Thoracic Oncology Preprint Ch44 PDF

International Association for the Study of Lung Cancer
Conquering Thoracic Cancers Worldwide
Conquering Thoracic Cancers Worldwide
Chapter Preprint
First-Line Systemic Therapy
Options for Non-Small Cell
Lung Cancer
Suresh S. Ramalingam, MD
Rathi N. Pillai, MD
Niels Reinmuth, MD
Martin Reck, MD, PhD
Full Textbook Available

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This Preprint Chapter is from the forthcoming text, The IASLC Multidisciplinary
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CHAPTER 44
first-line systemic therapy options

for non-small cell lung cancer
Suresh S. Ramalingham, MD; Rathi N. Pillai,MD; Niels Reinmuth,MD; Martin Reck, MD, PhD
Lung cancer is at an advanced stage at the time of diagnosis in the
NSCLC
majority of patients. The overall goals of treatment of advancedstage disease are palliation and prolonged survival. Local treatment modalities such as radiotherapy and surgery play a limited role and are implemented primarily for symptom control.
Nonsquamous Cell
Histology
Squamous Cell
Histology
Molecular Profiling by
CAP/IASLC Guidelines
Platinum Doublet
Targetable Mutation
No Targetable Mutation
(Wild-Type)
Systemic therapy remains the principal therapeutic modality for

advanced-stage non-small cell lung cancer (NSCLC). Until the late
1990s, treatment of advanced lung cancer followed the straightforward algorithm of platinum-based combination therapy
regardless of histologic subtype, without any option for further
lines of treatment. With the introduction of so-called third-generation cytotoxic drugs, the treatment of NSCLC changed and overall survival increased to approximately 8 months for patients with
a good performance status. In the past two decades, there has
been a gradual shift in therapy from the use of systemic chemotherapy in all patients to the current approach in which histology
EGFR
Mutation
ALK
Rearrangement
Platinum Doublet
with or without
Bevacizumab
Erlotinib
Afatinib
Crizotinib
Consider Maintenance
Therapy
and molecular status play a key role in treatment selection (Figure

1). This change has been made possible by greater insights into
Figure 1. Treatment algorithm for treatment-nave non-small cell lung cancer

(NSCLC). CAP/IASLC=College of American Pathologists/International Association
for the Study of Lung Cancer.
lung cancer biology, the availability of novel therapeutic agents,

and the increasing focus on identification of biomarkers to guide
therapy.1 Although a cure for the disease still remains elusive, a
significant subset of patients with NSCLC can now have long-term
Patient-related Factors
survival and improved quality of life.
Performance Status and Comorbidities
PROGNOSTIC FACTORS IN NSCLC
Performance status and comorbidities are among the most

important prognostic factors. Moreover, these determinants are
also of utmost importance for the selection of therapy, as outlined
Proper assessment of prognosis is important when selecting
later in this chapter. The systematic determination of comorbidi-
appropriate treatment for each patient. The variables associated
ties is an essential component of selecting appropriate chemo-
with prognosis can be grouped into categories: patient-related,
therapy regimens and providing the best supportive care.
such as performance status, comorbidity, and gender; tumor-
related, such as primary site, histology, and extent of disease; and
may also have symptoms related to the primary tumor, medi-
environmental factors, such as nutrition and the choice and qual-
astinal spread, or paraneoplastic syndromes. Moreover, lung
ity of treatment.
cancer commonly produces systemic effects such as anorexia,
In addition to noncancer-related comorbidities, patients
weight loss, weakness, and profound fatigue. In a study of 12,428

patients with NSCLC in the international staging database of the
Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer
International Association for the Study of Lung Cancer (IASLC),
patients with advanced NSCLC. Hence, accurate diagnosis of
performance status, age, and gender appeared to be indepen-
tumor histology has become essential in treatment decision-
dent prognostic factors for survival in addition to clinical stage.
making and can affect considerations of both toxicity and poten-
In advanced NSCLC, some routine laboratory tests (primarily
tial efficacy of selected agents used in the management of this
white blood cell count and hypercalcemia) were also found to
disease. For example, the use of the anti-vascular endothelial
be significant prognostic variables.
growth factor (VEGF) antibody bevacizumab is associated with

a higher risk of pulmonary bleeding when used in patients with
Age
predominantly squamous cell histology. In addition, the cyto-
Currently, the majority of lung cancer cases are diagnosed in
toxic drug pemetrexed was found to be inactive in patients with
people older than 65 years of age.3 Age at diagnosis is another
squamous NSCLC. Therefore, the classification of NSCLC into the
important factor that should be considered in treatment deci-
major categories of squamous cell carcinoma, adenocarcinoma,
sion-making. Often, increasing age is accompanied by multiple
and large cell carcinoma is crucial when making treatment deci-
comorbidities that can further limit therapy options and affect
sions. However, histologic subclassification of NSCLC remains
patient outcome.
a challenge for many reasons, as the tumor is heterogeneous

in every aspect: pathology, presence of molecular alterations,
Ethnicity
radiographic appearance, clinical presentation, and response to
Lung cancer continues to be a leading cause of mortality for all
systemic therapy. Initial diagnostic biopsies often yield an inad-
races, although recent research has focused on ethnic variations
equate amount of tissue for conducting necessary tests to identify
in this disease, such as the prevalence of the epidermal growth
histology and genotype. The availability of immunostains such as
factor receptor (EGFR) mutation. One of the most striking dispari-
thyroid transcription factor-1, p63, and p40 has greatly improved
ties is the difference in lung cancer risk and survival for African
the accuracy of histologic subclassification.
and Asian ethnicities. Epidemiologic research has focused on

behavioral, cultural, and socioeconomic factors that may influ-
Molecular Markers
ence risk, although no clear link has been established.4 Access
NSCLC tumors often harbor mutations in a number of critical
to care also varies among various ethnic groups and remains an
genes such as p53, Kirsten rat sarcoma (KRAS), and liver kinase
important barrier to the delivery of optimal therapy for patients
B-1 (LKB-1). The prognostic relevance of these mutations con-
with NSCLC.
tinues to be defined for patients with advanced NSCLC. Certain

molecular markers have also gained attention because they have
Tumor-related Factors
predictive value. For example, the presence of an activating EGFR
Stage
mutation translates into both predictive and prognostic informa-
The anatomic extent of the disease, as described by the TNM
tion. Patients with EGFR mutation have overall better outcomes
classification, is the most important prognostic factor in NSCLC.
than patients with wild-type EGFR, and also gain robust ben-
The 7th edition of the TNM classification, released in 2010, was
efits from specific therapeutic inhibitors of the EGFR pathway.
derived from the analysis of the largest database ever gener-
Similarly, limited early evidence indicates that patients with
ated for this purpose, with data from 46 sources in more than
rearrangement of the anaplastic lymphoma kinase (ALK) gene
19 countries about patients treated with all modalities of care.5,6
have higher risk of recurrence following surgery for early-stage
An important change in the TNM classification involves the rec-
disease and a greater clinical benefit from pemetrexed. The prog-
ognition that patients with extrathoracic disease have slightly
nostic role of KRAS mutations in lung adenocarcinoma has been
less favorable outcomes compared with patients with metastatic
debated extensively. Early evidence suggested poor sensitivity to
spread confined to the thorax, even with stage IV disease. The
chemotherapy and overall prognosis when a KRAS mutation is
result was a division of stage IV classification to M1a and M1b
present, but emerging data have failed to confirm this. Patients
based on the presence or absence of extrathoracic metastasis.
with KRAS mutations appear to have a very low likelihood of
Malignant pleural or pericardial effusions are also known to
objective response to EGFR inhibitors. The knowledge of the prog-
portend a particularly poor prognosis for patients with stage IV
nostic and predictive potential of various molecular markers is
disease. In order to recognize the significance of this prognostic
likely to increase considerably in the coming years as molecular
factor, malignant effusions have been moved from stage IIIB to
testing is adopted in routine practice settings.
IV disease in the new staging system.

Histology
Systemic Chemotherapy
Options
Identifying the distinction between squamous and nonsquamous

cell histology was the first step in the personalized treatment of
Compared with best supportive care alone, systemic chemother-
The IASLC Multidisciplinary Approach to Thoracic Oncology
apy prolongs survival and leads to symptom palliation for patients
therapy was shown to lead to higher response rates and longer
with advanced NSCLC.7 Similar to therapeutic developments for
survival than that associated with monotherapy, albeit with
other solid tumors, the efficacy of a variety of cytotoxic agents has
increased toxicity.7 Given the limited availability of supportive
been tested in both preclinical and clinical NSCLC studies during
care for chemotherapy-related toxicities in the early 1990s, the
the last few decades. Initial results on single-agent therapy
use of chemotherapy for patients with metastatic NSCLC was
including cisplatin (CDDP), ifosfamide, vinblastine, vindesine,
still debated despite consistent evidence of its modest activity.
etoposide, and mitomycin-Cindicated limited activity, leading

to objective response rates of 15% or less and median response
Platinum Agents
durations of 2-3 months. Complete responses after these treat-
Platinum agents form DNA adducts, which ultimately result in
ments were rare, and their benefit on median survival, with the
activation of p53-dependent and p53-independent apoptosis.12
exception of cisplatin, was inconsistent. The relatively modest
As monotherapy, cisplatin has anticancer activity comparable to
efficacy and substantial toxicity of these cytotoxic agents led to
that of other single agents, with a response rate of approximately
considerable nihilism regarding the use of chemotherapy for
15% and a median survival of 6-8 months.13 In order to increase
NSCLC for many years. Starting in the mid-1980s, several novel
the efficacy of systemic treatment, several combination regimens
cytotoxic drugs were evaluated in NSCLC, such as vinorelbine,
have been extensively studied (Table 2). Although many of the
paclitaxel, docetaxel, irinotecan, gemcitabine, and oxaliplatin,
phase III studies were underpowered, several randomized trials
which yielded response rates of 11-22% (Table 1).9
and meta-analyses provided scientific evidence that platinum-
Table 1. Single-agent Activity of Chemotherapy in Randomized

Trials Comparing Monotherapy to Combination Chemotherapy
Cytotoxic
Agent
Median
No. of Response
Reference
Survival,
Patients Rate (%)
(Year)
(Months)
advanced NSCLC. In 1995, a meta-analysis using updated data on

1,190 patients with advanced NSCLC from 11 randomized clinical
trials was published. The results, updated in 2008, demonstrated
a 27% reduction in the risk of death for patients treated with cisplatin-containing regimens compared with supportive care alone,
Vinorelbine
206
14
7.2
Irinotecan
129
21
10.6
Cisplatin
206
17
8.1
Gatzemeier
(2000)186
Cisplatin
262
11
7.6
Sandler
(2000)187
Cisplatin
219
14
6.4
Von Pawel
(2000)188
Cisplatin
209
12
6.0
Wozniak
(1998)189
ifosfamide, and mitomycin-C;14 cisplatin and vindesine;15 and
Gemcitabine
84
20
6.7
Vansteenkiste
(2001)190
inferior response rates, time to progression, and median overall
Gemcitabine
170
12
9.0
Sederholm
(2002)191
been pronounced in the gemcitabine-platinum combinations,
Georgouilas
(2004)192
quently with the classic treatments.14-16 Moreover, in the study by
Lilenbaum
(2005)51
cisplatin and vinorelbine were significantly better than those for
Docetaxel
Paclitaxel
152
277
22
17
8.0
6.7
Le Chevalier
(1994)184
based combination therapy prolonged survival for patients with
Negoro
(2003)185
which translated to an absolute improvement in survival of 10%

