First-line Systemic Therapy for Metastatic Non-small-cell Lung Cancer e A Review

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REVIEW ARTICLE

First-line Systemic Therapy for Metastatic Non-small-cell Lung Cancer

e A Review

Yuh-Min Chen

1

,

2 *

, Jacqueline Whang-Peng

2

,

3 , Chien-Ming Chen

2

,

3

1_{Chest Department, Taipei Veterans General Hospital, School of Medicine, National Yang-Ming University, Taipei, Taiwan} 2_{Center of Excellence in Cancer Research, School of Medicine, Taipei Medical University, Taipei, Taiwan}

3_{Division of Cancer Center, Shaun-Ho Hospital, Taipei Medical University, Taipei, Taiwan}

a r t i c l e i n f o

Article history: Received: Jan 18, 2011 Revised: Mar 28, 2011 Accepted: Apr 4, 2011 KEY WORDS: chemotherapy;

non-small-cell lung cancer (NSCLC); targeted therapy

Our aim was to review and update the current status of systemic therapy for metastatic non-small-cell lung cancer (NSCLC). We reviewed Phase II or Phase III clinical trials offirst-line third-generation chemotherapy regimens (docetaxel, gemcitabine, paclitaxel, pemetrexed, and vinorelbine) and targeted agents (bevacizumab, cetuximab, erlotinib, and gefitinib) identified through Medline, international conferences, and websites of related organizations. We found effort should be taken tofind out whether patients have a tumor epidermal growth factor receptor (EGFR)-active mutation. EGFR-tyrosine kinase inhibitor could be given as first-line treatment for patients with active EGFR mutations (Exon 19 deletions and Exon 21 L858R), whereas patients with a good performance status and wild-type or unknown EGFR mutation status should be treated with platinum-based doublets (platinum plus a third-generation chemotherapy agent). No specific third-third-generation agent is clearly superior for use in combination with a platinum agent. However, pemetrexed is more active in nonsquamous NSCLC. The survival advantage of platinum-based doublets over non-platinum combinations or older combinations is modest. Systemic chemotherapy beyond four to six cycles impedes quality of life without prolonging life. However, data suggest switching to maintenance with pemetrexed or erlotinib therapy is effective in prolonging patient survival. The addition of bevacizumab to carboplatin and paclitaxel has shown improved survival, and a large-scale Phase IV study showed the efficacy and safety of the combination of bevacizumab with platinum-based doublets. In conclusion, in tumor mutated NSCLC, EGFR-tyrosine kinase inhibitor is thefirst-line treatment of choice for patients with metastatic disease. The combination of a platinum agent plus a third-generation agent continues to be the standard of care for those patients with tumor EGFR wild-type or unknown status. Pemetrexed is more active in patients with non-squamous NSCLC, and bevacizumab in combination with platinum-based doublets can also be considered in patients with non-squamous NSCLC. As differences between the regimens are small, a detailed discussion with the patient regarding treatment toxicity and patient preference will help in making the regimen choice.

1. Introduction

Lung cancer is the leading cause of cancer death in the world and

non-small-cell lung cancer (NSCLC) accounts for the majority of

lung cancer cases.

1,2

Adenocarcinoma and squamous cell carcinoma

(SCC) are two major histologic subtypes of NSCLC. The incidence of

adenocarcinoma has increased in recent decades, whereas the

incidence of SCC has reached a plateau or has decreased, mainly

because of changes in smoking behavior with the use of

ﬁltered

cigarettes with low tar, low nicotine, and increased nitrate levels.

3,4

Most NSCLC patients face the option of systemic chemotherapy or

targeted therapy. Because more than 40% of NSCLC patients present

with metastatic disease, they are suggested to receive systemic

therapy, and the majority of patients with Stage I

eIII tumors

treated with curative intent eventually develop recurrence.

5

Third-generation anti-cancer drugs and their combination with

platinum have shown better response rates and survival than the

conventional regimens during the last decade.

6e8

Pemetrexed,

a recently available third-generation chemotherapeutic agent, was

found to be more effective in non-squamous NSCLC.

9,10

Further-more, bevacizumab, a monoclonal antibody of vascular endothelial

growth factor, was found to enhance chemotherapy ef

ﬁcacy against

non-squamous NSCLC.

