Evidence-based Synthesis Program Department of Veterans Affairs

Health Services Research & Development Service

October 2012

Prepared for:

Department of Veterans Affairs

Veterans Health Administration

Quality Enhancement Research Initiative

Health Services Research & Development Service

Washington, DC 20420

Prepared by:

Evidence-based Synthesis Program (ESP) Center

West Los Angeles VA Medical Center

Los Angeles, CA

Paul G. Shekelle, M.D., Ph.D., Director

Investigators:

Principal Investigators: 

Paul G. Shekelle, M.D., Ph.D.

Alicia R. Maher, M.D.

Research Associates:

Isomi M. Miake-Lye, B.A.

Jessica M. Beroes, B.S.

Treatment of Metastatic Non-Small 

Cell Lung Cancer: A Systematic Review 

of Comparative Effectiveness and

Cost-Effectiveness
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

PREFACE

Quality Enhancement Research Initiative’s (QUERI) Evidence-based Synthesis Program 

(ESP) was established to provide timely and accurate syntheses of targeted healthcare topics 

of particular importance to Veterans Affairs (VA) managers and policymakers, as they work to 

improve the health and healthcare of Veterans. The ESP disseminates these reports throughout 

VA.

QUERI provides funding for four ESP Centers and each Center has an active VA affiliation. The 

ESP Centers generate evidence syntheses on important clinical practice topics, and these reports 

help:

• develop clinical policies informed by evidence,

• guide the implementation of effective services to improve patient outcomes 

and to support VA clinical practice guidelines and performance measures, and 

• set the direction for future research to address gaps in clinical knowledge.

In 2009, the ESP Coordinating Center was created to expand the capacity of QUERI Central 

Office and the four ESP sites by developing and maintaining program processes. In addition, 

the Center established a Steering Committee comprised of QUERI field-based investigators, 

VA Patient Care Services, Office of Quality and Performance, and Veterans Integrated Service 

Networks (VISN) Clinical Management Officers. The Steering Committee provides program 

oversight, guides strategic planning, coordinates dissemination activities, and develops 

collaborations with VA leadership to identify new ESP topics of importance to Veterans and the 

VA healthcare system.

Comments on this evidence report are welcome and can be sent to Nicole Floyd, ESP 

Coordinating Center Program Manager, at nicole.floyd@va.gov.

Recommended citation: Maher, AR, Miake-Lye, IM, Beroes, JM, Shekelle, PG. Treatment of 

Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and 

Cost-Effectiveness. VA-ESP Project #05-226; 2012.

This report is based on research conducted by the Evidence-based Synthesis Program 

(ESP) Center located at the West Los Angeles VA Medical Center, Los Angeles, CA 

funded by the Department of Veterans Affairs, Veterans Health Administration, Office 

of Research and Development, Quality Enhancement Research Initiative. The findings 

and conclusions in this document are those of the author(s) who are responsible for 

its contents; the findings and conclusions do not necessarily represent the views of 

the Department of Veterans Affairs or the United States government. Therefore, no 

statement in this article should be construed as an official position of the Department 

of Veterans Affairs. No investigators have any affiliations or financial involvement (e.g., 

employment, consultancies, honoraria, stock ownership or options, expert testimony, 

grants or patents received or pending, or royalties) that conflict with material presented 

in the report
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

TABLE OF CONTENTS

EXECUTIVE SUMMARY

Background.................................................................................................................................................... 1

Methods......................................................................................................................................................... 1

Data Synthesis............................................................................................................................................... 2

Peer Review................................................................................................................................................... 2

Results ........................................................................................................................................................... 2

Abbreviations Table....................................................................................................................................... 4

INTRODUCTION............................................................................................................................................... 5

METHODS

Topic Development........................................................................................................................................ 6

Search Strategy.............................................................................................................................................. 6

Study Selection.............................................................................................................................................. 7

Data Abstraction ............................................................................................................................................ 7

Quality Assessment ....................................................................................................................................... 8

Data Synthesis............................................................................................................................................... 8

Rating the Body of Evidence......................................................................................................................... 9

Peer Review................................................................................................................................................... 9

RESULTS

Literature Flow ............................................................................................................................................ 10

Key Question #1. For patients with metastatic non-small cell lung cancer (NSCLC) what is the 

comparative effectiveness of the different recommended (e.g. NCCN guidelines) first line 

chemotherapy regimens? ............................................................................................................................. 11

Key Sub-question 1.1. Does doublet chemotherapy consisting of a platinum agent plus 

a new agent improve outcomes compared with doublets using older agents? ........................... 13

Key Sub-question 1.2. Does doublet chemotherapy consisting of a platinum agent plus 

a new agent improve outcomes compared with a new single agent alone or to a platinum 

agent alone? ................................................................................................................................ 14

Key Sub-question 1.3. Which doublet chemotherapy regimen consisting of a platinum 

agent plus a new agent is most effective in improving clinical outcomes?................................ 14

Key Sub-question 1.4. Does doublet chemotherapy consisting of a platinum agent plus 

a new agent improve outcomes compared with nonplatinum combination chemotherapy 

including a new agent? ............................................................................................................... 16

Key Sub-question 1.5. Are new doublets containing cisplatin more effective than doublets 

containing carboplatin?............................................................................................................... 18

Key Sub-question 1.6. Does triplet chemotherapy consisting of a platinum agent plus a 

new agent improve clinical outcomes compared with doublet chemotherapy consisting 

of a platinum agent plus a new agent?........................................................................................ 18 

Key Sub-question 1.7. Does the addition of targeted therapy to doublet chemotherapy 

consisting of a platinum agent plus a new agent improve outcomes compared with 

doublet chemotherapy consisting of a platinum agent and a new agent?................................... 19