(5% to 15%) at 1 year.7

Compared with older regimens such as cisplatin with vinde-
sine or vinblastine, cisplatin and mitomycin-C with vinblastine

or vindesine, or cisplatin with etoposide, combinations of cisplatin with newer drugs (third-generation drugs: gemcitabine,
taxanes, vinorelbine, topoisomerase I inhibitors) seem to have
somewhat higher efficacy and improved tolerability. For example,
compared with platinum-gemcitabine combinations, cisplatin,
cisplatin and etoposide16 regimens have been associated with
survival. Hematologic toxicity, especially thrombocytopenia, has
whereas nonhematologic side effects have occurred more freLe Chevalier et al., the response rate and survival associated with
cisplatin and vindesine.17
Modified from Milton DT, Miller VA. Advances in cytotoxic chemotherapy for
the treatment of metastatic or recurrent non-small cell lung cancer. Semin
Oncol. 2005;32(3):299-314.
Combining the newer agents (gemcitabine, paclitaxel, or
Combination chemotherapy has also been evaluated in
from the Southwest Oncology Group (SWOG) failed to demon-
patients with NSCLC. Two meta-analyses showed a clear signifi-
strate superiority of carboplatin and paclitaxel over cisplatin and
cant survival advantage for a two-drug regimen compared with
vinorelbine in 408 patients.18 Similarly, the Italian Lung Cancer
monotherapy, but alternately also demonstrated a significant
Study Group failed to detect any significant difference in outcome
increase in hematologic and nonhematologic side effects.10,11
for the cisplatin and gemcitabine, carboplatin and paclitaxel, and
Among several combinations of agents, platinum-based chemo-
cisplatin and vinorelbine regimens in 612 patients with previously
vinorelbine) with cisplatin does not seem to significantly affect

the treatment efficacy (Table 2). For instance, a phase III study by
p=0.044).21 Based on these findings, platinum-
Table 2. Phase III Trials Comparing Platinum-based Combinations

Regimen
No. of Response
Patients Rate (%)
Median
Reference
Survival p Value
(Year)
(Months)
Cisplatin/vindesine
200
19
7.4
Cisplatin/vinorelbine
206
30
9.2
202
28
8.0
Carboplatin/paclitaxel
206
25
8.0
201
32
9.9
201
30
9.5
Cisplatin/gemcitabine
205
30
9.8
Cisplatin/paclitaxel
305
21
7.8
288
22
8.1
Cisplatin/docetaxel
289
17
7.4
290
17
8.1
404
25
10.1
Cisplatin/docetaxel
408
32
11.3
0.04a
Carboplatin/docetaxel
406
24
9.4
NS
Cisplatin/vindesine
151
21
9.6
0.01
Cisplatin/docetaxel
151
37
11.3
Cisplatin/vindesine
122
32
10.9
Cisplatin/irinotecan
129
44
11.5
0.04
Le Chevalier
(1994)184
NS
Kelly
(2001)18
NS
Scagliotti
(2002)19
based chemotherapy remains the standard of

care for advanced or metastatic NSCLC. With
the current combination agents, a plateau of
efficacy has been reached.
Cisplatin Versus
Carboplatin
Carboplatin is another platinum derivate and
has a 10-fold longer half-life than cisplatin. Due
to the structural differences compared with cisplatin, carboplatin exhibits lower reactivity and
slower DNA binding kinetics in vitro. In clinical studies, the nonhematologic tolerability
NS
Schiller
(2002)20
of carboplatin is superior to that of cisplatin,

making it a more convenient platinum analog
for palliative chemotherapy.
The efficacy of cisplatin and carboplatin in
the management of advanced NSCLC has
been compared in several studies. Rosell et al.
Fossella
(2003)21
reported a significantly improved survival rate

for patients treated with cisplatin and paclitaxel compared with carboplatin and paclitaxel, with a higher rate of nonhematologic side
Kubota
(2004)193
0.12
Negoro
(2003)185
effects in the cisplatin arm and a higher rate of

neutropenia and thrombocytopenia in the carboplatin arm.22 In the TAX 326 trial, there was a
nonsignificant trend toward improved survival
for the combination of cisplatin and docetaxel
over carboplatin and docetaxel.21 In contrast,
In comparison to the cisplatin/vinorelbine arm. NS=not significant. Modified from Milton DT, Miller
VA. Advances in cytotoxic chemotherapy for the treatment of metastatic or recurrent non-small cell
lung cancer. Semin Oncol. 2005;32(3):299-314.
the ECOG 1594 trial found similar survival in
untreated advanced NSCLC. However, both studies demon-
therapy, there was a lower incidence of nonhe-
strated differences between the toxicity profiles of these regimens.
matologic events such as nausea, vomiting, nephrotoxicity, and
In the largest study (1,207 patients), by the Eastern Cooperative
neurotoxicity.20 This finding has also been noted in other smaller
Oncology Group (ECOG), no significant efficacy differences in
trials13 with carboplatin-based regimens.
response rates (17-22%) and median survival (7.4-8.1 months)
were found among four regimens: cisplatin and paclitaxel, cispla-
cisplatin-based chemotherapy offered a significantly higher
tin and gemcitabine, cisplatin and docetaxel, and carboplatin and
objective response rate than carboplatin-based chemotherapy
paclitaxel.20 Differences were noted only with respect to toxicity
(odds ratio, 1.36; 95% CI, 1.15-1.61; p=0.001) and a nonsignifi-
profiles, with cisplatin and gemcitabine causing more thrombo-
cant improvement in survival (hazard ratio, 1.050; 95% CI, 0.907-
cytopenia, cisplatin and docetaxel causing more neutropenia,
1.216; p=0.515).23 In this meta-analysis, a subgroup analysis of the
and carboplatin and paclitaxel being associated with the lowest
five trials that incorporated cisplatin or carboplatin with a new
rate of potentially life-threatening toxicities.
agent demonstrated a significantly superior median survival for
Another phase III study (TAX 326) randomly assigned 1,218
patients treated with cisplatin (hazard ratio, 1.106; 95% CI, 1.005-
patients to receive cisplatin and docetaxel, carboplatin and
1.218; p=0.039). These data were confirmed by another meta-
docetaxel, or cisplatin and vinorelbine. Compared with cispla-
analysis that included 2,968 patients from nine trials; the response
tin and vinorelbine, cisplatin and docetaxel was associated with
rate was significantly higher among patients treated with cisplatin
a significantly higher response rate (31.6% vs 24.5%; p=0.029)
(odds ratio, 1.37; 95% CI, 1.16-1.61; p<0.001).24 Moreover, cispl-
and a significantly longer median survival (11.3 vs 10.1 months;
atin-based treatment was associated with an improved median
19
both cisplatin- and carboplatin-based treatment arms. However, with carboplatin-based
A meta-analysis of data from eight trials demonstrated that
overall survival relative to treatment with carboplatin (9.1 vs 8.4
p<0.001)27; however, the median survival was not significantly
months; hazard ratio, 1.07; 95% CI, 0.99-1.15; p=0.1), and the
different (odds ratio, 1.10; 95% CI, 0.91-1.35; p=0.059), and the
results were similar in subgoup analyses for patients with non-
incidence of grade 3 or 4 hematologic toxicity, neuropathy, and
squamous cell tumors (hazard ratio, 1.12; 95% CI, 1.01-1.23) and
diarrhea was significantly increased with triplet therapy. Based on
patients treated with third-generation chemotherapy (hazard
these results, platinum-based doublet chemotherapy remains the
ratio, 1.11; 95% CI, 1.01-1.21). However, cisplatin-based che-
standard first-line treatment for patients with metastatic NSCLC.
motherapy was associated with more severe nausea, vomiting,

was associated with more frequent severe thrombocytopenia.24
Platinum-free versus Platinumbased Regimens
Therefore, the selection of the platinum agent should be made
In daily clinical practice, a substantial proportion of patients with
based on the regimen most likely to result in the best therapeutic
advanced NSCLC are not optimal candidates to receive platinum-
index. In recent years, the availability of effective antiemetic agents
based chemotherapy due to the presence of certain comorbidities
has improved the therapeutic index of cisplatin-based regimens.
such as renal insufficiency, borderline performance status, or pre-
and nephrotoxicity, whereas carboplatin-based chemotherapy
existing sensory neuropathy. Hence, studies have been conducted
Triplet Regimens
to evaluate whether the combination of two newer chemotherapy
To further increase the efficacy of systemic therapy in advanced
agents may be better suited for first-line therapy. In some earlier
NSCLC, a series of studies has evaluated the potential role for the
studies, a trend toward a higher survival was found for patients
use of three-drug regimens. These studies have consistently dem-
treated with platinum-based combinations compared with
onstrated that three-drug regimens are associated with higher
patients treated with platinum-free regimens.13,28,29 In a recent
toxicity, at times have higher objective response rates, but are
phase II study, a total of 433 patients with stage IIIB or IV NSCLC
not associated with a significant improvement in survival com-
received cisplatin and gemcitabine; gemcitabine and vinorel-
pared with that offered by standard doublet regimens (Table 3).
bine; cisplatin, ifosfamide, and gemcitabine; or gemcitabine, ifos-
For example, in a randomized phase III trial, 557 patients with
famide, and vinorelbine.26 The platinum-based regimens were
stage IIIB or IV NSCLC were assigned to receive cisplatin and
associated with a significantly longer overall survival compared
gemcitabine for six cycles; cisplatin, gemcitabine, and vinorelbine
with the nonplatinum regimens (11.3 vs 9.7 months; p=0.044)
for six cycles; or gemcitabine and vinorelbine for three cycles fol-
but also resulted in a higher incidence of grade 3 or 4 toxicity.
lowed by vinorelbine and ifosfamide for three cycles. Response
In a meta-analysis based on data from randomized phase II and
rates were inferior for the nonplatinum sequential doublet, and
III studies, DAddario et al. found a significantly higher 1-year
no differences in median survival or time to progression were
survival rate for platinum-based combination therapy compared
found. Predictably, toxicity was significantly higher for the triplet
with nonplatinum regimens (34% vs 29%; odds ratio, 1.21; 95%
regimen. Similarly, a recent phase II study showed no significant
CI, 1.09-1.35; p=0.0003).30 However, when single-agent trials were
difference between doublet (cisplatin and gemcitabine or gem-
excluded and platinum-based therapies were compared with
citabine and vinorelbine) and triplet (cisplatin, ifosfamide, and
third-generationbased combination regimens only, there was no
gemcitabine or gemcitabine, ifosfamide, and vinorelbine) combi-
significant survival difference (1-year survival: 36% for platinum
nations; however grade 3 or 4 leukopenia was significantly more
vs 35% for nonplatinum regimens). In a more recent systematic
common with triplet combinations.26
review of randomized controlled trials comprising 4,920 patients,
25
the use of cisplatin-
Table 3. Doublet Compared with Triplet Chemotherapy in Non-Small Cell Lung Cancer
Chemotherapy Regimen
based doublet regi-
Rate of Grade 3 or 4 Adverse Events (%)
mens was associ-
Response
Rate (%)
Neutropenia
Thrombocytopenia
Nausea/
Vomiting
ated with a higher
Cisplatin/gemcitabine/
ifosfamide
42 vs 41
32 vs 57
4 vs 19
22 vs 32
compared with non-
Cisplatin/ifosfamide/
gemcitabine
Gemcitabine/ifosfamide/
vinorelbine
29 vs 28
Doublet
Triplet
Cisplatin/
gemcitabine25
or Gemcitabine/
vinorelbine26
1-year survival rate

platinum regimens
36 vs 44
16 vs 20
8 vs 7
(relative risk, 1.16;

