
whether Belagenpumatucel-L can prolong the OS of
stage III and IV NSCLC patients by at least three months.
To qualify for enrollment, patients must have responded
to chemotherapy or had stable disease following a plati-
num-based chemo regimen. This study has OS as the
primary end-point and an estimated enrolled of 506 pa-
tients (ClinicalTrials.gov, number NCT00676507). There-
fore, in this scenario Belagenpumatucel-L has been tested
as maintenance therapy for stages III and IV NSCLC.
MAGE-A3 is a melanoma-associated antigen ex-
pressed in a variety of cancers, including 35% of NSCLC.
MAGE-A3 expression is associated with poor prognosis,
and its rate of expression increases as the disease pro-
gresses (30% in stage I NSCLC and 50% in stage II
NSCLC). The MAGE-A3 vaccine is an antigen vaccine
that consists of a full-length MAGE-A3 protein com-
plexed to part of the Hemophilus influenzae protein D,
packaged with lipid adjuvants. It has been designed for
use in the post-operative setting in patients with stage I,
II, or IIIa cancer. In patients who have undergone surgi-
cal resection, the clinical usefulness of these vaccines is
maximized because of the lower post-op tumor burden
and the more direct access vaccine has to all tumor cells
[59]. In this scenario the MAGE-A3 cancer vaccine is be-
ing tested as adjuvant therapy in stages Ib and II NSCLC.
In the phase II trial by Vansteenkiste et al in 2006, 182
MAGE-A3+ patients with surgically resected stage Ib
and II NSCLC received induction with 5 doses of either
MAGE-A3 300 μg vaccine or placebo every 3 weeks and
then maintenance therapy of 8 doses or placebo every 3
months. Follow-up at 28 months revealed improved dis-
ease free interval (primary endpoint) in the treatment
group (HR; 0.74; p = 0.107). Although these results did
not reach statistical significance, a clear survival benefit
was observed in this trial. After a median follow-up of 44
months, only 30.3% of the treatment group experienced
relapse, compared to 41.7% in the control group. The
vaccine was well tolerated with only mild flu-like symp-
toms and injection site reactions [60].
Following the results of the phase II trial, MAGRIT,
the largest phase III lung cancer study in history, was
designed and is ongoing. MAGRIT is a randomized,
double-blinded, placebo-controlled study that evaluates
the use of the MAGE-A3 vaccine as adjuvant therapy.
The study also compares the efficacy of MAGE-A3 vac-
cine in participants who underwent resection and adju-
vant chemotherapy with a control group who solely un-
derwent resection prior to vaccination. Patients in the
study are assigned in a 2:1 ratio to the treatment group vs
the placebo group. Five doses are to be administered at
3-week intervals for induction and followed by mainte-
nance therapy with vaccination every 12 weeks. The
primary objective is disease-free survival in MAGE-A3
treatment after complete resection. A recent meta-analy-
sis from 25 different randomized trials revealed a pro-
nounced correlation between disease-free survival and
OS. The MAGRIT trial is ongoing, with a planned en-
rollment of 2270 patients, and has an estimated comple-
tion date of October 2016 [61].
Mucin 1 (MUC1) is a transmembrane protein normally
found on the apical surface of cells. In many malignan-
cies, MUC1 is found to be overexpressed and un-
der-glycosylated or aberrantly glycosylated. MUC1, ab-
normally expressed in almost half of all NSCLC, has
been proven to inhibit physiologic T cell proliferation.
The glycosylation pattern on the abnormally expressed
MUC1 in NSCLC makes it an attractive target for im-
mune therapy [62]. L-BLP25 (Stimuvax) is a 20-amino-
acid peptide with low-dose cyclophosphamide in a lipo-
somal vehicle. This synthetic vaccine targets the exposed
core of MUC1 when aberrantly glycosylated, which in-
duces immune response against the tumor cell. Anti-
gen-specific CTL proliferation and production of IFN-γ
occur in response to vaccine administration [62].