Key Sub-question 1.8. Is a single new agent superior to best supportive care? ......................... 23
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Key Sub-question 1.9. Is a single new agent superior to single-agent or doublet 

therapy including older agents? .................................................................................................. 23

Key Sub-question 1.10. Which single new agent is most effective?.......................................... 23

Key Sub-question 1.11. What is the optimal administration, duration, and timing of 

chemotherapy for advanced NSCLC? ........................................................................................ 23

Key Sub-question 1.12. Is a doublet regimen better than a single agent for the elderly 

population? ................................................................................................................................. 24

Key Sub-question 1.13. Toxicity of first-line systemic chemotherapy regimens....................... 25

Key Question 2. For patients with metastatic NSCLC what is the comparative effectiveness of the 

different recommended (e.g. NCCN guidelines) second line chemotherapy regimens?............................. 26

Existing Systematic Reviews...................................................................................................... 26

Clinical Trials Published Since 2006.......................................................................................... 32

Toxicity of Second Line or Maintenance Agents........................................................................ 37

Key Question 3. For patients with metastatic NSCLC what is the benefit of maintenance therapy 

following first line chemotherapy regimens compared with no maintenance therapy? .............................. 37

Key Question 4. What is the relative cost and cost-effectiveness of the different approaches in Key 

Questions 1-3? ............................................................................................................................................. 43

Key Sub-question 4.1. Which platinum-doublet is the most cost-effective therapy in 

squamous and in non-squamous histology types? ...................................................................... 46

Key Sub-question 4.2. In non-squamous NSCLC, is the carboplatin-paclitaxelbevacizumab option more cost-effective than platinum-pemetrexed? ....................................... 47

Key Sub-question 4.3 Which of the three approved agents (docetaxel, pemtrexed for 

non-squamous histology, or erlotinib) is more cost-effective?................................................... 47

Key Sub-question 4.4. Which approach is more cost-effective: switch maintenance with 

pemetrexed, continuation maintenance therapy with pemetrexed or erlotinib? ......................... 49

SUMMARY AND DISCUSSION

Summary of Evidence by Key Question ..................................................................................................... 51

Limitations................................................................................................................................................... 53

Summary...................................................................................................................................................... 53

Recommendations for Future Research....................................................................................................... 53

REFERENCES ................................................................................................................................................... 54

TABLES

Table F1. New Doublets vs. Older Doublets.......................................................................................... 13

Table F2. Comparison of Doublets of New Agents in Combination with Platinum Analogues............. 15

Table F3. New Platinum-Based Doublets vs. New Nonplatinum-Based Doublets................................ 17

Table F4. Targeted Agents ...................................................................................................................... 21

Table F5. Targeted Monotherapy............................................................................................................ 22

Table F6. Summary of Grade 3 or 4 Chemotherapy Toxicity (% Patients) from Large, Selected 

Trials in NSCLC..................................................................................................................... 25

Table S1. Second Line Systematic Reviews Published Since 2010 ....................................................... 29

Table S2. Second Line Trials Appearing in a Systematic Review.......................................................... 33

Table S3. Trials Not Included in Existing Systematic Reviews ............................................................. 36

Table S4. Summary of Grade 3 or 4 Chemotherapy Toxicity (% Patients) from Large, Selected 

Trials of Maintenance or Second-line therapy ....................................................................... 37
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Table M1. Maintenance Systematic Reviews Published Since 2010....................................................... 38

Table M2. Trials Not Included in Existing Systematic Reviews ............................................................. 42

Table CE1. Cost-Effectiveness Analyses Published Since 2010 ............................................................... 44

FIGURES

Figure 1. A Summary of GRADE’s Approach to Rating Quality of Evidence........................................ 9

Figure 2. Literature Flow ....................................................................................................................... 11

Appendix A. Search Strategy for Systematic Reviews and Cost-Effectiveness

Analyses (Search #1) .................................................................................................... 71

Appendix B. Search Strategy for Trials (Search #2) ............................................................ 73

Appendix C. Screener Forms Used for Systematic Reviews and CostEffectiveness Analyses ................................................................................................ 75

Appendix D. Peer Reviewer Comments and Responses............................................................. 77
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

EVIDENCE REPORT

INTRODUCTION

Lung cancer is the leading cause of cancer death in both men and women in the United States, 

and male Veterans seeking care at VA hospitals have a much higher age-specific incidence of 

lung cancer than males in the general population.1 The personal and economic significance 

of lung cancer has led to a vast research endeavor to try and identify new and more effective 

treatments. Most patients with lung cancer are diagnosed when the cancer is already advanced 

(stage IIIB or IV), and they are no longer candidates for surgical resection. Small cell lung cancer 

and non-small cell lung cancer (NSCLC) are different diseases in terms of treatment. Until 

recently, all therapies for advanced NSCLC were based on their cytotoxic properties. In the last 

few years, several novel agents aimed at specific molecular targets have been developed. This 

review was requested to evaluate the current evidence on the effectiveness and cost-effectiveness 

of treatments for advanced lung cancer.
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

METHODS

TOPIC DEVELOPMENT

This project was nominated by Michael J Kelley, MD, National Program Director for Oncology/

MSS/PCS and Chief, Hematology/Oncology Durham VAMC, with input from a technical expert 

panel (TEP), including Oncology Field Advisory Committee Membership, Dr. Jennifer Malin 

-- Staff Physician, Oncology, West LA VA, and Dr. Apar Ganti -- Staff Physician, Oncology, 

Omaha VA. 

The final key questions are:

Key Question #1. For patients with metastatic non-small cell lung cancer (NSCLC) what is 

the comparative effectiveness of the different recommended (e.g. NCCN guidelines) first line 

chemotherapy regimens? 

Key Question #2. For patients with metastatic NSCLC what is the comparative effectiveness of 

the different recommended (e.g. NCCN guidelines) second line chemotherapy regimens?