95% CI, 1.06-1.27;
p=0.001), but also
with an increased risk
of anemia, neutrope-
In a systematic overview, third-generation triplet therapy was
nia, neurotoxicity, and nausea.31 Conversely, carboplatin-based
associated with a significantly higher response rate compared
doublet regimens were associated with a similar 1-year survival
with standard doublet therapy (odds ratio, 1.33; 95% CI, 1.50-2.23;
rate as nonplatinum doublets (relative risk, 0.95; 95% CI, 0.85-
1.07; p=0.43). Taken together, these results indicate that nonplati-
num regimens do not have a clearly defined role in NSCLC and are
larly targeted agents with good overall tolerability and low toxicity
The availability of newer effective cytotoxic and molecu-
considered appropriate only for patients who are not candidates
profiles has led to the concept of maintenance therapy in order
for platinum agents.
to maintain or improve the disease burden after completion of

first-line therapy. Maintenance therapy involves either switch-
Duration of Chemotherapy
ing to a different agent (switch maintenance) or the continuation of one drug partner of the induction regimen (continuation
The commonly used NSCLC chemotherapy regimens are admin-
maintenance) for patients who have a response to treatment or
istered in 3- or 4-week cycles, and imaging studies are recom-
stable disease.35 (The role of maintenance therapy is discussed
mended after every two or three cycles to assess the response to
extensively in chapter 44.)
therapy. For patients who have an objective response or stable

disease, the number of cycles of therapy has been the subject of
several randomized studies. Socinski et al. randomly assigned
Treatment According to
Histology
patients with advanced NSCLC to treatment with carboplatin

and paclitaxel for four cycles or to continuation of therapy until
NSCLC includes many histologic subtypes, including adenocar-
disease progression.32 The median number of treatment cycles
cinoma, squamous cell carcinoma, and large cell carcinoma, all
administered in both arms was four. There was no significant
of which have diverse clinical behaviors. Until a few years ago, all
improvement in overall survival for the extended chemotherapy
histologic subtypes of NSCLC were treated with similar systemic
approach, but predictably, toxicity was more common with che-
therapy regimens. Although these subtypes were associated with
motherapy beyond four cycles. In another study, Smith et al. com-
distinct differences in sites of metastasis, overall survival, and
pared three cycles of chemotherapy to six cycles and found no
smoking behavior, there was no specific reason to select systemic
improvement in overall survival with six cycles.33 In a systematic
therapy on the basis of histology. The importance of distinguish-
meta-analysis that included 13 randomized controlled trials, data
ing histology among NSCLC subtypes was realized with the devel-
on 3,027 patients receiving first-line (largely platinum-based)
opment of new therapies that resulted in different toxicities and
chemotherapy for three or four cycles were compared with that
outcomes based on histology. This effect was first found in the
for patients who received the same chemotherapy for six cycles
phase II study of bevacizumabthe risk of pulmonary hemor-
or until disease progression. Although extending chemotherapy
rhage was predominantly seen in patients with squamous cell
substantially improved progression-free survival (hazard ratio,
histology.36 Bevacizumab was subsequently restricted to patients
0.75; 95% CI, 0.69-0.81; p<0.00001), there was a statistically sig-
with predominant nonsquamous cell histology. Several other
nificant but clinically modest reduction in the hazard for death
antiangiogenic agents have also been associated with a higher
compared with the standard duration of chemotherapy (hazard
risk of bleeding with squamous cell histology, thus defining this
ratio, 0.92; 95% CI, 0.85- 0.99; p=0.03). Moreover, extension of
as a class effect.
chemotherapy was associated with higher toxicity and impaired
quality of life. As a result, most guidelines recommend limiting
a clear correlation between histology and efficacy. Scagliotti et
the duration of platinum-based first-line therapy to four to six
al. conducted a phase III study to compare the efficacy of cispla-
cycles and considering the induction of maintenance therapy.
tin and pemetrexed with that of cisplatin and gemcitabine for
34
Pemetrexed was the first cytotoxic agent that demonstrated
patients with advanced NSCLC.1 The overall and progression-free
Maintenance Therapy
survival were similar for the study population, which included

approximately 1,700 patients. A preplanned subset analysis to
After four to six cycles of first-line or induction chemotherapy,
study the outcomes for patients with nonsquamous cell histology
approximately two-thirds of patients have nonprogressive dis-
showed a significant improvement in survival for patients with
ease. Because of the lack of major survival advantage with con-
nonsquamous cell histology who received cisplatin and peme-
tinuation of first-line platinum-based combination regimens, the
trexed compared with patients who had squamous cell histology
standard therapeutic approach has been to stop treatment after
(11.8 vs 10.4 months; p=0.005). Conversely, the cisplatin and gem-
four to six cycles, provide close clinical and radiographic surveil-
citabine regimen was superior for patients with squamous cell
lance, and initiate second-line treatment at the time of progres-
histology. Based on the results of this study and similar findings
sion. This wait-and-watch approach is frequently chosen after
in other studies with pemetrexed, this agent is not considered
maximal response to initial therapy has been achieved. However
appropriate for the treatment of squamous cell lung cancer.
a so-called drug holiday is often associated with patient anxiety
about disease recurrence or progression, and concerns about clin-
of paclitaxel) benefits patients with squamous cell lung cancer
ical deterioration and the inability to receive subsequent therapy.
preferentially over patients with nonsquamous cell tumors. In a
In contrast, nab-paclitaxel (an albumin-bound formulation
phase III study of weekly nab-paclitaxel with carboplatin com-
clinical trials. In earlier studies, an age greater than 65 was often
pared with standard paclitaxel and carboplatin given every 3
used to define older patients. In recent older patient-specific
weeks, the overall survival was comparable for the two regimens.37
trials, older is defined as older than age 70. Another noteworthy
The response rate was superior with the nab-paclitaxel regimen
factor is that many studies in the general lung cancer population
for the overall patient population (32% vs 25%) and was also
limit entry to patients younger than 75 years of age. For all these
higher for nab-paclitaxel in patients with squamous cell histology
reasons, treatment decisions for older patients should be made
(response rate ratio, 1.6890; 95% CI, 1.271-2.221; p< 0.001). There
based on available data, patient preferences, comorbidities, and
was no difference in the overall response rate for patients with
molecular status of the tumor.
nonsquamous cell histology between the two regimens (26% with
nab-paclitaxel vs 25% with paclitaxel; p=0.808). Nab-paclitaxel
in a phase III study (ELVIS) that demonstrated superiority for
is approved by the U.S. Food and Drug Administration (FDA),
vinorelbine over best supportive care.46 The survival improve-
in combination with carboplatin, for the treatment of advanced
ment was noted despite early closure of the study due to slow
NSCLC. The drug has the advantage of not requiring premedi-
accrual, with the necessary sample size not being met. This study
cations, which is needed with the standard formulation of
was the first to define the role of chemotherapy specifically for
paclitaxel. Nab-paclitaxel is also associated with a lower incidence
older patients with advanced lung cancer. Subsequently, a study
of grade 3 or 4 neuropathy compared with paclitaxel. The biologic
in which the combination of gemcitabine and vinorelbine was
reasons behind the correlation between histology and efficacy of
compared with gemcitabine alone showed no therapeutic advan-
pemetrexed and nab-paclitaxel are not yet known; some explor-
tage for the combination.47 These studies led to the adoption of
atory hypotheses are described in a subsequent section of this
single-agent chemotherapy as the standard approach for older
chapter.
patients with lung cancer.

Treatment of Older Patients
The role of chemotherapy for older patients was established
The role of combination regimens in the treatment of older
patients was not defined until recently. Subset analysis from a

number of randomized trials demonstrated that outcomes for
In the United States, patients older than 65 years of age repre-
older patients enrolled in clinical trials were similar to those for
sent two-thirds of people with lung cancer, with a median age
younger patients.48-50 In a study by Lilenbaum et al., carboplatin
at diagnosis of older than 70 years. Furthermore, nearly 15% of
and paclitaxel was associated with an increase in response and
patients are over the age of 80 at diagnosis. A number of physi-
survival compared with single-agent paclitaxel, but the differ-
ologic functions, particularly renal and hematopoietic functions,
ences did not reach statistical significance.51 A benefit of similar
are altered with aging, which can have an effect on chemother-
magnitude was found for the combination regimen compared
apy tolerance and toxicity.38 Furthermore, older patients have
with monotherapy in a subgroup analysis of patients older than
more comorbidities than younger patients and are more likely
70 years, and there was no significant difference in survival
to take prescription medications for other conditions, which
between older and younger patients with carboplatin and pacli-
can interfere with the pharmacokinetic disposition of antican-
taxel. However, in a combined analysis of data from two SWOG
cer agents.39-41 Comorbidities can be evaluated with use of the
trials, patients 70 years or older treated with platinum-based
Charlson Comorbidity Index or by the more detailed Cumulative
combinations had a significantly shorter survival (7 vs 9 months;
Illness Rating Scale-Geriatric.43 In a Veterans Affairs Central
p=0.04) and more frequent grade 3 to 5 neutropenia compared
Cancer Registry containing data on 20,511 patients with NSCLC
with younger patients.52
from 2003 to 2008, the percentage of patients receiving guideline-
recommended chemotherapy treatment decreased with increas-
therapy for older patients have demonstrated some degree of
ing age.44 In an analysis of the Surveillance, Epidemiology and
a survival benefit for patients who received more aggressive
End Results-Medicare database, about 25% of older patients
therapy (Table 4).39 In a recent phase III study by Quoix et al.,
received systemic chemotherapy for advanced-stage disease.45
451 patients between the ages of 70 and 89 with locally advanced
Furthermore, platinum-based regimens were given to less than
or metastatic NSCLC and World Health Organization (WHO)
25% of the patients who received chemotherapy.
performance status scores of 0-2 received either four cycles of
Until recently, most treatment recommendations for che-
carboplatin and paclitaxel or five cycles of monotherapy with
motherapy for older patients with NSCLC were based on subset
either vinorelbine or gemcitabine.53 Second-line treatment with
analyses of outcomes for older patients in clinical trials that
erlotinib was used in both treatment arms. The median age for
enrolled patients in all age-groups. Older patients in these stud-
the study population was 77 years. The median overall survival
ies were likely to be highly selected based on functional status
was significantly superior for the doublet chemotherapy (10.3 vs
and may not be representative of the older patient population in
6.2 months; hazard ratio, 0.64; 95% CI, 0.52-0.78; p<0.0001). The
general. Moreover, the definition of older varies widely across
combination regimen was also associated with more hemato-
38
42
Most studies that directly address the benefit of chemo-
10
survival is shorter for
Table 4. Phase III Trials Including Older Patients with Advanced Non-Small Cell Lung Cancer
Author
(Year)
Median
No. of
Age
Patients
(Years)
Treatment
Response
Rate (%)
Median
Survival
(Months)
1-year
Survival
Rate (%)
19.7
6.5
4.9
patients with a perforp