A randomized phase II trial was conducted by Butts, et
al, in 2005 on 171 stage IIIb or IV NSCLC patients after
response or SD to first-line chemotherapy [63]. Partici-
pants were then randomized to receive either L-BLP25
with best supportive care or, alternatively, best suppor-
tive care alone. The primary objective was median OS,
which was 17.2 months in the treatment group vs 13.0

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 68
months in the control group (adjusted HR = 0.739; p =
0.112). Although this difference was not statistically sig-
nificant, a subgroup analysis performed in those patients
with stage IIIb locoregional disease (n = 35) showed a
more pronounced separation between the treatment and
control groups. Stage IIIb NSCLC patients in the treat-
ment group had a median OS of 30.6 months, compared
to 13.3 months in the control group (adjusted HR = 0.524;
p = 0.069) [63]. Common adverse events included mild
flu-like symptoms, injection site reactions, and nausea. In
patients who received ongoing maintenance therapy, ad-
verse events decreased with time and no long-term safety
issues were identified. Although phase II trials with
L-BLP25 did not produce statistically significant results,
L-BLP25 did seem to benefit patients with stage IIIb
NSCLC. These results have prompted a large phase III
randomized placebo-controlled clinical trial called START
in 1476 patients with unresectable stage III NSCLC and
response or stable disease after chemo, randomized 2:1 to
receive L-BLP25 with best supportive care or placebo
with best supportive care (ClinicalTrials.gov, number
NCT00409188). The primary endpoint was OS. Results
from this Phase III study initially presented in December
2012 showed that L-BP25 failed to meet its primary
endpoint of OS in patients with locally advanced stage III
NSCLC. Injection site reactions were seen in 17.3% in
L-BLP25 vs 11.9% in placebo group, whereas flu-like
symptoms were seen in 10.9% in L-BLP25 vs 9.9% in
placebo [64]. Currently, a second phase III trial, IN-
SPIRE, is being conducted with L-BLP25 in Asian pa-
tients suffering from unresectable, stage IIIa or IIIb
NSCLC who have had a response or SD after at least two
cycles of platinum-based chemo-radiotherapy. Therefore,
L-BLP25 is being extensively evaluated as a mainte-
nance therapy in patients with unresectable stage IIIa or
IIIb NSCLC.
The TG4010 DNA vaccine also targets the aberrant
MUC1 protein. A phase IIb trial by Acres et al., was
conducted in 2009 in which 148 untreated MUC1+ pa-
tients were randomized to receive cisplatin and gemcit-
abine, with or without TG4010 [65]. In the experimental
group, TG4010 was given every 3 weeks until PD was
detected. The primary endpoint was PFS. This endpoint
was observed in 44% of the experimental group vs 35%
in the control group (p = 0.13). Based on these results, a
phase IIb/III randomized, double-blinded, placebo-con-
trolled trial is now enrolling roughly 1000 patients with
stage IV NSCLC. In this study (TIME), participants will
either receive chemotherapy with TG4010 or chemo-
therapy with a placebo until PD is observed. The primary
endpoint is OS and the study is estimated to be complete
in December 2016. Therefore, the TG4010 cancer vac-
cine is mainly being tested as a first-line therapy in pa-
tients MUC1+ and stage IV NSCLC.
6. How to Insert Cancer Vaccines in the
Existing Arsenal of Therapies for
Advanced NSCLC? A Case Example:
CIMAvax EGF
As previously described, cancer vaccines currently in
phase III clinical trials are being tested to be included in
the algorithm for treatment NSCLC patients either as
maintenance, adjuvant or first-line therapy. CIMAvax
EGF is a therapeutic cancer vaccine, devoted to create an
immune response against the Epidermal Growth Factor
(EGF) as specific antibodies that recognize and bind to
this protein, with the formation of immune-complexes,
eliminated through the kidneys [66-68]. Once eliminated,
the EGF cannot exert its physiological action of binding
to the EGFR, initial event that unchain cell proliferation
mechanisms. It should be noticed that, one of the main
characteristics of cancer, is its uncontrolled cell prolif-
eration, mainly due to EGFR overexpression. Elimina-
tion of circulating EGF through vaccination with CI-
MAvax EGF stops the cascade of cell proliferation sig-
nals from the very beginning (EGF/EGFR binding). This
mechanism of action is basically different from other
cancer vaccines devoted to induce the immune system to
create cytotoxic responses towards cancer cells.