Key Question #3. For patients with metastatic NSCLC what is the benefit of maintenance 

therapy following first line chemotherapy regimens compared with no maintenance therapy? 

Key Question #4. What is the relative cost and cost-effectiveness of the different approaches in 

Key Questions 1-3? 

SEARCH STRATEGY

Preliminary searches done by the ESP coordinating center established that there is a very large 

literature on this topic, including numerous systematic reviews. With this knowledge, we 

employed a two-step search strategy. The first step was to identify recently published systematic 

reviews, and then the second step was to identify relevant clinical trials published subsequent 

to those reviews. We did not search conference abstracts specifically, although those that were 

identified in databases or through peer review were eligible for inclusion.

Search #1 Systematic Reviews and Cost-Effectiveness Analyses

We searched PubMed and Cochrane databases for systematic reviews and cost-effectiveness 

analyses from 1/1/1966 through 3/16/2012, using standard search terms such as lung neoplasms, 

lung cancer, non-small-cell, non-small cell, non small cell, metastatic, metastasic, advanced, 

cost-effective, cost-benefit, cost analysis, and economic. We limited the search to peer-reviewed 

articles involving human subjects and published in the English language (Appendix A).

Search #2 New Clinical Trials

Our second search identified trials by searching Medline (OVID), Embase, and Cochrane 

Register of Controlled Trials from 1/1/2007 through 5/8/2012, using search terms such as 

randomized controlled trial, carcinoma, non-small-cell, gemcitabine, etc. We limited the search 

to English language (Appendix B).
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Additional Strategies

We also obtained a list of key publications from the technical expert panel. Additionally, 

systematic reviews identified in the first search were reference mined for relevant trials.

STUDY SELECTION 

For the systematic reviews and cost-effectiveness analyses, titles obtained from the first search 

were reviewed in descending chronological order, starting with reviews published in 2012 and 

continuing backward. Given that the lag between end date of a search and publication is typically 

one year or more, we stopped this search at 2010, in order to capture the more recent reviews. 

Full-text articles of potentially relevant titles were retrieved, and each article was reviewed using 

the appropriate screener form (either systematic review or cost-effectiveness) in Appendix C. To 

be included, articles either had to present a systematic review or cost-effectiveness analysis, and 

had to present data on metastatic NSCLC, either for a range of stages, or more specifically for 

stage IIIB, IV, or advanced NSCLC. The systematic reviews also had to assess a first line, second 

line, or maintenance therapy. Exclusion criteria included duplicate publications, not presenting 

data on NSCLC, presenting data only for stage I or II NSCLC, or not capturing treatments of 

interest for the systematic reviews. 

After having reviewed the existing systematic reviews, we determined that the best available 

existing review used a search ending in December 2007. We therefore conducted a second 

search, starting in January 2007, for all relevant clinical trials. For trials identified by this second 

search, titles were screened for relevance. Abstracts for included titles were then sorted by type 

of therapy: first line, second line, or maintenance. This corresponded with the first three key 

questions. The articles that did not address at least one of these types of therapy were excluded. 

Full-text articles were then retrieved for these trials.

Some literature prior to 2007 was included in the review because it came from our TEP or peer 

reviewers.

DATA ABSTRACTION

We abstracted the following data for each included systematic review and cost-effectiveness 

analysis: Inclusion and exclusion criteria discussed above, type of therapy assessed, treatment 

captured/assessed, outcomes reported/used, and conclusions per abstract. For systematic reviews, 

we also abstracted the search end date, databases searched, and number of studies included. For 

cost-effectiveness analyses, we also abstracted whether the data were from a single study or 

multiple studies and what perspective the analysis was from (US payer, non-US payer, societal, 

or other).

For trials, the data abstracted depended on the Key Question, or sub-question, the article 

addressed. Potential types of data include: treatment/drug being assessed or compared, overall 

survival, response rate, sample size, study/setting, and conclusions per abstract.
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

QUALITY ASSESSMENT

All studies included as evidence for key questions 1-3 are randomized trials or systematic 

reviews of randomized trials. For practical reasons, these cannot (in general) be blinded, as the 

dosing regimens are different for the various agents being compared (the exception being the 

some of the newer targeted therapies that can be taken orally). Using conventional metrics of 

quality assessment (randomization, blinding, withdrawals and dropouts) will not discriminate 

between studies except on the follow up rate, which has been recorded where applicable in the 

evidence tables. Where reported, the follow up rate is usually above 80 percent. Consequently, 

almost all studies in key questions 1-3 are considered approximately equivalent in terms of their 

risk of bias, and no subgroup analysis are performed that use risk of bias as a stratifying factor. 

DATA SYNTHESIS

For Key Question #1 (first-line therapy), we identified an existing systematic review from the 

Cancer Care Ontario Program in Evidence-Based Care (CCO) by Goffin and colleagues which 

was both comprehensive and good quality, and used this article as the basis for presenting data 

pertinent to first-line therapy.2

 This report was divided into sub-questions, into which we sorted 

the systematic reviews and trials identified by our search strategies #1 and #2, detailed above. 

When the CCO had created evidence tables for a sub-question and our search identified new 

information relevant to that particular sub-question, these tables were reproduced and the new 

trials were added. Data were then narratively summarized for all sub-questions of interest.

For Key Question #2 (second-line therapy), we created three evidence tables. The first evidence 

table presents data for the relevant systematic reviews, including search end date, treatments 

being compared, included articles, outcomes reported, and conclusions per abstract. The second 

evidence table presents an abbreviated citation and whether or not the article was included in any 

of the systematic reviews for all articles identified by the second search and the TEP. The final 

evidence table presents data for trials not included in the existing identified systematic reviews, 

including number of patients randomized, agents being compared and patients in each of these 

treatment groups, median survival, one year survival, and overall response. We then narratively 

summarized evidence within each identified group of similar trials. 