Value
mance status of 2.53,58,59
32
14
0.03
even pooled patients

status of 2 with older
ELVIS
(1999)46
76
85
74
Vinorelbine
BSC
Frasci
(2000)194
60
60
74
Vinorelbine
Gemcitabine + vinorelbine
22
15
7
4.5
13
30
<0.01
Gridelli
(2003)47
700
74
Vinorelbine
Gemcitabine
Gemcitabine + vinorelbine
21
16
18.1
8.5
6.5
7.4
42
28
34
NS
Kudoh
(2006)195
182
76
Vinorelbine
Docetaxel
9.9
22.7
9.9
14
NR
NR
NS
Quoix
(2011)53
226
225
77
Vinorelbine or gemcitabine
Carboplatin + weekly
paclitaxel
10
6.2
25.4
0.0004
27
10.3
44.5
Some studies have

with a performance
patients (most commonly defined as older
than age 70). Although
BSC=best supportive care, NS=not significant, NR=not reported. Modified from Quoix E, Westeel V, Zalcman G, Milleron B.
Chemotherapy in elderly patients with advanced non-small cell lung cancer. Lung Cancer. 2011;74(3):364-368.
a decline in performance status is often

related to high disease burden related to
lung cancer, the status
should be distinguished
from poor performance
status related to comor-
logic and nonhematologic toxicity, including neutropenia (48.4%
bidities. Until now, studies conducted in older patients have not
vs 12.4%) and asthenia (10.3% vs 5.8%). This study is the first
adequately made this distinction, which makes it difficult to
prospective trial for older patients that demonstrated a survival
recommend aggressive therapies for patients with a poor per-
benefit with combination chemotherapy. It is noteworthy that
formance status. In recent years, several studies have been con-
the treatment schedule used in the study was weekly paclitaxel
ducted exclusively for this population of patients. The combina-
with carboplatin given every 4 weeks, which appears to have a
tion of carboplatin and paclitaxel was superior to single-agent
slightly favorable tolerability over the standard every 3-weeks
paclitaxel (median survival, 4.7 vs 2.4 months) among patients
schedule. This cumulative evidence indicates that older patients
with a performance status of 2 in a prospectively specified sub-
with a good performance status are appropriate candidates for
group analysis of data for patients with poor performance status
platinum-based chemotherapy. Also, consideration for primary
enrolled in a Cancer and Leukemia Group B (CALGB) trial.51 In
prophylaxis with granulocyte colony stimulating factor may be
another study of patients with poor performance status, the
54
appropriate for certain combination regimens for older patients.
combination of carboplatin and paclitaxel was superior to sin-
Given the potential detrimental effects of cisplatin on the kidneys
gle-agent erlotinib (9.7 vs 6.5 months).51,60 In a recent phase III
and other end organs in older individuals, carboplatin-based regi-
trial for patients with advanced NSCLC, patients with a perfor-
mens are preferred for the treatment of advanced NSCLC. For less
mance status of 2 were randomly assigned to carboplatin and
fit patients, monotherapy may be suitable ; however, the possible
pemetrexed or to pemetrexed alone.61 Performance status was
benefits and risk must be balanced and discussed with patient.
determined by the treating physician and verified by another phy-
55
sician at each participating site. The doublet therapy was associ-
Treatment of Patients with

Poor Performance Status
ated with a statistically and clinically significant improvement

in response rate (23.8% vs 10.3%; p=0.032), median progressionfree survival (5.8 vs 2.8 months; hazard ratio, 0.46; 95% CI, 0.35-
As noted earlier, the performance status of the patient is an
0.63; p<0.001), and median overall survival (9.3 vs 5.3 months;
important prognostic factor in lung cancer. An ECOG perfor-
hazard ratio, 0.62; 95% CI, 0.46-0.83; p=0.001). However, toxicity
mance status of 2, alternatively termed marginal performance
was also higher with the doublet, with more treatment-related
status or poor risk, is defined as being ambulatory and capable
deaths (3.9% vs. 0%). This study was the first prospective study
of all self-care but unable to carry out any work activities; up
to demonstrate benefit from platinum-based therapy for patients
and about more than 50% of waking hours.56 The designation
with poor performance status. Future trials should address the
of performance status remains subjective, as evidenced by the
impact of comorbidities compared with cancer burden as the
discordance between physician assessments and patients self-
reason for decline in performance status, as well as the correla-
assessments.57 In general, physicians tend to overestimate the
tion to outcome with combination therapies.
performance status of patients.
Subset analyses of trials for patients with advanced NSCLC
ease burden and poor performance status may also be offered
with a performance status of 0-2 have historically shown that
combination therapy. As with any clinical decision, therapy
Taking the recent data into account, patients with heavy dis-
selection depends on patient preference and physician judg-
survival (11 vs 11.3 months; p=0.66) or response rate (36.5% vs
ment throughout the process of selecting palliative treatment
38.8%). In addition to these disappointing results, problems
in the setting of advanced NSCLC. Molecular testing is strongly
regarding the sensitivity of the antibodies used for detection of
recommended, even for patients with a poor performance status,
ERCC1 expression have recently been reported.67
as the use of appropriate targeted therapy for selected patients

has been reported to result in robust responses and improved
physical function.
dylate synthase (TS), dihydrofolate reductase, and glycinamide
62
Pemetrexed exerts anticancer effects by inhibiting thymi-
ribonucleotide formyl transferase.68 TS is an enzyme that con-
Biomarkers for Selection of

Chemotherapy
verts deoxyuridylate to deoxythymidylate, which is necessary

for DNA synthesis. Because TS is the main target of pemetrexed,
low levels of TS have been hypothesized to predict an increased
The use of biomarkers to select appropriate chemotherapy regi-
response to treatment with pemetrexed. In a study of 56 patients
mens has long been a focus of research. Lung cancer cells have
with NSCLC, TS mRNA and protein levels were higher in patients
a relative deficiency of DNA repair machinery compared with
with squamous cell carcinoma.69 TS levels may explain why resis-
normal cells; this makes lung cancer cells more sensitive to the
tance to pemetrexed is greater among patients with squamous
DNA damaging effects of cytotoxic chemotherapy.63 Somatic
cell histology than among patients with adenocarcinoma histol-
excision repair cross-complementing gene 1 (ERCC1) has been
ogy, although this explanation remains to be confirmed.
evaluated as a prognostic and predictive biomarker of response
to treatment with platinum agents. Ribonucleotide reductase
tubules, resulting in apoptosis. High levels of -tubulin have
M1 (RRM1) is the catalytic subunit of ribonucleotide reductase,
been associated with resistance to treatment with docetaxel and
which converts ribonucleoside diphosphates into deoxyribonu-
paclitaxel in cell lines.70 In a study of 91 patients with advanced
cleosides in DNA synthesis.64 Since RRM1 is the primary target
NSCLC, 47 who were treated with paclitaxel and 44 with non-
of gemcitabine, it has been studied as a predictive biomarker for
taxane regimens, low expression of class III -tubulin on IHC
efficacy of that agent.
was associated with improved response rates, progression-free
A randomized phase III study was conducted to evaluate
survival, and overall survival when paclitaxel was used.71 In a
the use of ERCC1 expression to personalize therapy for NSCLC.65
meta-analysis of 552 patients in 10 studies that examined either
The hypothesis was to treat patients with ERCC1-overexpressing
paclitaxel- or vinorelbine-containing regimens, decreased expres-
tumors with nonplatinum regimens and to treat patients with
sion of class III -tubulin was associated with improved overall
low ERCC1 expression in the tumor with platinum-containing
survival (hazard ratio, 1.40; p<0.00001).72 These findings have not
regimens. Of the randomly assigned patients, 82.4% had adequate
been confirmed in prospective studies, and the role of -tubulin
tissue for ERCC1 mRNA expression analysis. Four hundred forty-
as a predictive marker for taxanes remains unproven.
Taxanes bind to -tubulin and lead to stabilization of micro-
four patients with stage IIIB or IV NSCLC were then randomly

assigned in a 2:1 ratio to the genotypic arm, in which patients
were treated according to the ERCC1 status of the tumor (gemcitabine and docetaxel for tumors with low ERCC1 expression and
Combination of Targeted
Agents and Platinum-based
Chemotherapy
cisplatin and docetaxel for tumors with high ERCC1 expression)

or to the control arm, in which all patients received cisplatin and
The development of molecularly targeted agents has led to the
docetaxel regardless of biomarker status. The study achieved its
evaluation of several novel compounds in combination with plati-
primary endpoint of improvement in response rate, with a rate of
num-based chemotherapy for the first-line treatment of advanced
50.7% in the genotypic arm compared with 39.3% in the control
NSCLC. These studies were usually supported by supra-additive
arm (p=0.02). However, the lack of significant improvement in
or synergistic pre-clinical interactions between agents. However,
survival in the genotypic arm limited the utility of ERCC1 as a pre-
most of these studies failed to demonstrate an improvement in
dictive biomarker. In another recently published phase III study,
survival with the addition of a targeted agent to standard chemo-
treatment was assigned based on tumor expression of ERCC1 and
therapy. These studies were typically conducted in unselected
RRM1 for patients with chemotherapy-nave advanced NSCLC.
patient populations and did not include efforts to identify pre-
ERCC1 and RRM1 expression were determined by an automated
dictive biomarkers. More recently, studies with novel combina-
quantitative analysis based on immunohistochemistry (IHC).
66
tions are focused on identifying a subset of patients who are more
Of 275 eligible patients, 183 were randomly assigned to the cus-
likely to gain robust benefits. The first combination strategy to
tomized approach and 92 to the control group. There was no
demonstrate survival benefit was the addition of bevacizumab,
difference between the two groups for the primary endpoint of
a monoclonal antibody against the vascular endothelial growth
progression-free survival or the secondary outcomes of overall
factor (VEGF), to standard chemotherapy.
11
12
Bevacizumab
progression-free survival with the addition of low-dose (7.5 mg/
It has been widely reported that for tumor development and
kg) bevacizumab (hazard ratio, 0.75; 95% CI, 0.640.87; p=0.0003)
growth to proceed beyond a defined volume, the development
or high-dose (15 mg/kg) bevacizumab (hazard ratio, 0.85; 95%
of a new blood supply is necessary.73,74 Therefore, most solid
CI, 0.731.00; p=0.0456) to standard chemotherapy of cisplatin
tumors need new blood vessels for continued growth and metas-
and gemcitabine.78 In the latter study, however, the median net
tasis, which may be achieved by the induction of endothelial cell
gain of progression-free survival was relatively modest with beva-
sprouting from the pre-existing vasculature (angiogenesis).73,75,76
cizumab, and, more important, there was no improvement in
The monoclonal anti-VEGF antibody bevacizumab, which blocks
overall survival (low-dose bevacizumab: hazard ratio, 0.93; 95%
the binding of VEGF to its high-affinity receptors, was the first
CI, 0.781.11; p=0.42; high-dose bevacizumab: hazard ratio, 1.03;
angiogenesis inhibitor to complete clinical development and is
95% CI, 0.86-1.23; p=0.761).79 As a result of these phase III trials
currently the only antiangiogenesic agent approved for the treat-
of chemotherapy-nave patients with NSCLC, bevacizumab has
ment of lung cancer.
been approved for the treatment of advanced NSCLC, excluding
predominantly squamous cell histology, in combination with
In a phase II trial of 99 unselected patients with NSCLC,
treatment with carboplatin and paclitaxel plus bevacizumab (15
platinum-containing chemotherapy.
mg/kg) was compared with a chemotherapy control arm; the
addition of bevacizumab was associated with a higher response
with a low but significant risk of grade 3 or higher or fatal (grade
rate (31.5% vs 18.8%), a longer median time to progression (7.4
5) pulmonary hemorrhage. Two meta-analyses have found that
vs 4.2 months), and a modest increase in survival (17.7 vs 14.9
the use of bevacizumab in combination with chemotherapy for
months).36 However, 9% of patients treated with bevacizumab
the treatment of various tumor types conferred a significantly
had life-threatening pulmonary hemorrhage, which was fatal in
increased risk of severe and fatal bleeding events and treat-
four patients. Most patients with hemoptysis had squamous cell
ment-related mortality compared with chemotherapy alone.80,81
histology, tumor cavitation, and disease location close to major
However, patients with NSCLC are at an increased risk of pulmo-
blood vessels, and these clinical situations were excluded in sub-
nary hemorrhage because of the underlying disease process. In
sequent studies.
a study of 877 patients, 16% had nonlife-threatening bleeding;
Two large clinical trials demonstrated efficacy of beva-
nearly 3% of these were fatal.82 Massive pulmonary hemorrhage
cizumab in combination with a platinum-containing chemo-
was associated with squamous cell tumors, cavitation, and bron-
therapy for patients with advanced NSCLC of nonsquamous cell
chial (versus peripheral) tumors.82 Recently, an expert panel rec-
histology, resulting in the FDA approval of bevacizumab for this
ommended that patients with squamous cell histology and/or a
setting (Table 5).77,78 In the ECOG 4599 study, a substantial clinical
history of grade 2 or higher hemoptysis (2.5 ml per event) should
benefit was found for patients with NSCLC treated with bevaci-
not receive bevacizumab.83 However, no clinical or radiographic
zumab (15 mg/kg) plus carboplatin and paclitaxel compared with
features (including cavitation and central tumor location) reli-
chemotherapy alone; the median progression-free survival was
ably predict severe pulmonary hemorrhage in patients treated
6.2 compared with 4.5 months (hazard ratio, 0.66), and the median
with bevacizumab. Major blood vessel infiltration and bronchial
overall survival was 12.3 compared with 10.3 months (hazard
vessel infiltration, encasement, and abutting may increase the risk
ratio, 0.79).77 These results were partly confirmed by another large
of pulmonary hemorrhage; however, standardized radiographic
phase III trial in which patients with NSCLC had an improved
criteria for defining infiltration have not been established. In all of
Bevacizumab and other antiangiogenic agents are associated
Table 5. Comparison of Phase III Studies of Platinum Doublet Therapy with Bevacizumab
Median Survival (%)
Trial
Doublet
Bevacizumab
Dose (mg/kg)
Response Rate
(%)
ProgressionFree
Overall
ECOG
459977
Carboplatin and
paclitaxel
15
35 vs 15
6.2 vs 4.5
12.3 vs 10.3
HR=0.79; 95%
CI= 0.67-0.92;
p=0.003
AVAiL78,79
Carboplatin and
gemcitabine
Low: 7.5
High: 15
34 (low) vs
30 (high) vs 20
6.7 (low) vs
6.5 (high) vs 6.1
13.6 (low) vs
13.4 (high) vs 13.1
HR=0.93; 95%
CI= 0.78-1.11;
p=0.42 (low)
HR=1.03; 95%
CI= 0.86-1.23;
p=0.76 (high)
HR=hazard ratio.
Significance
these studies, patients received maintenance therapy with bevaci-
significantly improved by the addition of nintedanib (3.4 vs 2.7
zumab after completion of chemotherapy; still, the benefit of this
months; hazard ratio, 0.79; 95% CI, 0.68-0.92; p=0.0019), but over-
maintenance therapy has not yet been prospectively addressed
all survival was not significantly different (10.1 vs 9.1 months;
in large clinical trials of NSCLC.
hazard ratio, 0.94; 95% CI, 0.83-1.05; p=0.2720). However, in a