As compared with other cancer vaccines, CIMAvax
EGF has two main strengths in its mechanism of action:
firstly, it targets the EGF/EGFR system; which is one of
the main current targets for cancer therapy. This system
has been validated with different therapeutic approaches
such as monoclonal antibodies and small molecules tyro-
sine kinase inhibitors of demonstrated clinical efficacy in
different tumors [69]. Secondly, it has a mechanism of
action similar to hormone-deprivation [70]; where the
specific anti-EGF antibodies (provoked by vaccination)
“castrate” the EGF from circulation, avoiding this growth
factor stimulus. The hormone therapy is one of the older
and most validated cancer therapies, with demonstrated
efficacy, mainly based in deprivation of hormonal sti-
mulus by different procedures [71].
The clinical testing of CIMAvax EGF began in 1995.
From there up to date, more than 3000 advanced NSCLC
patients had received this vaccine, which has demon-
strated immunogenicity, safety, and efficacy (defined as
an increase in survival of vaccinate patients as compared
with randomized non-vaccinated controls). The vaccine
has been applied in different clinical scenarios, making it
a versatile product to be inserted in the algorithm of
treatments for advanced NSCLC patients (Table 4 and
Figure 2).
CIMAvax EGF has been tested in the first-line treat-
ment scenarios for advanced NSCLC patients [72,73]. In
a Phase I/II trial, CIMAvax EGF was given before and
fter standard first-line chemotherapy to patients recently a

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 69
Table 4. Summarized results of CIMAvax EGF as first-line, maintenance, and second-line therapy in advanced NSCLC.
Patients % of NSCLC population
amenable to this treatment
Treatment
line Safety Efficacy Ref
Advanced
NSCLC
(PS 0-2)
100% First line
Mild or moderated adverse events:
Flu-like, pain at the site
of injection
OS 12.4 months One-year
survival rate: 70%. [72,73]
Advanced
NSCLC
(PS 0-2)
100% Second line
Mild or moderated adverse events:
Flu-like, pain at the site
of injection
OS (CIMAvax EGF vs control):
6.47 vs 5.33 months
OS in patients who responded to
first-line chemo (CIMAvax EGF
vs control): 11.57 vs 6.77 months
[68]
Advanced
NSCLC
(PS 0-2)
100% Maintenance
Mild or moderated adverse events:
Flu-like, pain at the site
of injection
OS (CIMAvax EGF vs control):
11.2 vs 7.7 months
Survival rate at 6; 24; and 48
months: 73%; 27% and 19%
vs 72%; 14% and 4%
[83]
Abbreviations: NSCLC, non-small cell lung cancer; OS, overall survival; PS, performance status.
diagnosed with advanced (stages IIIb and IV) NSCLC
[72,73]. Two vaccinations were given before the begin-
ning of chemotherapy; with subsequent monthly vaccine-
tions after concluding chemotherapy.
Chemotherapy and active immunotherapy are gener-
ally regarded as unrelated or even mutually exclusive in
cancer treatment, due to chemotherapy-induced immune
suppression, dampening the therapeutic efficacy of fur-
ther active immunotherapies. This trial design giving
vaccine-chemotherapy-vaccine was devoted to search the
best combination between CIMAvax EGF and chemo-
therapy. The rationale of this combination was based on
studies of homeostatic lymphocyte repopulation after
chemotherapy, done by Mckal et al. [74-77]. That group
reported the recovery of lymphocytes from the expansion
of the peripheral pool (including memory cells) rather
than de novo naive cells exported from bone marrow
[78,79]. This vaccination scheme increased the anti-EGF
antibody response, with titers 20-folds higher, when vac-
cination was applied after chemotherapy. It was also ob-
served that anti-EGF antibody titers reached during the
induction period before chemotherapy did not decreased
during the cytotoxic treatment. That means the effect of
vaccination is prolonged on time.
There was not influence of previous vaccination in the
expected response to chemotherapy. In 20 patients
evaluated for objective responses, 2 complete responses
and 5 partial responses were observed, for an objective
response rate of 35%. Five out of the responses appeared
at the end of chemotherapy, but, interestingly, 2 re-
sponses occurred during the second vaccination period
(V-Ch-V). Additionally, 10 patients reached disease sta-
bilization for a disease control rate of 85%. Moreover,
the mean survival was 18.74 months (median 12.4
months), and a 1-year survival rate of 70%. Chemother-
apy-related adverse events were not influenced by pre-
vious vaccination. Vaccine-related adverse events con-
sisted of mild to moderated flu-like symptoms and pain
at the site of injection; as previously described when the
CIMAvax EGF has been administered under different
schemes of vaccination [67,72,80-82]. This trial demon-
strated the feasibility of using CIMAvax EGF in the
first-line treatment for advanced NSCLC patients with
PS 0-2, independently of their molecular and histological
characterization.