For Key Question #3 (maintenance therapy), we identified a good quality, comprehensive recent 

review by Zhang and colleagues.3

 Analogous to what was done for first-line therapy, we searched 

for new relevant trials in addition to the existing review. The first evidence table presents data 

for the relevant systematic reviews, including search end date, treatments being compared, total 

trials and number of patients included, included articles, outcomes reported, and conclusions per 

abstract. The second evidence table presents data for trials identified by the second search and 

TEP that were not included in the existing systematic reviews. Data presented includes study 

or setting, type of therapy the maintenance is following, treatments being compared, outcomes 

reported, and results and conclusions per abstract.

For Key Question #4 (cost-effectiveness analyses), data are organized by therapy type (firstline therapy, second-line therapy, maintenance therapy, and other therapy). For each article, 

treatments assessed, data origin, analysis perspective, outcomes used, and conclusions per 
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

abstract are presented. After obtaining input from our TEP, we focused on specific costeffectiveness analyses of greatest interest.

RATING THE BODY OF EVIDENCE

We assessed the overall quality of evidence for outcomes using a method developed by the 

GRADE Working Group, which classified the grade of evidence across outcomes according to 

the following criteria:

• High = Further research is very unlikely to change our confidence on the estimate of 

effect.

• Moderate = Further research is likely to have an important impact on our confidence in 

the estimate of effect and may change the estimate.

• Low = Further research is very likely to have an important impact on our confidence in 

the estimate of effect and is likely to change the estimate.

• Very Low = Any estimate of effect is very uncertain.

Figure 1. A summary of GRADE’s approach to rating quality of evidence4

Study design Initial quality of a body of 

evidence Lower if Higher if Quality of a body of evidence

Randomized 

trials

High Risk of Bias

 -1 Serious

 -2 Very serious

Inconsistency

 -1 Serious

 -2 Very serious

Indirectness

 -1 Serious

 -2 Very serious

Imprecision

 -1 Serious

 -2 Very serious

Publication Bias

 -1 Likely

 -2 Very likely

Large Effect

 +1 Large

 +2 Very large

Dose response

 +1 Evidence 

 of a gradient

All plausible residual 

 confounding

 +1 Would reduce a 

 demonstrated effect

 +1 Would suggest a spurious 

 effect if no effect was 

 observed

High (four plus: ⊕⊕⊕⊕)

Moderate (three plus: ⊕⊕⊕)

Low (two plus: ⊕⊕)

Very low (one plus: ⊕)

Observational 

studies

Low

PEER REVIEW

A draft version of this report was reviewed by four technical experts as well as clinical 

leadership. Their comments and our responses are presented in Appendix D.
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

RESULTS

LITERATURE FLOW

From the search for systematic reviews and cost-effectiveness analyses, we received 736 titles. 

We narrowed the scope to systematic reviews published after 2010 during the title screen, 

and identified 88 potential citations for inclusion. Full articles were retrieved and screened for 

55 articles. Of these, 22 were cost-effectiveness analyses relevant to Key Question #4. The 

remaining 33 included articles were systematic reviews of first line, second line, or maintenance 

therapies for advanced, stage III, or stage IV NSCLC. These were then distributed among the 

relevant Key Questions: 22 were relevant to Key Quest #1, 6 were relevant to Key Question #2, 

and 3 were relevant to Key Question #3. One additional systematic review was identified by our 

peer reviewers relevant to Key Question #3.

From the search for trials, we received 820 titles, and after a title screen, there were 158 citations 

identified for potential inclusion. From these citations, 120 articles were identified for full 

article screening. Of the 60 meeting the final inclusion criteria, there were 43 articles relevant 

to Key Question #1, 14 relevant to Key Question #2, and three relevant to Key Question #3. An 

additional seven trials, plus one update on a trial already included in the review, were identified 

by our peer reviewers and distributed as follows: four were relevant to Key Question #1, two 

were relevant to Key Question #2, and one trial plus the update were relevant to Key Question 

#3.

Figure 2 details the review process and the number of references related to each of the key 

questions. 
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Figure 2. Literature Flow

TEP

N=28

Unique 

contributions*:

KQ1: 2

KQ2: 4

Searches

N=1556

KQ#4

N=22

Full Screen

Reviews=55

Trials=120

Excludes

Reviews=33

Trials=38

KQ#1

Systematic Reviews: 22

Additional Trials: 47

KQ#2

Systematic Reviews: 7

Additional Trials: 16

KQ#3

Systematic Reviews: 3

Additional Trials: 4

Excludes

Trials=60

Title Screen

Reviews= 88

Trials=158

Peer Review

KQ1: 4

KQ2: 3

KQ3: 1 update 

for a trial 

already 

included

*Most TEP recommendations were already included in either a systematic review or the newly identified 

trials in from our search. Only the six noted above were not included from another source.

KEY QUESTION #1. For patients with metastatic non-small cell lung 

cancer (NSCLC) what is the comparative effectiveness of the different 

recommended (e.g. NCCN guidelines) first line chemotherapy 

regimens?

We identified 22 systematic reviews or meta-analyses published since 2010 that addressed 

NSCLC first-line therapy. 2, 5-25 Most of these reviews were narrowly targeted at specific 

questions. The most comprehensive of these reviews was published by the Cancer Care Ontario 

Program in Evidence-Based Care (CCO) in 2010 by Goffin and colleagues.2 This review scored 

a “yes” on 9 out of 11 of the AMSTAR criteria,26 searched multiple databases through 2007, and 

included 10 systematic reviews and 46 randomized trials. The CCO first searched for relevant 
12

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

systematic reviews, and then added new trials that were not included in those reviews. In our 

review we follow the same format: we summarize the literature included in the CCO review and 

then discuss additional trials, systematic reviews, and meta-analyses not included in this main 

review. The CCO review had 13 key questions, which we incorporate into this report as key subquestions:

• Does doublet chemotherapy consisting of a platinum agent plus a new agent improve 

outcomes compared with doublets using older agents?