prespecified subgroup analysis, patients with adenocarcinoma
Other Antiangiogenic Agents
had both a significant and clinically meaningful improved pro-
The therapeutic success achieved with bevacizumab for NSCLC
gression-free survival (4.0 vs 2.8 months; hazard ratio, 0.77; 95%
has prompted the evaluation of several other antiangiogenic
CI, 0.62-0.96; p=0.0193) and overall survival (12.6 vs 10.3 months;
agents. Various small-molecule tyrosine kinase inhibitors (TKIs)
hazard ratio, 0.83; 95% CI, 0.70-0.99; p=0.0359HR). Also, there was
have been tested in clinical studies of advanced NSCLC. The spec-
a significant improvement in the disease control rate with the
trum of receptors inhibited by TKIs is not limited to the VEGF
nintedanib plus docetaxel combination (adenocarcinoma: 60.2%
receptor (VEGFR), but comprises various additional growth fac-
vs 44%; odds ratio, 1.93; p<0.0001 and squamous cell carcinoma:
tors and signaling pathways. Although the broader activity of
49.3% vs 35.5%; odds ratio, 1.78; p<0.0009). These findings were
TKIs was considered likely to improve the therapeutic benefit,
supported by the results of another phase III trial to evaluate the
the number of side effects also increased, thus making it difficult
second-line combination of pemetrexed with or without nint-
to draw conclusions about the relevance of targeting VEGFR. To
edanib for patients with advanced or recurrent nonsquamous cell
date, no drug in this class has demonstrated survival improve-
NSCLC after treatment with first-line chemotherapy (LUME-Lung
ment in randomized studies. Phase II studies addressing mono-
2).91 Despite stopping the trial after recruitment of 713 of the 1,300
therapy with multi-TKIs have demonstrated modest activity, with
intended patients, the primary endpoint was still met, as progres-
response rates ranging from 7% to 10% and the median time to
sion-free survival was significantly superior after treatment with
progression ranging from 2.4 to 5.8 months in pretreated patients
nintedanib plus pemetrexed (4.4. vs 3.6 months; hazard ratio,
with NSCLC. Moreover, several phase III trials have recently been
0.83; 95% CI, 0.70-0.99; p=0.0435). The LUME Lung-1 study is the
completed that have assessed multi-kinase antiangiogenic TKIs
first phase III study to demonstrate a survival benefit of adding a
in a second-, third-, and/or fourth-line setting, including such
multi-TKI to chemotherapy in a prespecified subgroup.
agents as sunitinib (in combination with erlotinib),84 vandetanib
(in combination with docetaxel or pemetrexed),85,86 and sorafenib
VEGFR-2 and blocks ligand binding and activation. Currently, a
(as a single agent).87 The outcomes of these trials were disappoint-
phase III study (REVEL) is evaluating ramucirumab in combina-
ing; despite an improvement in response rates and progression-
tion with docetaxel as second-line therapy after treatment failure
free survival in most trials, these antiangiogenic TKIs had no effect
with platinum-based therapy. Aflibercept is an investigational
on overall survival. Some additional phase III trials are ongoing
recombinant protein composed of epitopes of the extracellular
to assess novel agents, such as pazopanib and apatinib, that have
domains of human VEGFR fused to the constant region (Fc) of
shown promising activity in phase II trials.88
human immunoglobulin (IgG) 1 functioning as a soluble decoy
In a recent meta-analysis of 15 randomized controlled trials
receptor. The addition of aflibercept to second-line docetaxel in
investigating multi-targeted antiangiogenic TKIs (vandetanib,
patients with NSCLC was associated with an improved overall
sunitinib, cediranib, sorafenib, motesanib) in combination with
response rate, but there was no improvement in overall survival.92
chemotherapy or as monotherapy in advanced NSCLC, treat-
Vascular disrupting agents that cause destruction of existing
ment with multi-TKIs was associated with a significantly longer
tumor vasculature have also been studied in lung cancer, but
progression-free survival (hazard ratio, 0.824; 95% CI, 0.759-0.895;
without much success.93
Ramucirumab is a monoclonal antibody that binds to
p<0.001) and superior response rate (odds ratio, 1.27; 95% CI,
survival was not significantly different (hazard ratio, 0.962; 95%
Biomarker Discovery Efforts for

Antiangiogenic Therapy
CI, 0.912-1.015; p=0.157). Other VEGFR inhibitors currently under
At the present time, patient selection for treatment with anti-
development include the previously mentioned pazopanib and
angiogenic agents remains largely driven by perceived safety
apatinib, and, more recently, nintedanib.
concerns. Predictive markers for the selection of patients who
Recently, two phase III trials (LUME-Lung 1 and 2) investi-
may benefit from antiangiogenic therapy are needed for the use
gated nintedanib, a TKI targeting VEGF, platelet-derived growth
of antiangiogenic drugs. Furthermore, similar to resistance to
factor (PDGF), and fibroblast growth factor (FGF) receptors. The
EGFR TKIs, both pre-existing and adaptive resistance mecha-
study included 1,314 patients with stage IIIB or IV NSCLC for
nisms have been postulated to lead to failure of antiangiogenic
whom first-line chemotherapy failed; the patients were randomly
drugs, which would make proper patient selection even more
assigned to receive docetaxel with or without nintedanib (LUME-
important.94-96 Several markers have been studied for their ability
Lung 1). The primary endpoint, progression-free survival, was
to predict the therapeutic value of antiangiogenic agents,97 but to
1.13-1.42; p<0.0001) compared with the control89; however, overall
90
13
14
date, no marker has been validated for use in this setting. Some
VEGF or VEGFR1 may have predictive value.103 Other important
of the candidate markers include measures of angiogenesis itself,
candidates for potential predictive markers include cadherins
such as visual quantification of microvessel density, and, more
such as E-cadherin and vascular endothelial (VE)-cadherin, as
recently, evaluation of gene signatures or expression levels at the
well as the large family of integrins, which mediate cell-extracel-
messenger RNA or protein level.97
lular matrix and cell-cell interactions.
In retrospective analyses, the predictive value of pretreat-
In general, the identification of biomarkers is complicated
ment circulating VEGF levels has been inconsistent in several
by the lack of standardization of analytic technologies, including
studies, including anti-VEGFR inhibitors in patients with NSCLC.
interpretation and scoring of the data generated by these meth-
In the ECOG 4599 study, patients with high VEGF levels before
ods. Moreover, most biomarker analyses have been performed
treatment were more likely to have a response to bevacizumab-
only on small subsets of patients who have been recruited in clini-
containing therapy, but high levels were not predictive of sur-
cal studies, making it difficult to draw conclusions for the clinical
vival.98 A meta-analysis of data from four phase III trials of bevaci-
collective. Thus, future trials should incorporate carefully planned
zumab in colorectal cancer, lung cancer, and renal cell carcinoma
and hypothesis-driven biomarker assessments, placing particular
(total of 1,816 patients) identified circulating VEGF as a prognos-
emphasis on the recruitment of tissue and blood samples from
tic marker, but not a predictive one. Some studies have shown
as many patients as possible.104
99
elevations of VEGF levels and decreases in serum VEGFR-2 levels

during anti-VEGF therapy.100,101 Interestingly, similar changes were
also seen in normal mice free of any tumor treated with sunitinib,
Epidermal growth factor