11

Epidermal growth factor receptor-tyrosine kinase inhibitors

(EGFR-TKIs), such as erlotinib and ge

ﬁtinib, are a new class of

anti-cancer agents that have been used for nearly one decade.

6

It

was found that adenocarcinoma had a better response to this class

* Corresponding author. Chest Department, Taipei Veterans General Hospital,

No. 201, Sec. 2, Shih-Pai Rd, Taipei 112, Taiwan. E-mail: Y.-M. Chen <ymchen@vghtpe.gov.tw>

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of targeted agent, whereas other subtypes of NSCLC had a less

satisfactory response because of the differing frequencies of tumor

epidermal growth factor receptor (EGFR) mutations.

12

Recent

clinical trials have also shown the high ef

ﬁcacy of EGFR-TKIs as

ﬁrst-line treatment for EGFR-mutated NSCLC, compared with

platinum-based doublets, in terms of prolongation of

progression-free survival (PFS) and less toxicity.

13e15

Together with the above

ﬁndings, patients with adenocarcinoma have had better treatment

options available and improved survival in recent years.

9,16

In the present review, we brie

ﬂy summarize the important

studies performed in recent years, review guidelines, and analyze

the feasibility of current therapy options for patients with NSCLC.

2. Systemic Chemotherapy

2.1. Platinum-based doublet chemotherapy

An updated review by a committee of the American Society of

Clinical Oncology provides evidence supporting the use of

chemotherapy in Stage IV NSCLC patients with Eastern Cooperative

Oncology Group (ECOG) performance status (PS) 0, 1, and possibly

2.

6

Clinical trials have supported the use of two chemotherapy

agents rather than one, in terms of response rates and survival,

although toxicity is increased.

17

No one speci

ﬁc platinum-based

doublet containing a third-generation anti-cancer agent had

better ef

ﬁcacy than the others, before the data of pemetrexed trials

was available.

10,18e20

Drugs that may be combined with platinum

include the third-generation cytotoxic drugs docetaxel,

gemcita-bine, paclitaxel, pemetrexed, and vinorelbine. Patients

’ quality of

life is usually improved with chemotherapy, with improvements in

disease-speci

ﬁc symptoms at a cost of some degree of worsening in

drug-induced toxicities or symptoms.

21

Assessments of several

regimens of chemotherapy also have shown that chemotherapy

against NSCLC is cost effective.

22

In spite of these treatment

bene-ﬁts, it should be noted that the patients studied in most Phase II and

Phase III chemotherapy clinical trials had a good PS, typically ECOG

PS 0

e1, and only a few PS 2 patients were enrolled. In addition,

many studies restricted eligibility to patients more than 70 years

old.

2.2. Cisplatin, carboplatin, or non-platinum-based chemotherapy

Platinum combinations are preferred over non-platinum

combi-nations because they are superior in response rate and result in

a marginally/insigni

ﬁcantly longer overall survival.

6

_{The choice of}

either cisplatin or carboplatin is acceptable. However, carboplatin is

not reimbursed in Taiwan except for patients with impaired renal

function. Cisplatin is slightly more effective than carboplatin, but

also has more adverse effects. Cisplatin combinations have a higher

response rate than carboplatin and may improve survival when

combined with third-generation agents.

6,23,24

Carboplatin is less

likely to cause nausea, vomiting, neurotoxicity, and nephrotoxicity

than cisplatin, but is more likely to cause myelosuppression,

especially thrombocytopenia. Non-platinum therapy combinations

are reasonable in patients who have contraindications to the use of

platinum therapy, such as pre-existing heart failure, renal insuf

ﬁ-ciency or failure, neuropathy, or hearing impairment. Triplet

chemotherapy showed no survival bene

ﬁt, but had signiﬁcantly

higher toxicities.

17,19

2.3. Treatment cycles

How many cycles of

ﬁrst-line chemotherapy should be given? It is

generally accepted that

ﬁrst-line cytotoxic chemotherapy should be

stopped at disease progression or after four cycles in stage IV NSCLC

patients whose disease is not responding to treatment.

6

Cytotoxic

doublet chemotherapy should be administered for no more than six

cycles, even in those patients who have responded to treatment.

For patients who have stable disease or who respond to

ﬁrst-line

chemotherapy, the present evidence does not support the

contin-uation of doublet chemotherapy beyond six cycles.