• Does doublet chemotherapy consisting of a platinum agent plus a new agent improve 

outcomes compared with a new single agent alone or to a platinum agent alone?

• Which doublet chemotherapy regimen consisting of a platinum agent plus a new agent is 

most effective in improving clinical outcomes?

• Does doublet chemotherapy consisting of a platinum agent plus a new agent improve 

outcomes compared with nonplatinum combination chemotherapy including a new agent?

• Are new doublets containing cisplatin more effective than doublets containing 

carboplatin?

• Does triplet chemotherapy consisting of a platinum agent plus a new agent improve 

clinical outcomes compared with doublet chemotherapy consisting of a platinum agent 

plus a new agent?

• Does the addition of targeted therapy to doublet chemotherapy consisting of a platinum 

agent plus a new agent improve outcomes compared with doublet chemotherapy 

consisting of a platinum agent and a new agent?

• Is a single new agent superior to best supportive case?

• Is a single new agent superior to single-agent or doublet therapy including older agents?

• Which single new agent is most effective?

• What is the optimal administration, duration, and timing of chemotherapy for advanced 

nsclc?

• Is a doublet regimen better than a single agent for the elderly population? This was 

modified by our tep from the original question in the cco review: which single or doublet 

regimen including a new agent is superior for the elderly population?

• Toxicity of first-line systemic chemotherapy regimens

The overall conclusion of the review by the CCO was that “data continue to support the use 

of a platinum agent plus a new agent as the reference standard.”2

 They also concluded that the 

combination of a platinum agent and a new agent had “a slight advantage over pairs of new 

agents, although at the cost of greater toxicity.” Cisplatin combinations were judged to have a 

“slight” advantage over carboplatin combinations, although carboplatin combinations had a more 

favorable toxicity profile. Finally, the CCO concluded that “as differences between regimens are 

small, toxicities and patient preference should help guide treatment choice.” Data on the new 

targeted therapies were just emerging at the time of the CCO review. A subsequent addendum 

limited to pemetrexed concluded that the data “are sufficiently compelling to recommend that 

pemetrexed should not be used in the treatment of squamous cell carcinomas for first line 

treatment.”
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Key Sub-question 1.1. Does doublet chemotherapy consisting of a platinum agent 

plus a new agent improve outcomes compared with doublets using older agents?

The CCO review included one meta-analysis by Baggstrom and colleagues,27 which itself 

consisted of six RCTs, and five additional RCTs.28-32 The meta-analysis of six trials of doublet 

regimens found results favoring chemotherapy regimens containing platinum and a new agent, 

with a 1-year survival rate risk difference of 6% (95% CI: 2-10%).27 The five additional trials 

comparing old to new doublet therapies, only one found superior survival with a newer agent, 

that being docetaxel plus cisplatin over vindesine plus cisplatin.29

New Literature Since 2007 Relevant to this Sub-question

Our update search identified seven new RCTs relevant to this sub-question.33-39 Details of these 

studies, plus those from the CCO review, are in Table F1. Among these seven new studies, 

none reported significant benefit in outcomes when comparing the newer, to older, doublets. 

One study actually found worse outcomes with the newer agent, pemetrexed, versus the older 

agent, etoposide.36 Overall survival was 8.1 months with pemetrexed, versus 10.6 months with 

etoposide (HR=1.56, 95% CI: 1.27-1.92; log-rank P<.01) and the objective response rate was 

31% vs. 52% (P<.001).

Table F1. New Doublets vs. Older Doublets (adapted from Goffin)

Trial Comparison Survival (95% CI), p Value Overall Response (95% CI),

Reference Nrand/Neval p Value a Agents Nrand/Nevala Median (mo) 1-yr %

Belani et al.28 369 PCb

EtC

190

179

 7.7 (p = 0.086)

 9.0

32

37

23 (NR), p = 0.061

15

Ichinose et al.29 311/302 DC

VdC

NR/151

NR/151

11.4 (NR)

 9.6 (NR)

24 (NR) [2 yr]p=0.01

12 (NR)

37 (NR), p = 0.004

21 (NR)

Kim et al.30b 75/62 GC

EtC

39/33

36/29

18.7 (NR) p = 0.29

15 (NR)

NR

NR

63.6 (NR), p = 0.001

20.7 (NR)

Park et al.31 78/67 DC

EtC

40/34

38/33

NR

NR

NR

NR

NR

NR

Takiguchi32 210 IrC

VdC

104

106

10

11.1

43

48

29 (28/98)

22 (22/101)

Schmittel33 216 IrCb

EtCb

106

110

10.0 (8.4-11.6) 

p=0.06

9.0 (7.6-10.4)

37.1 (26.1-48.1)

p=0.36)

30.3(20.5-40.1) 

54

52

Zatloukal34 407/405 IrC

EtC

202

203

10.2(9.0-11.7) 

p=0.06

9.7(8.9-11.1)

41.9

38.9

39.1

46.6

Yamamoto35 (+TRT) 456/440 IrCb

PCb

MVPVdC

152/147

151/147

153/146

19.8,p=.876

22.0

20.5,p=.392

NR

NR

NR

56.5

63.0

66.4

Hermes39

(+brain radiation)

209 IrCb

EtCb

105

104

8.5

7.1

34

24

NR

NR

Dimitroulis38 108 PC

EtC

53

55

12 (11.0-13.0)

,p=0.354

13(11.7-12.85)

NR

NR

71.7 (38/53) (44.99-76.07), 

p=0.815

70.9 (39/55) (42.19-73.59)

Lee37 241 GCb

EtC

121

120

8.0 (1.84-2.56)

8.1

30.6

31.0

63.3

62.7

Socinski36 908 PemCb

EtCb

453

455

8.1 (1.27-1.92), 

p<.01

10.6

26(20-32)

40(33-48)

31

52

*New entries are shaded.

a Neval only reported when analysis was not intention-to-treat b

 “Preliminary results” noted. Not clear whether referring to preliminary report, or interim analysis. No other indication this is an interim analysis.