RECEPTOR blockade in NSCLC
indicating that these molecular changes are a host response to

drug treatment.101
EGFR TKIs
Cell-adhesion molecule (CAM) families have been inves-
EGFR is a member of the ErbB family of transmembrane tyrosine
tigated because antiangiogenic agents alter the function and
kinase receptors, which bind ligands such as EGF. Upon ligand-
survival of endothelial cells and shed CAMs into the circula-
binding, the receptor undergoes either homodimerization or
tion. Thus, some CAMs have been studied as potential markers
heterodimerization with another member of the ErbB family,
to monitor antiangiogenic therapies. For example, endothelial
resulting in activation of downstream signaling cascades that
(E)-selectin is synthesized by endothelial cells and is involved in
lead to cell proliferation and survival.105 The determination that
the recruitment of leukocytes and tumor progression. Elevated
many cancers, including NSCLC, have aberrant EGFR signaling
expression of soluble E-selectin in the peripheral blood has been
led to the development of EGFR blocking therapies. Gefitinib
found in some series of patients with lung cancer. The ECOG
and erlotinib are small-molecule EGFR TKIs that have activity in
4599 study analyzed E-selectin as a potential predictive marker
NSCLC, particularly in patients who have tumors with activating
in peripheral blood samples from 149 of 878 patients. E-selectin
EGFR mutations.
significantly decreased during treatment, and the overall survival
was significantly longer when levels were less than 5.35 ng/mL
NSCLC in the second- and third-line setting. Erlotinib was found
in patients treated with chemotherapy and bevacizumab (hazard
to benefit patients with previously treated metastatic disease in
ratio, 1.98; 95% CI, 1.1-3.57; p=0.02).
the BR.21 study.106 Initial phase II studies with gefitinib were
98
EGFR TKIs were first studied in unselected patients with
Another important class of CAMs is the IgG superfamily,
also conducted in unselected patients, and response rates were
including ICAM-1, which seems to be produced particularly
approximately 10-19%. With both of these agents, the likelihood
in activated endothelial cells. The ECOG 4599 study identified
for response was greater for women, never-smokers, patients with
low baseline ICAM levels as a significant predictive factor for
Asian ethnicity, and patients with adenocarcinoma histology. The
improved progression-free survival (hazard ratio, 2.14; 95% CI,
biologic rationale for these findings emerged with the discovery of
1.31-3.48) but not overall survival (hazard ratio, 1.39; 95% CI, 0.84-
EGFR mutations in 2004.107,108 Patients who had robust responses
2.3) when bevacizumab was added to cytotoxic therapy.98
to EGFR TKIs were likely to harbor an activating mutation in the
In an exploratory substudy of the BRAIN trial, which evalu-
tyrosine kinase-binding pocket of the EGFR gene. The mutations
ated the value of first-line treatment with erlotinib and bevaci-
were primarily localized to two so-called hot spots on exons 19
zumab for patients with advanced NSCLC, the analysis of cir-
and 21. The prevalence of the activating mutations was greater
culating endothelial and tumor cells using flow cytometry was
in the clinical subset of patients with a higher response rate to
described as feasible ; however, with a median of 30 detectable
EGFR TKIs. Following this landmark discovery, a number of phase
circulating endothelial cells per sample, the counts did not corre-
II studies were conducted exclusively for patients with tumors
late with outcome. In a cohort of 48 patients, baseline circulating
with EGFR mutation. Treatment with either gefitinib or erlotinib
tumor cells were indicative of poor progression-free survival.
resulted in response rates of 50-80%, with a median progression-
free survival of 8-12 months.
102
Lastly, single nucleotide polymorphism (SNP) analyses of
Before the description of activating EGFR mutations, phase
different chemotherapy regimens in patients who have lung
III studies were conducted to combine erlotinib and gefitinib with
tumors with the EGFR mutation in the first-line setting; all of
standard chemotherapy for the first-line treatment of advanced
these studies have shown overall response rates of 56-83%, with
NSCLC. None of these studies demonstrated an improvement in
progression-free survival benefit (Table 6).115-118 Maemondo et
overall survival.
Subsequent trials included clinical enrich-
al. published the results of the first study comparing first-line
ment to identify patients who may benefit from an EGFR TKI
treatment with an EGFR TKI with chemotherapy for patients with
given alone or in combination with chemotherapy. The CALGB
activating EGFR mutations in the tumor.115 Patients were selected
conducted a randomized phase II study in never-smokers with
by the presence of activating EGFR mutation; patients with the
advanced NSCLC.113 Patients received erlotinib alone or in com-
resistant T790M mutation were ineligible. This study randomly
bination with carboplatin and paclitaxel. Overall, there was no
assigned 230 patients to treatment with either gefitinib or car-
difference in efficacy between the two treatment arms. However,
boplatin and paclitaxel. For patients who received gefitinib, the
in the 40% of the patients with an EGFR mutation, the response
overall response rate was 73.7% compared with 30.7% for patients
rate and overall survival were higher than in those with wild-type
who received chemotherapy (p<0.001). Patients with EGFR muta-
EGFR. There was no suggestion of improvement in efficacy with
tions treated with gefitinib also had a longer median progression-
the addition of chemotherapy to erlotinib for patients with an
free survival (10.8 vs 5.4 months; hazard ratio, 0.30; 95% CI, 0.22-
EGFR mutation. The findings of this study suggested that clini-
0.41; p<0.001). This finding was consistent with the results seen
cal selection is unlikely to help identify patients appropriate for
in the subgroup analysis of patients with an EGFR mutation in
EGFR TKI therapy.
the IPASS study. Although there was a trend toward longer overall
109-112
This issue was definitively addressed by the Iressa Pan-Asia
survival with a TKI (30.5 months vs 23.6 months), the difference
Study (IPASS) that enrolled Asian patients with adenocarcinoma
was not significant (p=0.31). Similar to other EGFR TKI studies,
of the lung and who had never smoked or had a history of light
almost all (94.6%) of the patients in the chemotherapy arm went
cigarette smoking. Patients were randomly assigned to treatment
on to receive an EGFR TKI at the time of disease progression. In a
with gefitinib or chemotherapy (carboplatin and paclitaxel) as
subgroup analysis performed according to EGFR mutation type,
first-line treatment of advanced-stage disease.114 The progression-
there was no difference between the progression-free survival
free survival was significantly better for gefitinib than for chemo-
or response rate for patients with exon 19 deletions and patients
therapy (hazard ratio, 0.74; 95% CI, 0.65-0.85; p<0.001). In 261
with point mutations in L858R on exon 21. The findings of this
patients who had tumors with EGFR mutations, treatment with
study helped confirm that activating EGFR mutations are predic-
gefitinib achieved an overall response rate of 71.2% compared
tive of therapeutic benefit from treatment with EGFR TKIs.
with 47.3% for chemotherapy, with an increase in progression-free
survival (hazard ratio, 0.48; 95% CI, 0.36-0.64; p<0.001). Among
TKIs for patients with an EGFR mutation have been conducted
176 patients who had tumors that tested negatively for EGFR
in predominantly Asian populations. The EURTAC study was a
mutations, the response rate was 1.1% for patients who received
randomized phase III study in which the efficacy of erlotinib
gefitinib, compared with 23.5% for patients who received chemo-
and chemotherapy (cisplatin and docetaxel or cisplatin and
therapy; in contrast, chemotherapy provided benefit in progres-
gemcitabine) were compared in white patients with activating
sion-free survival for patients who did not have an EGFR muta-
EGFR mutations in the tumor. This study achieved its primary
tion (hazard ratio, 2.85; 95% CI, 2.05-3.98; p<0.001). These results
endpoint of progression-free survival benefit at the first interim
The majority of studies demonstrating the success of EGFR
demonstrated that
EGFR TKIs benefit only
Table 6. EGFR TKI Compared with Platinum Doublet Chemotherapy in EGFR-mutated Non-Small Cell Lung Cancer
patients with EGFR

mutations in the firstline setting. Therefore,
molecular selection,
Hazard Ratio (95% CI); p Value

Platinum Doublet
EGFR TKI
Response Rate
(%)
Carboplatin/paclitaxel115
Gefitinib
Cisplatin/docetaxel116
Progression
Death
31 vs 74
0.30 (0.22-0.41)
p<0.001
Not reported
p=0.31
Gefitinib
32 vs 61
0.489 (0.336-0.71)
p<0.0001
1.638 (0.749-3.582)
p=0.211
Carboplatin/gemcitabine117
Erlotinib
36 vs 83
0.16 (0.10-0.26)
p<0.0001
Not reported
Cisplatin/docetaxel or
gemcitabine122
Erlotinib
18% vs 64%
0.37 (0.25-0.54)
p<0.0001
1.04 (0.65-1.68)
p=0.87
Cisplatin/pemetrexed121
Afatinib
23% vs 56%
0.58 (0.43-0.78)
p=0.001
1.12 (0.73-1.73)
p=0.60
and not clinical selection, should be used to

identify patients who
will benefit from the
first-line use of EGFR
TKIs.

Several studies
have compared gefitinib or erlotinib with
15
16
efficacy analysis with only 174 patients enrolled: the median
studies. The FLEX study randomly assigned 1,125 patients with
progression-free survival was better for patients who received
chemotherapy-nave advanced NSCLC (stage IIIB or IV) with
erlotinib than for patients who received chemotherapy (9.7 vs 5.2
EGFR expression by IHC to cisplatin and vinorelbine with or
months; hazard ratio, 0.37; 95% CI, 0.25-0.54; p<0.0001). The pro-
without cetuximab.123 The study demonstrated a superior overall
gression-free survival benefit appeared to be greater for patients
survival with the addition of cetuximab to chemotherapy (11.3 vs
with tumors with exon 19 deletions than for patients with tumors
10.1 months; hazard ratio for death, 0.871; 95% CI, 0.762-0.996;
with L858R mutations, which was also found in the IPASS study.
p=0.044). However, the median progression-free survival was sim-
Again, similar to previous studies of an EGFR TKI compared with
ilar for the two arms, at 4.8 months (hazard ratio, 0.943; p=0.39).
chemotherapy, the overall response rate for erlotinib was 64%
The overall response rate increased from 29% with chemotherapy
compared with 18% for chemotherapy, and there was no sur-
alone to 36% with the addition of cetuximab (p=0.01).
vival benefit (hazard ratio, 1.04; 95% CI, 0.65-1.68; p=0.87). This
study was the first to examine the efficacy of EGFR TKI therapy
benefit with the addition of cetuximab to first-line chemother-
in a non-Asian population, and its findings were similar to the
apy in the metastatic setting.124 This trial randomly assigned 676
progression-free survival advantages seen in Asian populations
patients with metastatic NSCLC to chemotherapy consisting of
with EGFR mutations treated with an EGFR TKI. These studies
carboplatin and a taxane (either paclitaxel or docetaxel) with or
substantiate the evidence that patients should be tested for the
without cetuximab. Unlike the FLEX study, this study did not
presence of activating EGFR mutations at the time of lung cancer
select patients based on EGFR expression status. The addition
diagnosis, as robust therapeutic gains are derived from EGFR TKI
of cetuximab improved the overall response rate (25.7% vs 17.2%;
therapy.
p=0.007) but this did not result in a difference in the median pro-
Afatinib, an irreversible inhibitor of EGFR, HER2, and ErbB4
gression-free survival, which was the primary endpoint (hazard
receptors, was first studied in patients with advanced NSCLC in
ratio, 0.902; 95% CI, 0.761-1.069; p=0.236). The lack of benefit
whom treatment with an EGFR TKI after chemotherapy had failed
remained consistent in an analysis of overall survival: the median
in the LUX-Lung 1 study.
Another phase III study (BMS099) failed to detect a survival
In patients with EGFR-positive tumors
overall survival for cetuximab was 9.69 months compared with
who were EGFR TKI-nave, afatinib was associated with a response
8.38 months for chemotherapy alone, but the difference was not
rate of more than 60%.120 Patients were initially treated with the
significant (hazard ratio, 0.89; 95% CI, 0.754-1.051; p=0.169). In an
maximum tolerated dose of 50 mg of afatinib; however, the higher
exploratory post hoc analysis, the development of a rash prior to
dose resulted in severe rash and diarrhea, and the 40 mg/day dose
day 21 among patients who received cetuximab correlated with
was used thereafter. Recently, a phase III study was conducted
an overall survival benefit: (10.4 vs 8.9 months; hazard ratio, 0.76;
to compare the efficacy of afatinib and standard chemotherapy
95% CI, 0.59-0.98).
for patients with EGFR-positive tumors. In the first-line setting,
afatinib was associated with a longer progression-free survival
been studied in NSCLC. Matuzumab, a humanized IgG1 mono-
than cisplatin and pemetrexed (11.1 vs 6.9 months; hazard ratio,
clonal antibody against EGFR, was tested in a phase II study in
0.58; 95% CI, 0.43-0.78; p<0.001); the benefit was even greater
combination with pemetrexed in the second-line treatment of
for patients with exon 19 deletions and L858R mutations, with
NSCLC.125 This study failed to achieve its primary endpoint of an
a progression-free survival of 13.6 months (hazard ratio, 0.47;
increased overall response rate (11% with matuzumab compared
95% CI, 0.34-0.65; p<0.001).121 On the basis of these results, the
with 5% with pemetrexed alone; p=0.332) with a trend toward an
US FDA approved afatinib for the treatment of EGFR-positive
increase in survival with the addition of matuzumab (12.4 months
NSCLC. Afatinib is associated with a higher incidence of skin rash,
for weekly matuzumab, 7.9 months for pemetrexed alone, and
diarrhea, and mucositis compared with the first-generation EGFR
5.9 months for every-3-week matuzumab). Eighty-seven percent
TKIs. Dacomitinib, another irreversible EGFR inhibitor, also dem-
of tumors had EGFR expression by IHC; in a subgroup analysis,
onstrated favorable efficacy in a randomized phase II study when
all but one of the responses was seen in EGFR-positive tumors.
compared with erlotinib.122 Based on these findings, phase III
Panitumumab, a fully human IgG2 monoclonal anti-EGFR anti-
studies are presently underway to compare irreversible inhibi-
body, was tested in combination with multiple chemotherapy
tors with first-generation compounds in patients with advanced
regimens in phase I and II trials of patients with metastatic
NSCLC.
NSCLC in first-line treatment and beyond, with modest results.126
119
Other novel EGFR-targeted antibody therapies have also
Necitumumab (IMC-11F8), a recombinant human antibody with
Monoclonal Antibodies against