6,25,26

2.4. Maintenance therapy

With the advent of effective second-line cytotoxic drugs that

improve survival for NSCLC patients who have progressive disease

after

_{ﬁrst-line chemotherapy, there is a renewed interest in}

whether initiation of a different or non-cross-resistant drug

immediately after completion of

ﬁrst-line chemotherapy, or the

initiation of a different chemotherapy before disease progression,

will improve survival.

27e30

In general, most studies showed

improvement in PFS, but not overall survival, either by continuing

an effective chemotherapy beyond four cycles or by immediately

initiating alternative chemotherapy.

27e30

However, the

improve-ment in PFS is tempered by an increase in adverse effects from

additional cytotoxic chemotherapy. Of the many chemotherapeutic

agents, including gemcitabine, vinorelbine, docetaxel, and

peme-trexed, used in maintenance therapy, only pemetrexed was

approved by the Food and Drug Administration on 2 July 2010 for

maintenance therapy in NSCLC patients with advanced disease.

Pemetrexed maintenance therapy has demonstrated a signi

ﬁcant

survival bene

ﬁt compared with the best supportive care after

ﬁrst-line chemotherapy.

28

Another type of maintenance therapy after

ﬁrst-line

chemo-therapy is the use of EGFR-TKIs.

31

Median PFS was longer with

erlotinib maintenance therapy than with placebo treatment

[2.9 months vs. 2.6 months, hazards ratio (HR) 0.71, 95% con

ﬁdence

interval 0.62

e0.82; p < 0.0001] and overall survival was prolonged

with erlotinib maintenance treatment versus placebo treatment

(median 12 months vs. 11 months, HR 0.81, 95% con

ﬁdence interval

0.7 e0.95, p ¼ 0.0088) in a large Phase III randomized trial.

2.5. Chemotherapy with targeted therapy

Chemotherapy in combination with targeted therapy has been

used for a decade already, although chemotherapy combined

with small molecular tyrosine kinase inhibitors has generally

failed.

32e35

However, a small study showed promise with

preliminary ef

ﬁcacy when chemotherapy was combined with

intercalated EGFR-TKIs.

36

A Phase III randomized study is ongoing

to verify this treatment strategy. Chemotherapy in combination

with EGFR monoclonal antibody has also been studied in Phase II

and Phase III trials, and only the FLEX study showed a signi

ﬁcant

1.2-month survival prolongation when adding cetuximab to

vinorelbine plus cisplatin chemotherapy.

37

Cetuximab is suggested

for use in combination with vinorelbine plus cisplatin as one of the

treatment choices in treatment-naïve advanced NSCLC patients

with clinical characteristics similar to those in the FLEX study in

the USA,

6

but not in Europe at present, because of the lack of a

predictor of who will respond well to this combination of

treat-ment. However, a recently published retrospective analysis of the

correlation of

ﬁrst-cycle skin rash with treatment response in the

FLEX study showed

ﬁrst-cycle skin rash was associated with

a better outcome. First-cycle skin rash might be a surrogate

clin-ical marker that could be used to tailor cetuximab treatment for

advanced NSCLC in those patients who would be most likely to

derive a signi

ﬁcant beneﬁt.

38

_{With regard to anti-angiogenesis}

targeted

therapy,

only

bevacizumab

(monoclonal

antibody

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of vascular endothelial growth factor) was approved for use in

ﬁrst-line NSCLC treatment in combination with pacliaxel plus

carboplatin.

6,11

The recommended dose is 15 mg/kg every 3 weeks

in combination with paclitaxel and carboplatin in non-squamous

NSCLC patients with a PS of 0 or 1, and without brain

metas-tases Bevacizumab may be continued until disease progression.

This recommendation is based on a Phase III randomized trial

(ECOG4599) involving 878 non-squamous NSCLC patients. The

study showed there was a two-month improvement in overall

survival when bevacizumab was added to a paclitaxel plus

car-boplatin regimen (12.3 months vs. 10.3 months; HR

¼ 0.79,

p

¼ 0.003).

11

_{The chemotherapy regimen was con}

_{ﬁned to}

pacli-taxel plus carboplatin only because another Phase III randomized

trial of bevacizumab in combination with gemcitabine and

cisplatin showed an improvement in response rate and modest

PFS improvement, but not overall survival.