C, cisplatin; Cb, carboplatin; CI, confidence interval; D, docetaxel; Et, etoposide; G, gemcitabine; Ir, Irinotecan; Neval, number of patients evaluable; Nrand, 

number of patients randomized; NR, not reported; P, paclitaxel; Vd, vindesine; MVP, mitomycin; Pem, pemetrexed
14

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Summary of Key Sub-question 1.1

New trials continue to support the conclusion by the CCO that any differences in survival 

between platinum-based doublets are modest (GRADE=High).

Key Sub-question 1.2. Does doublet chemotherapy consisting of a platinum agent 

plus a new agent improve outcomes compared with a new single agent alone or 

to a platinum agent alone?

The review by the CCO included a meta-analysis by Hotta, which itself included eight trials of 

2,374 patients.40 In these trials, a doublet of platinum plus a new agent versus a new agent alone 

found an improvement in survival for platinum-based doublets (HR=0.87; 95% CI: 0.80-0.94; 

p<0.001) and a higher response rate (OR=2.32, 95% CI: 1.68-3.20) compared with new single 

agent therapy. 

New Literature Since 2007 Relevant to this Sub-question

We identified one new published trial relevant to this Key Sub-question. Reynolds and colleagues 

randomized 170 patients with performance status of two to either gemcitabine or gemcitabine 

plus carboplatin.41 The median survival was 6.7 (4.9-10.0) months in the gemcitabine plus 

carboplatin group and 5.1 (3.9-6.3) months for gemcitabine. This difference was not statistically 

significant (p=0.14). Overall survival at one year was 31.3 percent in the doublet therapy group 

and 21.2 percent in the gemcitabine alone therapy group (statistical testing not performed). 

There was a statistically significant higher rate of confirmed response in the gemcitabine 

plus carboplatin (21.1%) group compared to gemcitabine alone (6.3%, p=.01). In addition, 

patients’ tumors were evaluated for RRM1 and ERCC1 protein levels and found that these were 

significantly and inversely correlated with disease response. 

During peer review, we were directed to a recently presented abstract of a second relevant 

study42. Patients with advanced NSCLC and a performance status of 2 were randomized to 

receive pemetrexed or carboplatin plus pemetrexed. During the trial, eligibility was later restriced 

to only patients with nonsquamous histology. Overall survival among 205 patients studied was 

9.1 months versus 5.6 months, favoring doublet therapy (p=0.001). We await full publication of 

these results, which provide additional support favoring doublet therapy, even in patients with a 

poor performance status.

Summary of Key Sub-question 1.2

This result continues to support the conclusions by the CCO that doublet chemotherapy including 

a platinum agent has a higher survival rate and a higher response rate than a single agent 

(GRADE=High).

Key Sub-question 1.3. Which doublet chemotherapy regimen consisting of 

a platinum agent plus a new agent is most effective in improving clinical 

outcomes?

The review by the CCO identified two meta-analyses43, 44 and nine studies,32, 45-52 three of which 

were included in one of the two meta-analyses.45, 46, 50 The first meta-analysis, by Le Chevalier et 

al, examined the efficacy of gemcitabine plus platinum combinations versus any other platinum-
15

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

based regimen.43 Out of six trials, there was a trend toward superior survival with gemcitabinebased regimens and improved progression-free survival (HR= 0.89; 95% CI: 0.82-0.96). 

The second meta-analysis, by Douillard et al., compared seven trials of docetaxel-containing 

regimens with vinca-alkaloid regimens.44 Docetaxel led to greater overall survival (HR=0.89; 

95% CI: 0.82-0.96; P=0.004). In the nine additional studies, median survival ranged from 6.4-

14.0 months, without consistent differences between arms. 

New Literature Since 2007 Relevant to this Sub-question

Our search identified nine additional studies53-61 and two subsequent meta-analyses62, 63 relevant 

to this Key Sub-question. These new results did not alter the conclusions reached by the CCO. 

The combinations studied included gemcitabine, paclitaxel, paclitaxel poliglumex (CT-2013 

PPX), S-1, pemetrexed, vinorelbine, and docetaxel. Details of these studies, as well as the studies 

contained in the CCO review, are in Table F2. No particular combination was shown to be 

significantly superior in outcomes. Median survival ranged from 7.0 to 15.2 months. Of note, the 

study comparing paclitaxel plus carboplatin vs. gemcitabine plus oxaliptin had to be terminated 

after adverse events exceeded the safety threshold set by the data safety and monitoring board.60

We also identified one clinical trial comparing doublet chemotherapy regimens, but neither 

included a platinum agent. This study compared paclitaxel and gemcitabine to paclitaxel and 

vinorelbine in 39+ patients with stage IIIB or IV NSCLC. There was no difference in median 

overall survival (11.1 months vs. 8.6 months, p=0.14); the group treated with vinorelbine had 

more grade 3/4 toxicities.25

Table F2. Comparison of Doublets of New Agents in Combination with Platinum Analogues 

(adapted from Goffin)