EGFR
a structure similar to that of cetuximab, is being combined with
Cetuximab is a chimeric monoclonal antibody that binds and
and gemcitabine in squamous cell lung cancer (ClinicalTrials.gov
inhibits EGFR. Cetuximab has been tested in combination with
identifier: NCT00981058).
chemotherapy for patients with metastatic NSCLC in phase III
chemotherapy in the SQUIRE trial in combination with cisplatin
Biomarkers for EGFR Blockade
tions, regardless of clinical characteristics or the presence of
Many different biomarkers have been assessed in patients treated
other histologies mixed with adenocarcinoma. Testing should
with EGFR-targeted therapies. Biomarker analyses of early studies
be performed at the time of diagnosis for patients with metastatic
have demonstrated no consistent association with EGFR expres-
disease and can be performed on resection specimens based on
sion on IHC, copy number by fluorescence in situ hybridization
institutional preferences. Specimens that can be used for testing
(FISH), or KRAS mutations.
The CA dinucleotide repeat, a
include fresh, frozen, or formalin-fixed paraffin-embedded tissue.
polymorphism present in intron 1 of EGFR that modulates its
Many methodologies are acceptable for detecting EGFR muta-
transcription, has also been studied as a potential biomarker
tions (Sanger sequencing, polymerase chain reaction [PCR]-based
for EGFR-targeted therapies. Data about the utility of short CA
assays, single-base extension genotyping, and high-performance
repeats as a biomarker have been conflicting, as CA repeats cor-
liquid chromatography assays). It is recommended that the assay
related with response and progression-free survival in a Korean
used should be able to detect mutations in samples with at least
study, but not in a retrospective analysis of the BR.21 study.131,132
50% tumor content. Based on the findings in the studies discussed
Given the challenges of obtaining adequate tumor tissue for anal-
here, it is not recommended to routinely test for EGFR by IHC,
ysis of EGFR mutations, there has been interest in utilizing serum
copy number by FISH, or KRAS mutations to select patients for
proteomics to develop a predictive algorithm with matrix-assisted
EGFR TKI therapy.
127-130
laser desorption ionization (MALDI) mass spectrometry (MS).133

Patients can be stratified into good and poor prognosis subgroups
Resistance to EGFR TKIs
by MALDI MS, which has been commercially developed as the
The efficacy of EGFR TKIs in EGFR-mutated NSCLC is eventu-
VeriStrat assay (Biodesix, Boulder, CO). The utility of this assay
ally overcome by the development of acquired resistance, with
has been evaluated in retrospective patient cohorts,134,135 and
a median progression-free survival ranging from approximately
more recently, was tested prospectively in the phase III PROSE
10 to 14 months. The Jackman criteria were developed to clearly
study, which randomly assigned patients with metastatic NSCLC
define patients with acquired resistance to help guide future stud-
to treatment with erlotinib or chemotherapy (either pemetrexed
ies for this specific patient population.139 The Jackman criteria
or docetaxel).136 The assay was able to identify patients who ben-
define acquired resistance as the development of disease progres-
efited from erlotinib in the second-line setting. The utility of this
sion during treatment with an EGFR TKI for at least 30 days, with
test in first-line therapy setting has not yet been studied.
no other intervening systemic therapy, in patients treated with
In 2004, two groups independently described sensitizing
a single-agent EGFR TKI with either a known sensitizing EGFR
mutations in EGFR in patients with NSCLC who had an objec-
mutation or documented disease stabilization, or response by
tive response to gefitinib.
The predictive potential of EGFR
RECIST criteria for at least 6 months during treatment with an
mutations was confirmed in the IPASS study, which demonstrated
EGFR TKI if the mutation status is unknown. Multiple mecha-
an improved overall response rate and benefit in terms of pro-
nisms of resistance have been described by studying tumor
gression-free survival among patients treated with gefitinib.114
tissue from patients in whom resistance to EGFR-targeted ther-
In an updated analysis of data in the IPASS study, there was no
apy develops. The most common mechanism is the develop-
overall survival benefit found for patients treated with gefitinib
ment of the T790M mutation in nearly 50% of patients; T790M
compared with carboplatin and paclitaxel (hazard ratio, 0.90; 95%
is a gatekeeper mutant, which hinders the binding of the TKI to
CI, 9.79-1.02; p=0.109), regardless of EGFR mutation status.137
the enzyme active site, similar to the T315I mutation in chronic
These results suggest that the presence of an EGFR mutation is
myelogenous leukemia.140,141 Surprisingly, T790M mutants have a
the strongest predictor of overall response rate and progression-
slower rate of growth compared with the parent mutated EGFR.
free survival for patients treated with EGFR TKIs. The lack of
New TKIs that can overcome the steric hindrance of the T790M
association of EGFR mutation with prediction of overall survival
mutation are being developed, and combination strategies such
benefit is likely due to the crossover design of the IPASS study
as afatinib and cetuximab have shown some promise in the labo-
and subsequent EGFR TKI studies in the first-line setting.
115-118
ratory setting.141,142 This combination can also overcome HER2
Multiple studies have demonstrated the utility of activating EGFR
overexpression, which is another resistance pathway seen in
mutations as the selection criterion for first-line therapy with an
nearly 10% of patients with acquired resistance.143 Amplification
EGFR TKI.115-118
of the MET oncogene has been described in 5-20% of patients
On the basis of the results of these studies, new guidelines
with resistance to an EGFR TKI and can occur in the presence
have been created for testing of NSCLC tissue for EGFR muta-
or absence of the T790M mutation.144,145 Other mechanisms of
tions in pathology laboratories.138 These guidelines confirm that
resistance include phenotypic transformation to small cell lung
molecular testing should be performed to select patients with
cancer (14%), PIK3CA mutations (5%), and epithelial to mesen-
adenocarcinoma of the lung for EGFR TKI therapy. All patients
chymal transformation.146 These varied resistance mechanisms
with adenocarcinoma histology should be tested for EGFR muta-
highlight the importance of obtaining biopsies at the time of dis-
107,108
17
18
ease progression during treatment with an EGFR TKI in order to
patients with ALK rearrangements, with an overall response rate
guide subsequent therapies.
of 57% in the initial phase I study.156 In a recent update of the
Although the T790M mutation is a common mechanism of
expanded phase I study, the overall response rate was reported to
acquired resistance to treatment with an EGFR TKI, it has also
be 60.8% and the median progression-free survival, 9.7 months157;
been described as a de novo mutation in the absence of exposure
on the basis of these results, the FDA approved crizotinib for the
to an EGFR TKI. Inukai et al. first described nine patients with de
treatment of ALK-rearranged NSCLC. Among patients treated
novo T790M mutation in a cohort of 280 patients when testing
with crizotinib in the second-line setting, the overall response
with a mutant-enriched PCR assay; none of the patients had a
rate is 65% and the progression-free survival is higher than that
response to gefitinib, including four patients with concurrent acti-
associated with pemetrexed or docetaxel (7.7 vs 3 months; hazard
vating EGFR mutations.147 The IPASS study also had few patients
ratio, 0.49; 95% CI, 0.37-0.64; p<0.001).158 Crizotinib is generally
with de novo T790M mutations (11 patients), seven of whom had
well tolerated with gastrointestinal toxicities, vision changes (that
either L858R mutation or exon 19 deletion as well; however, treat-
usually subside with continued therapy), and peripheral edema
ment responses for these patients were not reported.114 In the
as the most frequently occurring adverse events.
iTARGET study, one patient had a de novo T790M mutation and
disease was resistant to treatment with gefitinib.
Unfortunately, similar to EGFR inhibition with EGFR TKIs,
In a study of
the benefits of crizotinib are frequently overcome by the develop-
detection of EGFR mutations by sequencing of circulating tumor
ment of resistance. A secondary mutation in the EML4-ALK gene,
cells or plasma-free DNA, low levels of T790M were detected in
at C1196M, which is a gatekeeper mutation similar to T790M with
pretreatment samples in more than one-third of patients (10
EGFR mutation, was noted in an initial report.159 Amplification
of 26 patients); the low levels were associated with a shorter
of the ALK gene also contributes to acquired resistance to crizo-
progression-free survival (7.7 months) compared with patients
tinib.160 Evaluation of patients in whom resistance to crizotinib
149
with an EGFR mutation treated with EGFR TKIs (16.5 months).
developed has also shown other novel mutations in the ALK
Recently, a small series of patients with de novo T790M mutation
kinase, autophosphorylation of EGFR, KRAS mutation, and ampli-
was reported.
fication of KIT as other mechanisms of resistance.161,162
150
148
The clinical features of these patients were similar
to those of patients with activating EGFR mutations; however,
the de novo T790M mutation was associated with a low rate of
of these resistance mechanisms. LDK378 is a potent ALK inhibi-
response to erlotinib and shorter median progression-free and
tor that has shown impressive activity in a phase I study of 131
overall survival (1.5 months and 16 months, respectively) com-
patients with ALK-rearranged NSCLC: the overall response rate
pared with patients with activating EGFR mutations (median
was 70%, with a median duration of response of 7.4 months and a
overall survival, 3 years). In this cohort, all patients had concur-
median progression-free survival of 8.6 months.163 Clinical activ-
rent activating EGFR mutations (80% with L858R and 20% with
ity was seen in patients in whom crizotinib had previously failed.
exon 19 deletions). The findings of these studies suggest that de
LDK378 was mainly associated with gastrointestinal toxicities
novo T790M mutations may exist subclinically in some patients
and fatigue. Another novel ALK inhibitor, CH5424802, was tested
and are selected as a dominant clone with EGFR-TKI therapy,
in a phase I/II study in Japan for patients with ALK-rearranged
leading to poor response rates and survival outcomes with TKI
NSCLC; the maximum tolerated dose was defined as 300 mg twice
therapy. The presence of germline T790M mutations has been
daily, although no dose-limiting toxicities were found.164 The over-
linked with familial lung adenocarcinoma cancer risk.
Newer ALK inhibitors are in development to overcome some
In an
all response rate was 93.5%, with two complete responses, and
evaluation of 10 patients with de novo T790M mutations, 50% car-
the median progression-free survival had not been reached at the
ried germline T790M alterations. There is an ongoing prospective
time of the report. The most frequent grade 3 adverse events were
trial (INHERIT-EGFR) to better characterize the lung cancer risk
neutropenia and an elevated creatinine phosphokinase. Lastly,
in carriers of germline T790M mutations.153
heat shock protein 90 (Hsp90) inhibition with IPI-504165 and
151,152
STA-9090166 has shown promise in patients with ALK-rearranged
Treatment of ALK-rearranged
NSCLC
NSCLC and may provide alternative approaches to overcoming
The echinoderm microtubule-associated protein-like 4 (EML4)-
ALK translocation in NSCLC was first described in 2007. This
ALK rearrangement, including FISH and IHC. A break-apart FISH
genetic abnormality induces the transformation of lung cancer
assay was used to select patients for the initial phase I and II stud-
cells by constitutive activation of the ALK gene.
crizotinib resistance.
Various diagnostic assays are available for the detection of
The EML4-ALK
ies of crizotinib; the commercially available Vysis ALK Break Apart
translocation is present in 1-5% of NSCLC cases and tends to occur
FISH Probe Kit (Abbott Molecular, Abbott Park, IL) was approved
more frequently in younger patients with NSCLC who are never-
by the US FDA as a companion diagnostic test to select patients
smokers, with a median age at diagnosis of 52 years.155 Crizotinib,
with tumors with ALK rearrangement to be treated with crizo-
a dual inhibitor of ALK and MET, was found to have activity in
tinib.167 A positive result on the FISH assay is the presence of at
154
least 15% split red and green signals or isolated red signals.168 IHC
Genome Atlas (TCGA).178 The TCGA data have shown that squa-
is a cheaper testing methodology and is more readily available in
mous cell lung cancers, similar to other smoking-related cancers,
most pathology laboratories compared with the more technically
have a high rate of somatic mutations. Multiple pathways are
challenging FISH test. The sensitivity and specificity of ALK detec-
altered in these tumors (Table 7), but as many as 70% of squa-
tion with IHC has ranged from 90% to 100% and 95.8% to 99%,
mous cell lung tumors have alterations in receptor tyrosine kinase
respectively, when correlated with the results of ALK FISH in mul-
pathways, which may be developed as targets for therapy.
tiple studies.
169-171
Recent guidelines from the College of American
Pathologists and IASLC recommend the use of ALK FISH for the
diagnosis of ALK-rearranged NSCLC to select patients for treat-
Table 7. Prevalence of Common Molecular Targets in Adenocarcinoma and Squamous Cell Non-Small Cell Lung Cancer
ment with crizotinib; IHC may be used as an initial screening
Molecular Target
assay.138
Adenocarcinomas (LCMC)
Frequency (%)
KRAS
25
EGFR: sensitive to EGFR TKI