CIMAvax EGF has also been tested as second-line
therapy [68]. In a phase II clinical trial, 80 patients with
advanced stages (IIIb and IV) NSCLC, after finishing
first-line chemotherapy, were randomized to receive
CIMAvax EGF or best supportive care. Patients were
included in the trial independently of their response or
not to the first-line treatment: patients with objective
response, stable disease or progressive disease after
chemotherapy were vaccinated and evaluated for vaccine
efficacy based on OS. Vaccination was safe and adverse
events were observed in less than 25% of cases and were
grade 1 or 2 according to National Cancer Institute
Common Toxicity Criteria (CTC). In this trial OS was
measured since one month after concluding first-line
chemotherapy. In this scenario, vaccinated patients had a
mean survival of 12.73 months (median 6.47 months)
whereas the control arm survival was 8.52 months (me-
dian 5.33 months). In addition, in those patients who
responded to first-line chemotherapy, the mean survival
was of 22.45 months (median 11.57 months) whereas
responding control patients had a mean survival of 9.32
months (median 6.77 months) [68]. Therefore, CIMAvax
EGF in a second-line scenario (after first-line chemo-
therapy), benefits advanced NSCLC patients with PS 0-2,
independently of their molecular and histological char-
acterization. There is a trend of increased benefit in pa-
tients that respond to first-line chemotherapy.
CIMAvax EGF has also been tested in a phase III trial
in patients that respond to first-line chemotherapy and
receive the vaccine as maintenance therapy until and
beyond disease progression [83]. In this scenario, pa-
tients who responded to first-line chemotherapy were
randomized to receive CIMAvax EGF or best supportive

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 70
care. As previously demonstrated, vaccination was safe
and not severe-adverse events related with vaccination
were observed. In a statistically planned partial cut-off in
results, vaccinated patients survived significantly more
that not vaccinated controls. Survival times considered
from diagnose, had a median of 11.2 months for vacci-
nated patients (mean 20.6 months) whereas a median of
7.7 months was observed for not vaccinated controls
(mean 14.1 months). Survival rates at 6-month, 24-
month and 48-month were 73%, 27% and 19%, respec-
tively for the vaccinated group; while 72%, 14% and 4%
for the control group. Vaccination with CIMAvax EGF
as maintenance therapy in patients who respond to first-
line chemotherapy provides benefit to advanced NSCLC
patients with PS 0-2, independently of their molecular
and histological characterization.
After its regulatory registration, CIMAvax EGF has
been tested in open population both, in Cuba (Phase IV
trial) and in Peru. This patient population is mainly
composed by patients that received all possible onco-
specific treatment and are in disease progression. Up to
date 1080 cuban patients received CIMAvax EGF in a
Phase IV trial performed at primary attention level. This
vaccinated patient population has showed a median over-
all survival of 14.16 months. According to the National
Register of Cancer (2002-2007), advanced NSCLC pa-
tients in Cuba have a median survival of 9.6 months. In
the 2012 ASCO meeting, it was presented the post-mar-
keting experience with application of CIMAvax EGF in
12 metastatic NSCLC patients that progressed after
first-line therapy; the patients received the vaccine alone
or in combination with chemotherapy. Vaccination was
safe (not adverse events grade III or IV were reported)
and produced a clinical benefit associated with improves
of OS (18.8 months) and PFS (7.3 months).
An ongoing clinical trial is applying CIMAvax EGF to
patients unfit for onco-specific therapies. These patients
do not meet the criteria for receiving currently available
therapies or they simply refuse to receive other therapy
(mainly due to toxicity). The patient population unfit for
onco-specific treatments is not small. It has been reported
that 30% of advanced stages NSCLC patients with PS
0-1 unfit chemotherapy; a figure that increase substan-
tially in patients with PS 2-3 [84]. These patients can
receive CIMAvax EGF without additional toxicity. Con-
sidering this clinical experience, CIMAvax EGF can be
inserted in the algorithm for treatment of advanced
NSCLC in different scenarios: first-line, second-line and
maintenance; the updated clinical experience demon-
strates the feasibility of combining it with other available
treatments as well as in patients unfit for other therapies.