39

However, a recently

published Phase IV study of bevacizumab in combination with

platinum-based chemotherapy (SAiL) documented its safety and

ef

ﬁcacy, with a median survival of 12.3 months for NSCLC patients

and 14.6 months for patients with adenocarcinoma.

40

The disease

control rate was 88%, and median survival was high up to

18.9 months for Asian patients with adenocarcinoma. Thus, it

seems there is no need to con

ﬁne bevacizumab treatment to use

with paclitaxel plus carboplatin only. Patients with SCC are not

suggested to receive

bevacizumab-containing

chemotherapy

because of the risk of massive hemoptysis.

41,42

2.6. Histologic subtype and choice of chemotherapeutic agent

It is true that the histologic subtype of NSCLC affects the choice of

ﬁrst-line chemotherapy regimen. Three large Phase III randomized

trials involving pemetrexed (second-line docetaxel vs. pemetrexed;

ﬁrst-line gemcitabine þ cisplatin vs. pemetrexed þ cisplatin;

pemetrexed maintenance therapy vs. best supportive care)

20,28,43

showed pemetrexed had better ef

ﬁcacy, including PFS and overall

survival, in patients with non-squamous cell carcinoma than in

those with SCC (

Table 1

).

10

3. EGFR-TKI

3.1. First-line EGFR-TKI treatment in tumor EGFR-mutated NSCLC

patients

EGFR-TKIs, such as erlotinib and ge

ﬁtinib, are a new class of

anti-cancer agents that have been used for nearly a decade.

6

It was

found that the tumor EGFR mutations that occur mainly in

adenocarcinoma, especially tumor EGFR exon 19 deletions and

exon 21 L858R mutations (activating mutations), predicted a better

response to this class of targeted agents.

12,44

In clinically or

molecularly unselected NSCLC patients, erlotinib or ge

ﬁtinib should

not be used in combination with cytotoxic chemotherapy as

ﬁrst-line therapy,

32e35

and in clinically or molecularly unselected

patients, evidence is insuf

ﬁcient to recommend single-agent

erlo-tinib or ge

ﬁtinib as ﬁrst-line therapy. In contrast, recent Phase III

randomized clinical trials showed the high ef

ﬁcacy of EGFR-TKIs as

ﬁrst-line treatment for EGFR-mutated NSCLC, compared with

platinum-based doublets, in terms of prolongation of PFS, better

quality

of

life,

and

fewer

treatment-induced

toxicities

(

Table 2

).

13e15,45

Thus,

_{ﬁrst-line treatment with erlotinib or}

geﬁti-nib may be recommended for patients with activating EGFR

mutations. If the EGFR mutation status is negative or unknown,

then cytotoxic chemotherapy is preferred.

3.2. Erlotinib or ge

ﬁtinib

Both agents are highly active in those patients whose tumors had

activating mutations, such as exon 19 deletions or exon 21 L858R

mutations.

46,47

Thus, both agents can be used in

ﬁrst-line treatment

of patients whose tumors have EGFR activating mutations.

However, the side effects of EGFR-TKIs, such as skin rashes and

a nausea sensation, are relatively more frequent or severe in

patients who receive erlotinib than in those taking ge

ﬁtinib. The

occurrence of other side effects, such as diarrhea, was similar

between the two agents, or even slightly less frequent, such as

pneumonitis, with erlotinib treatment. It is also recommended that

patients with central nervous system metastases or meningeal

carcinomatosis be treated with erlotinib instead of ge

ﬁtinib,

because of the higher blood-brain-barrier penetration rate and

higher cerebrospinal

ﬂuid concentrations of erlotinib and its active

metabolites than with ge

ﬁtinib.

48e51

3.3. Second-generation TKI

Second-generation TKI or multi-targeted agents, such as afatinib

(BIBW-2992) and vandetanib, are still in clinical trials and not

available for routine clinical use at present.

52,53

In general, these

agents can be used alone or in combination with other targeted

agents if the agent belongs to the EGFR-TKI family; and they are

usually used in combination with chemotherapy when they are

anti-angiogenetic agents.