Trial Comparison Survival (95% CI), p Value Overall Response (95% 

Reference N CI), p Value rand/Nevala Agents Nrand/Nevala Median (mo) 1-yr %

Fossella et al.50 1218/— DC

DCb

VC

104

406

404

11.3 (10.1–12.4) p = 

0.044

 9.4 (8.7–10.6)

 9.9–10.1 (9.0–11.3)b

46 (42–51)c

38 (33–43)

40–41 (35–46)

vs. VC, 31.6 (NR) p = 

0.029

vs. VC, 23.9 (NR) p = 

0.870

24.5 (NR)

Gebbia et al.49 400/NR GC

VC

GI ->VC

VC->GI

138/NR

140/NR

62/NR

60/NR

 8.2 (NR) p = 0.187

 9.0 (NR)

NR

NR

20 (NR) p = 0.4

24 (NR)

NR

NR

33 (26–42) p = 0.032

44 (36–53) p = 0.007d

19 (10–31)d

32 (20–45)d

Helbekkmo et al.52 432 VCb

GCb

218

214

 7.3 (NR) p = 0.89

 6.4 (NR)

28

30

NR

NR

Martoni et al.48 272/— VC

GC

137

135

 11 (9–13) p = 0.759

 11 (9–13)

39.7 (NR)

44.4 (NR)

32.1 (24.5–40.5) p = 0.32

26.7 (19.5–35.1)

Ohe et al.51 602/— IrC

PCb

GC

VC

151

150

151

150

 13.9 (NR) p = ns

 12.3 (NR)

 14.0 (NR)

 11.4 (NR)

59.2 (NR)e

51.0 (NR)

59.6 (NR)

48.3 (NR)

31 (NR)

32.4 (NR) p = 0.80

30.1 (NR) vs. IrC, p = 0.87

33.1 (NR) vs. IrC, p = 0.71

Rubio and Sahagun47 60 DCb

VCb

29

31

 10.2 (NR) p = ns

 10.7 (NR)

NR

NR

46.4 (NR)

45.2 (NR)

Scagliotti et al.46 612/— VC

GC

PCb

203

205

204

 9.5 (8.3–11.0)

 9.8 (8.6–11.2)

 10.0 (9.0–12.5)

37 (NR) p = 0.48f

37 (NR)

43 (NR)vs.VC, 

p = 0.1g

30 (24–36) p = 0.98

30 (24–37)

32 (25–38) vs. VC, p = 0.75
16

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Trial Comparison Survival (95% CI), p Value Overall Response (95% 

Reference N CI), p Value rand/Nevala Agents Nrand/Nevala Median (mo) 1-yr %

Schiller et al.45 1207/1155 PC

GC

DC

PCb

303/288

301/288

304/289

299/290

 7.8 (7.0–8.9) p = ns

 8.1 (7.2–9.4)

 7.4 (6.6–8.8)

 8.1 (7.0–9.5)

31 (26–36)

36 (31–42)

31 (26–36)

34 (29–40)

21 (NR) p = ns

22 (NR)

17 (NR)

17 (NR)

Takiguchi et al.32 210 IrC

VdC

104

106

 10

 11.1

43

48

29 (28/98)

22 (22/101)

Treat, 201059 1135 GCb

GP

PCb

379

377

379

7.9, p=0.693

8.5

8.7

33.9

36.2

35.6

25.3

32.1

29.8

Weissman60 383 PCb

GOx

Study terminated after 

383 patients randomizedadverse events exceeded 

safety threshold

Kelly, 200164 408 VC

PCb

202

206

8.1(6.7-9.6)

8.6(7.2-10.7)

36

38

28

25

Okamoto55 564 PCb

S-1Cb

281

282

13.3 (11.7-15.1)

15.2 (12.4-17.1)

55.5

57.3

29.0, p=.019

20.4

Rodrigues-Pereira56 260 PemCb

DCb

128

132

14.9 (12.2-10-19.0)

14.7 (10.8-19.8)

NR 34.0

22.9

Scaggliotti57 1725 PemC

GC

862

863

10.3 (0.84-1.05)

10.3

43.5

41.9

30.6

28.2

Chang53 83/73 GC

VC

34

39

12.9

9.0

55.9

33.3

38 (13/34)(21-55)

p=0.622

31 (12/31)(16-460)

Tan58 390/ 381 VC

DC

190

191

9.9 (8.41-11.6)

9.8 (8.80-11.5)

39.4

40.9

31.2 (24-39)

29.6 (22.8-37)

Gronberg54 446 PemCb

GCb

225

221

7.3, p=.63

7.0

34

31

NR

NR

Langer61 400 PxCb

PCb

199

201

7.8

7.9

31 (24-37)

31 (25-38)

20(15-27)

37(30-44)

*New entries are shaded.

a Neval only reported when analysis was not intention-to-treat. b Survival estimates were adjusted for prognostic factors, and minor differences in the distribution of those factors produced slightly different values.

c The hazard ratios and 95% CI of overall survival for DC and DCb vs. VC were 97.2 (0.989 –1.416) and 97.2 (0.877–1.253), respectively.

d Data are from an interim analysis of 243 patients. At interim, VC response was statistically superior to GI–_VC, p _ 0.007, all other interim 

comparisons not significant at a 95% confidence level.

e This was a noninferiority trial. The difference in 1-yr survival between arms was as follows: IrC vs. PCb -8.2% (-19.6 -3.3%), PCb vs. GC 0.4% (-10.9 

-11.7%), GC vs. VC -10.9% (-22.3 -0.5%). Conclusions of this trial are faulty. They report they cannot reject the null hypothesis of noninferiority, but 

still say agents are similar. The values reported here are the difference in 1-yr survival between agents and the IrC arm.

f Hazard ratio of survival was 0.87 (0.69 –1.09).

g Hazard ratio of survival for VC vs. PCb was 0.84 (0.67–1.05).

