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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

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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

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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

Cisplatin/vinorelbine

202

28

8.0

Carboplatin/paclitaxel

206

25

8.0

Carboplatin/paclitaxel

201

32

9.9

Cisplatin/vinorelbine

201

30

9.5

Cisplatin/gemcitabine

205

30

9.8

Cisplatin/paclitaxel

305

21

7.8

Cisplatin/gemcitabine

288

22

8.1

Cisplatin/docetaxel

289

17

7.4

Carboplatin/paclitaxel

290

17

8.1

Cisplatin/vinorelbine

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

The IASLC Multidisciplinary Approach to Thoracic Oncology

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
Cisplatin/gemcitabine
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-

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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

The IASLC Multidisciplinary Approach to Thoracic Oncology

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

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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-

The IASLC Multidisciplinary Approach to Thoracic Oncology

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

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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

The IASLC Multidisciplinary Approach to Thoracic Oncology

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

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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

The IASLC Multidisciplinary Approach to Thoracic Oncology

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

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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

The IASLC Multidisciplinary Approach to Thoracic Oncology

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

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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

The IASLC Multidisciplinary Approach to Thoracic Oncology

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

Chapter 44: First-Line Systemic Therapy Options for Non-Small Cell Lung Cancer

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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