Table 1 Response rate, progression-free survival, and overall survival by histologic subtype in three pemetrexed studies Histologic subtype Second-line pemetrexed versus

docetaxel (n¼ 571)

First-line pemetrexedþ cisplatin versus gemcitabineþ cisplatin (n¼ 1725)

Maintenance pemetrexed versus placebo (n¼ 663) Pemetrexed Docetaxel Pemetrexed Gemcitabine Pemetrexed Placebo

Squamous cell carcinoma (n) 78 94 244 229 116 66

Response rate (%) 2.8 8.1 23.4 31.4 3.1 1.8

Median PFS (mo) 2.3 2.7 4.4 5.5 2.4 2.5

HR (95% CI) 1.40 (1.01e1.96) 1.36 (1.12e1.65) 1.03 (0.71e1.49)

Median survival (mo) 6.2 7.4 9.4 10.8 9.9 10.8

HR (95% CI) 1.56 (1.08e2.26) 1.23 (1.00e1.51) 1.07 (0.77e1.50)

Non-squamous NSCLC 205 194 618 634 325 156

Response rate (%) 11.5 9.0 28.6 22.2 3.4 0

Median PFS (mo) 3.1 3.0 5.3 5.0 4.4 1.8

HR (95% CI) 0.82 (0.66e1.02) 0.95 (0.84e1.06) 0.47 (0.37e0.60)

Median survival (mo) 9.3 8.0 11.0 10.1 15.5 10.3

HR (95% CI) 0.78 (0.61e1.00) 0.84 (0.74e0.96) 0.70 (0.56e0.88) CI¼ conﬁdence interval; HR ¼ hazards ratio; NSCLC ¼ non-small-cell lung cancer; PFS ¼ progression-free survival.

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4. Conclusions

In NSCLC patients with a tumor-active EGFR mutation and

meta-static disease, EGFR-TKI is the

_{ﬁrst-line treatment of choice. The}

combination of a platinum agent with a third-generation agent

continues to be the standard of care for those patients with tumor

EGFR of a wild-type or unknown status. Pemetrexed is more active

in patients with non-squamous NSCLC, and bevacizumab in

combination with platinum-based doublets can also be considered

in non-squamous NSCLC.

References

1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics 2009. CA Cancer J Clin 2009;59:225e49.

2. Chen YM, Chao JY, Tsai CM, Shiau CY, Liang MJ, Yen SH, Perng RP. Treatment of non-small-cell lung cancer: the Chinese experience in a general teaching hospital. J Chin Med Assoc 2000;63:459e66.

3. Alberg AJ, Ford JG, Samet JM. Epidemiology of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:29Se55S. 4. Alberg AJ, Brock MV, Samet JM. Epidemiology of lung cancer: looking to the

future. J Clin Oncol 2005;23:3175e85.

5. Carney DN, Hansen HH. Non-small-cell lung cancere stalemate or progress? N Engl J Med 2000;343:1261e2.

6. Azzoli CG, Baker Jr S, Temin S, Pao W, Aliff T, Brahmer J, Johnson DH. American society of clinical oncology clinical practice guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009;27:6251e66. 7. Fathi AT, Brahmer JR. Chemotherapy for advanced stage non-small cell lung

cancer. Semin Thorac Cardiovasc Surg 2008;20:210e6.

8. Berhoune M, Banu E, Scotte F, Prognon P, Oudard S, Bonan B. Therapeutic strategy for treatment of metastatic non-small cell lung cancer. Ann Phar-macother 2008;42:1640e52.

9. Scagliotti GV, Ceppi P, Novello S, Papotti M. Chemotherapy treatment decisions in advanced non-small cell lung cancer based on histology. Edu Book Am Soc Clin Oncol 2009;27:431e5.

10. Scagliotti G, Brodowicz T, Shepherd FA, Zielinski C, Vansteenkiste J, Manegold C, Simms L, et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011;6:64e70.

11. Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, et al. Paclitaxelecarboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542e50.

12. Mitsudomi T, Kosaka T, Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol 2006;11:190e8.

13. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, et al. Geﬁtinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. New Eng J Med 2009;361:947e57.

14. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, et al. Geﬁtinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380e8.

15. Zhou C, Wu YL, Chen G, Feng J, Liu X, Wang C, Zhang S. Efﬁcacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing ﬁrst-line erlotinib versus carboplatin (CBDCA) plus gemcitabine (GEM), in Chinese advanced non-small-cell lung cancer (NSCLC) patients (PTS) with EGFR acti-vating mutations. Ann Oncol 2010;21(Suppl. 8):LBA13 [Abstract].