(deletion 19, L858R, L861Q, G719X)
17
ALK rearrangement
EGFR: not sensitive to EGFR TKI

(exon 20 insertions, T790M)
HER2 (exon 20 insertions)
BRAF
PIK3CA
were in KRAS, EGFR, EML4-ALK, and BRAF (Table 7). Based on
NRAS
the testing, 28% of patients received a targeted therapy directed
MEK1
<1
to the driver mutation, including several in ongoing clinical trials.
MET amplification
<1
The median survival was longer for patients treated with targeted
AKT1
therapy (3.5 years) than for patients who did not receive targeted
Squamous cell (TCGA)
MOLECULAR CHARACTERIZATION
OF NSCLC
A number of genetic alterations beyond EGFR mutations and ALK
rearrangements have been discovered in lung adenocarcinoma
through the efforts of the Lung Cancer Mutation Consortium.172,173
More than 1,000 adenocarcinomas have been characterized for
the presence of 10 driver mutations. More than 60% of tumors
had at least one mutation; the most frequently found mutations
therapy or who had tumors with wild-type genes and thus, no
TP53
81
MLL2
20
PIK3CA
16
CDKN2A
15
carcinoma are ongoing. In fact, BRAF, which is a serine threo-
NFE2L2
15
nine kinase in the RAS-RAF-MEK pathway, is mutated in 2-5%
KEAP1
12
of NSCLC cases. Similar to melanoma and colon cancer, NSCLC
NOTCH1
can harbor activating mutations in BRAF, such as V600E, which
PTEN
accounts for at least half of BRAF mutations in NSCLC, and non-
RB1
HLA-A
targeted therapy options (2.4 years and 2.1 years, respectively,

p<0.0001).

Based on the efforts of the Consortium, multiple early phase
studies of novel targeted therapies for patients with lung adeno-
V600E mutations, which can be activating or inactivating.174-176

Patients with BRAF mutations tend to have a smoking history,
in contrast to patients with EGFR mutations and ALK rearrange-
LCMC=Lung Cancer Mutation Consortium. TCGA=The Cancer

Genome Atlas.
ments. Ongoing clinical trials are examining the activity of dabrafenib in V600E-mutated NSCLC or by inhibition of downstream
IMMUNOTHERAPY
pathways of RAF with the MEK inhibitor, trametinib, in patients

with NSCLC without the V600E mutation. ROS1 fusions have been
Recent developments in the use of agents that modify immune
described in 1-2% of adenocarcinomas, which have been suc-
checkpoints are finally being realized through immune modula-
cessfully targeted with crizotinib based on phase I data.177 These
tion in patients with NSCLC. Ipilimumab, a monoclonal antibody
studies emphasize the importance of routine genetic testing of
that blocks the binding of a T-cell inhibitory receptor CTLA-4 to
lung adenocarcinomas to select patients who may benefit from
its ligands and results in activation of T cells, can infiltrate and
new therapies.
attack tumors. Ipilimumab was combined with carboplatin and
In contrast, squamous cell lung cancers have lagged behind
paclitaxel in a randomized phase II study of 204 patients with
adenocarcinomas with targeted treatments, although a major
treatment-nave metastatic NSCLC.179 Patients were randomly
breakthrough came as a result of the efforts of The Cancer
assigned to chemotherapy with placebo, concurrent Ipilimumab
19
20
with four doses of chemotherapy followed by two doses of che-
CONCLUSION
motherapy with placebo, or phased Ipilimumab, where the first

two cycles of chemotherapy were given with placebo followed by
The treatment of NSCLC has evolved dramatically from the early
four cycles of chemotherapy with Ipilimumab. The primary end-
use of alkylating agents to the use of cisplatin doublet therapy,
point of immune-related progression-free survival was achieved
to the development of newer, more tolerable, drugs that can be
in the phased Ipilimumab group (hazard ratio, 0.72; p=0.05) but
used beyond the first-line setting and in maintenance strategies,
not in the concurrent Ipilimumab group (HR, 0.81; p=0.81). In a
and, more recently, to targeted therapies against pathways acti-
subgroup analysis of patients treated with phased Ipilimumab,
vated in NSCLC, such as VEGF, EGFR, and ALK. Novel immuno-
the immune-related progression-free survival benefit was greater
therapies now show promise for patients with advanced NSCLC.
for patients with squamous cell histology (hazard ratio, 0.55) than
Future studies will better characterize patients likely to benefit
for patients with nonsquamous cell histology (hazard ratio, 0.82).
from these targeted strategies by the identification of predictive
The overall response rate in the phased group was 32% compared
biomarkers. Assessment of tumor tissue prior to treatment and at
with 21% in the concurrent group and 14% in the placebo group;
the time of disease progression will become more integral to the
the median overall survival was 12.2, 9.7, and 8.3 months, respec-
development of targeted therapies for specific genetic aberrations
tively. The rates of grade 3 or 4 immune-related adverse events
that drive metastasis and treatment resistance. The genomics
such as rash, diarrhea, and elevated liver function tests were
revolution will ultimately lead to the realization of personalized
between 6% and 20%, with the highest incidence found in the
therapy for NSCLC and improved outcomes for patients.
concurrent group. Based on these results, a phase III study has

been initiated to confirm the findings.

Another immune checkpoint that has been targeted with
initial success in NSCLC is the programmed death-1 (PD-1) recep-
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International Association for the Study of Lung Cancer

Conquering Thoracic Cancers Worldwide

Conquering Thoracic Cancers Worldwide

Full Textbook Available

first-line systemic therapy options

Lung cancer is at an advanced stage at the time of diagnosis in the

Systemic therapy remains the principal therapeutic modality for

and molecular status play a key role in treatment selection (Figure

Figure 1. Treatment algorithm for treatment-nave non-small cell lung cancer

lung cancer biology, the availability of novel therapeutic agents,

survival and improved quality of life.

Performance Status and Comorbidities

PROGNOSTIC FACTORS IN NSCLC

Performance status and comorbidities are among the most

Proper assessment of prognosis is important when selecting

later in this chapter. The systematic determination of comorbidi-

appropriate treatment for each patient. The variables associated

ties is an essential component of selecting appropriate chemo-

with prognosis can be grouped into categories: patient-related,

therapy regimens and providing the best supportive care.

such as performance status, comorbidity, and gender; tumor-

related, such as primary site, histology, and extent of disease; and

may also have symptoms related to the primary tumor, medi-

environmental factors, such as nutrition and the choice and qual-

astinal spread, or paraneoplastic syndromes. Moreover, lung

cancer commonly produces systemic effects such as anorexia,

In addition to noncancer-related comorbidities, patients

weight loss, weakness, and profound fatigue. In a study of 12,428

International Association for the Study of Lung Cancer (IASLC),

patients with advanced NSCLC. Hence, accurate diagnosis of

performance status, age, and gender appeared to be indepen-

tumor histology has become essential in treatment decision-

dent prognostic factors for survival in addition to clinical stage.

making and can affect considerations of both toxicity and poten-

In advanced NSCLC, some routine laboratory tests (primarily

tial efficacy of selected agents used in the management of this

white blood cell count and hypercalcemia) were also found to

disease. For example, the use of the anti-vascular endothelial

be significant prognostic variables.

growth factor (VEGF) antibody bevacizumab is associated with

predominantly squamous cell histology. In addition, the cyto-

Currently, the majority of lung cancer cases are diagnosed in

toxic drug pemetrexed was found to be inactive in patients with

people older than 65 years of age.3 Age at diagnosis is another

squamous NSCLC. Therefore, the classification of NSCLC into the

important factor that should be considered in treatment deci-

major categories of squamous cell carcinoma, adenocarcinoma,

sion-making. Often, increasing age is accompanied by multiple

and large cell carcinoma is crucial when making treatment deci-

comorbidities that can further limit therapy options and affect

sions. However, histologic subclassification of NSCLC remains

a challenge for many reasons, as the tumor is heterogeneous

radiographic appearance, clinical presentation, and response to

Lung cancer continues to be a leading cause of mortality for all

systemic therapy. Initial diagnostic biopsies often yield an inad-

races, although recent research has focused on ethnic variations

equate amount of tissue for conducting necessary tests to identify

in this disease, such as the prevalence of the epidermal growth

histology and genotype. The availability of immunostains such as

factor receptor (EGFR) mutation. One of the most striking dispari-

thyroid transcription factor-1, p63, and p40 has greatly improved

the accuracy of histologic subclassification.