There is not a known limit for CIMAvax EGF applica-
tion. All advanced NSCLC patients, independently of
their PS, their histologic sub-group or their molecular
markers characterization (gene mutations or others), are
amenable to receive and benefit from this cancer vaccine.
7. General Discussion
Patients with NSCLC face a dismal prognosis at the time
of diagnosis due to an advanced and aggressive disease,
coupled with the limited available treatment options. The
treatment of advanced lung cancer has started to make a
plateau during the last two decades. After the introduc-
tion of platinum doublets, and later on the concept of
maintenance treatment with pemetrexed, cytotoxic che-
motherapy has not delivered a major advance. A lot of
hope has been put on molecular stratification according
to specific mutations and drugs that target them. How-
ever, the very same results of targeted therapy, no matter
how impressive they are for specific patients niches, are
showing a major limitation: as a consequence of the spe-
cificity of the target, they usually show early resistance.
Seemingly, second-generation products will not change
this scenario dramatically.
The current challenge is try to transform advanced
cancer from a terminal, untreatable disease into a chronic
disease that could be controlled for a long time keeping
patients with a good quality of life. That implies a com-
plete change in the management of advanced cancer,
introducing in the current algorithms of treatments new
products that, because of their low toxicity, can be given
chronically or even in combination with other existing
therapies without significantly increasing toxicity. The
need of a treatment, which is endowed with amplification
mechanisms, targeted diverse cell populations at the
same time, and co-evolved with the tumor cell population
itself, has switched the attention again towards active
immunotherapy. Therapeutic cancer vaccines should be
introduced in the complex therapeutic algorithm early
enough to profit the partial remissions or disease stabili-
zations induced by chemotherapy or targeted therapies,
and to have time to boost the host antitumor immune
reaction. Early studies of active immunotherapy agents
developed for treating NSCLC patients have exhibited
promising results, especially in advanced disease where
the OS rate has been, historically, very grim. While
therapeutic vaccination may not be a panacea, it could be
served as a vital adjunct to traditional surgical and che-
motherapeutic treatment regimens as we see in the case
of the MAGE 3 vaccine for adjuvant therapy or in the
case of CIMAvax EGF when it is used in combination
with chemotherapy in advanced disease patients.
The identification of better antigenic targets, addition
of immune-stimulating adjuvants, and production of im-
proved delivery mechanisms have resulted in a group of
vaccines that appear to elicit an effective immune re-
sponse against tumor cells. This has been a major change
in the area of cancer immunology where lung cancer

Current Algorithm for Treatment of Advanced NSCLC Patients: How to Include Active Immunotherapy? 71
vaccines have never been a popular topic. Phase II stud-
ies show that these vaccines can produce statistically
significant improvements in the PFS or OS for patients,
irrespective of the stage of the patient’s disease. These
vaccines have demonstrated low toxicity together with
improved survival and an enhanced quality of life rela-
tive to the baseline prognosis. As a result of these studies,
for first time in the history of lung cancer and immuno-
therapy, several phase III trials are ongoing to examine
the efficacy of therapeutic vaccination in a larger number
of patients with all stages of NSCLC and in different
therapeutic scenarios. Some of these vaccines have shown
in the clinical setting that their effects are independent of
patient’s characteristics (tumor histology and presence of
driver mutations). This is the case of CIMAvax EGF,
which is applicable not only to all advanced NSCLC pa-
tients, but also in different lines of the treatment (as
first-line, maintenance and second-line therapy).
The mild toxicity of cancer vaccines makes them use-
ful for chronic application and then, it is more probable
to accomplish the challenge of converting advanced can-
cer into a chronic disease. The inclusion of cancer vac-
cines, alone or combined with other approved therapies,
in the current algorithm of advanced NSCLC treatment
should represent a major change in the clinical outcome
of the disease.
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Abbreviations
EGF: epidermal growth factor
EGFR: EGF receptor
NSCLC: non-small cell lung cancer
OS: overall survival
PD: progressive disease
PFS: progression free survival
PR: partial response
PS: performance status
SD: stable disease
TKI: tyrosine kinase inhibitor
VEGF: vascular endothelial growth factor