16. Takano T, Fukui T, Ohe Y, Tsuta K, Yamamoto S, Nokihara H, Yamamoto N, et al. EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J Clin Oncol 2008;26:5589e95. 17. Delbaldo C, Michiels S, Syz N, Soria JC, Le Chevalier T, Pignon JP. Benefits of

adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small cell lung cancer: a meta-analysis. JAMA 2004;292: 470e84.

18. Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92e8.

19. Gofﬁn J, Lacchetti C, Ellis PM, Ung YC, Evans WK. First-line systemic chemo-therapy in the treatment of advanced non-small cell lung cancer: a systematic review. J Thorac Oncol 2010;5:260e74.

20. Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008;26:3543e51.

21. Fallowﬁeld LJ, Harper P. Health-related quality of life in patients undergoing drug therapy for advanced non-small-cell lung cancer. Lung Cancer 2005;48:365e77.

22. Dranitsaris G, Cottrell W, Evans WK. Cost-effectiveness of chemotherapy for non-small-cell lung cancer. Curr Opin Oncol 2002;14:375e83.

23. Scagliotti GV, De Marinis F, Rinaldi M, Crino L, Gridelli C, Ricci S, Matano E, et al. Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002;20:4285e91. 24. Zatloukal P, Petruzelka L, Zemanova M, Kolek V, Skrickova J, Pesek M, Fojtu H.

Gemcitabine plus cisplatin vs. gemcitabine plus carboplatin in stage IIIb and IV non-small cell lung cancer: a phase III randomized trial. Lung Cancer 2003;41:321e31.

25. Park JO, Kim SW, Ahn JS, Suh C, Lee JS, Jang JS, Cho EK, et al. Phase III trial of two versus four additional cycles in patients who are non progressive after two cycles of platinum based chemotherapy in non-small-cell lung cancer. J Clin Oncol 2007;25:5233e9.

26. von Plessen C, Bergman B, Andresen O, Bremnes RM, Sundstrom S, Gilleryd M, Stephens R, et al. Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life beneﬁts in advanced non-small-cell lung cancer. Br J Cancer 2006;95:966e73.

27. Fidias PM, Dakhil SR, Lyss AP, Loesch DM, Waterhouse DM, Bromund JL, Chen R, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2009;27:591e8.

28. Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet 2009;374:1432e40.

29. Brodowicz T, Krzakowski M, Zwitter M, Tzekova V, Ramlau R, Ghilezan N, Ciuleanu T, et al, Central European Cooperative Oncology Group CECOG. Cisplatin and gemcitabineﬁrst-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer 2006;52:155e63.

30. Westeel V, Quoix E, Moro-Sibilot D, Mercier M, Breton JL, Debieuvre D, Richard P, et al, French Thoracic Oncology Collaborative Group (GCOT). Randomized study of maintenance vinorelbine in responders with advanced non-small-cell lung cancer. J Natl Cancer Inst 2005;97:499e506.

31. Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczésna A, Juhász E, Esteban E, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010;11:521e9.

32. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, et al. Geﬁtinib (ZD1839) in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial (INTACT 1). J Clin Oncol 2004;22:777e84.

33. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, et al. Geﬁtinib (ZD1839) in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial (INTACT 2). J Clin Oncol 2004;22:785e94.

34. Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (osi-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005;23:5892e9.

35. Gatzemeier U, Pluzanska A, Szczesna A, Kaukel E, Roubec J, De Rosa F, Milanowski J, et al. Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small cell lung cancer: the Tarceva lung cancer investigation trial. J Clin Oncol 2007;25:1545e52.

Table 2 Four phase III randomized trials comparing ﬁrst-line epidermal growth factor receptor-tyrosine kinase inhibitors and chemotherapy treatment in clinically or molecularly selected non-small-cell lung cancer patients

I-PASS NEJSG WJTOG3405 OPTIMAL (CTONG 0802)

Gefitinib Paclitaxelþ carboplatin (#_p) Gefitinib Paclitaxelþ carboplatin (#_p) Gefitinib Docetaxelþ cislatin (#_p) Erlotinib Gemcitabineþ carboplatin (#_p)

EGFR active mutation*_(n) ₁₃₂ ₁₂₉ ₁₁₄ ₁₁₀ ₈₈ ₈₉ ₈₂ ₇₂

Response rate (%) 71.2 47.3 (<0.001) 73.7 30.7 (<0.001) 62.1 32.2 (<0.0001) 83 36 (<0.001) Progression-free survival, mo 9.5 4.9 (<0.001) 10.8 5.4 (<0.001) 9.2 6.3 (<0.0001) 13.1 4.6 (<0.001) Overall survival, mo 21.6 21.9 (0.99) 30.5 23.6 (0.31) UA UA UA UA

#_{p value when comparing epidermal growth factor receptor-tyrosine kinase inhibitors group.}

EGFR¼ epidermal growth factor receptor; UA ¼ unavailable.

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36. Mok T, Wu YL, Yu CJ, Zhou C, Chen YM, Zhang L, Ignacio J, et al. Randomized, placebo-controlled, phase II study of sequential erlotinib and chemotherapy as ﬁrst-line treatment for advanced non-small-cell lung cancer. J Clin Oncol 2009;27:5080e7.

37. Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet 2009;373:1525e31.

38. Gatzemeier U, von Pawel J, Vynnychenko I, Zatloukal P, de Marinis F, Eberhardt WEE, Paz-Ares L, et al. First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with ﬁrst-line chemotherapy: a subgroup analysis of data from the FLEX phase 3 study. Lancet Oncol 2011;12:30e7.

39. Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bev-acizumab asﬁrst-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 2009;27:1227e34.

40. Crinò L, Dansin E, Garrido P, Griesinger F, Laskin J, Pavlakis N, Stroiakovski D, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol 2010;11:733e40.

41. Johnson DH, Fehrenbacher L, Novotny WF, Herbst RS, Nemunaitis JJ, Jablons DM, Langer CJ, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2004;22:2184e91.

42. Hainsworth JD, Fang L, Huang JE, Karlin D, Russell K, Faoro L, Azzoli C. BRIDGE: an open-label phase II trial evaluating the safety of bevacizumabþ carboplatin/ paclitaxel as ﬁrst-line treatment for patients with advanced, previously untreated, squamous non-small cell lung cancer. J Thorac Oncol 2011;6:109e14. 43. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, Gatzemeier U, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemo-therapy. J Clin Oncol 2004;22:1589e97.

44. Murray S, Dahabreh IJ, Linardou H, Manoloukos M, Bafaloukos D, Kosmidis P. Somatic mutations of the tyrosine kinase domain of epidermal growth factor receptor and tyrosine kinase inhibitor response to TKIs in non-small cell lung cancer: an analytical database. J Thorac Oncol 2008;3:832e9.

45. Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, Seto T, et al. Geﬁtinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 2010;11:121e8.

46. Gandhi J, Zhang J, Xie Y, Soh J, Shigematsu H, Zhang W, Yamamoto H, et al. Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS ONE 2009;4:e4576. doi:10.1371/journal.pone.0004576.

47. Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 2007;7:169e81.

48. Jackman DM, Holmes AJ, Lindeman N, Wen PY, Kesari S, Borras AM, Bailey C, et al. Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose geﬁtinib. J Clin Oncol 2006;24:4517e20.

49. Katayama T, Shimizu J, Suda K, Onozato R, Fukui T, Ito S, Hatooka S, et al. Efﬁcacy of erlotinib for brain and leptomeningeal metastases in patients with lung adenocarcinoma who showed initial good response to geﬁtinib. J Thorac Oncol 2009;4:1415e9.

50. Togashi Y, Masago K, Fukudo M, Terada T, Ikemi Y, Kim YH, Fujita S, et al. Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis. J Thorac Oncol 2010;5:601e5.

51. Fan WC, Yu CJ, Tsai CM, Huang MS, Lai CL, Hsia TC, Tien YJ, et al. Different efﬁcacies of erlotinib and geﬁtinib in Taiwanese patients with advanced non-small cell lung cancer: a retrospective multi-center study. J Thor Oncol 2011;6:148e55.

52. Dempke WCM, Suto T, Reck M. Targeted therapies for non-small cell lung cancer. Lung Cancer 2010;67:257e74.

53. Somaiah N, Simon GR. Molecular targeted agents and biologic therapies for non-small cell lung cancer. J Thor Oncol 2010;5(Suppl. 6):S434e54.