C, cisplatin; D, docetaxel; Cb, carboplatin; CI, confidence interval; G, gemcitabine; I, ifosfamide; Ir, irinotecan; Neval, number of patients evaluable; 

Nrand, number of patients randomized; NR, not reported; ns, not significant; P, paclitaxel; V, vinorelbine; Vd, Vinblastine; Ox, oxaliptin; Px, Paclitaxel 

poliglumex (CT-2103 PPX)

Summary of Key Sub-question 1.3

New trials continue to support the conclusion by the CCO that any differences in outcomes 

between doublet therapies with platinum-based agents are modest (GRADE=High).

Key Sub-question 1.4. Does doublet chemotherapy consisting of a platinum agent 

plus a new agent improve outcomes compared with nonplatinum combination 

chemotherapy including a new agent?

The review by the CCO identified two meta-analyses and four additional relevant RCTs.65-70 The 

first meta-analysis, by Pujol et al., analyzed 11 RCTs comparing platinum-based new doublets 

or a combination of new nonplatinum agents, in 4602 patients.67 There was a 2.9% absolute 

reduction in the risk of death at 1-year with the platinum-based regimens (OR=0.88; 95% CI: 

0.78-0.99, P=0.044). The other meta-analysis, by D’Addario et al, examined 14 trials and found 
17

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

no survival benefit with platinum-based agents over nonplatinum chemotherapy regimens (OR, 

1.11; 95% CI: 0.096-1.28; P=0.17).65 In the four additional studies, median survival ranged 

from 7.6 to 13.8 months.66, 68-70 One of these studies, Tan et al, found improvement in the median 

survival in those patients receiving gemcitabine-vinorelbine (11.5 months) compared to those 

receiving vinorelbine-carboplatin (8.6 months, P=0.01).69

New Literature Since 2007 Relevant to this Sub-question

The additional three trials we identified did not find a significant difference between agents and 

did not alter the conclusions reached by the CCO.59, 71, 72 Details of these three and the four RCTs 

identified by the CCO are presented in Table F3. In one of these trials, platinum-based regimens 

of gemcitabine or paclitaxel with carboplatin led to a median survival of 7.9 (7.1-9.2, P=0.693) 

and 8.7 (7.7-9.9) months, compared to gemcitabine with paclitaxel which led to 8.5 (7.6-10.0) 

months.59 In another trial, the combination of gemcitabine with paclitaxel led to a median 

survival of 9.97 (8.74- 12.0) months compared to 10.49 months with gemcitabine and carboplatin 

(9.04-11.94).72 Though the final study appeared to favor gemcitabine and epirubicin with a 

median survival of 21.5 months versus 13.2 months for gemcitabine-cisplatin, the confidence 

intervals were wide (9.4-33.6 and 10.4-16.0) and the number of patients small (80 and 85).71

Table F3. New Platinum-Based Doublets vs. New Nonplatinum-Based Doublets (adapted from 

Goffin)

Study Comparison Survival (95% CI), p Value Overall Response (95% 

Reference Nrand/Neval CI), p Value a Agents Nrand/Nevala Median (mo) 1-yr %

Kawahara et al.66 401/393 VG->D

PCb

NR

NR

13.1 (NR) p = 0.28

13.8 (NR)

55.6 (NR)

55.6 (NR)

23 (NR) p = 0.008

36 (NR)

Rigas et al.68 928 DCb

GD

466

463

8.1

8.3

35

34

NR

NR

Tan et al.69 316/— VCb

VG

159

157

 8.6 (NR) p = 0.01

11.5 (NR)

34.4 (NR)

48.9 (NR)

20.8 (NR) p = 0.15

28.0 (NR)

Treat70 929/788 GCb

GP

PCb

309/265

312/262

308/261

 7.6 (6.83–8.96)

 8.2 (7.09–9.46)

 7.9 (6.86–8.86)

32.1 (NR)

33.0 (NR)

33.0 (NR)

31.7 (26–38)

38.4 (32–44)

36.8 (31–43)

Treat, 2010 59 1135 GCb

GP

PCb

379/356

377/355

379/366

7.9 (7.1-9.2) p=0.693

8.5 (7.6-10.0)

8.7 (7.7-9.9)

33.9 (29.1-38.7)

36.2 (31.3-41.1)

35.6 (30.7-40.4)

96 (21.0-30.0)

121 (27.4-37.1)

113 (25.3-34.7)

Kosmidis 72 512/ 452 PG

GCb

219

219

9.97 (8.74-12.0)

10.49 (9.04-11.94)

42

42

31(25.12-37.60)

27 (21.63-33.60)

Hsu71 85/ 80 GC

GEp

41

39

13.2 (10.4-16.0)

21.5 (9.4-33.6)

54.8

74.4

31.0 (16.4-45.5)

37.2 (22.2-52.3)

*New entries are shaded.

a Neval only reported when analysis was not intention-to-treat.

Cb, carboplatin; CI, confidence interval; D, docetaxel; G, gemcitabine; Neval, number of patients evaluable; Nrand, number of patients randomized; NR, not 

reported; P, paclitaxel; V, vinorelbine; Ep, epirubicin

Summary of Key Sub-question 1.4

New trials continue to support the conclusion by the CCO that doublet chemotherapy including a 

platinum agent probably has a slight advantage over nonplatinum doublets (GRADE=moderate).
18

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Key Sub-question 1.5. Are new doublets containing cisplatin more effective than 

doublets containing carboplatin?

The review by the CCO identified three relevant meta-analyses.73-75 In the meta-analysis by 

Jiang et al., they found a higher overall response rate with cisplatin-based regimens when added 

to new drugs (RR 0.87;0.78-0.97, P=0.01) and when added to the same drug (RR 0.79; 0.70-

0.89; P=0.0001) without a corresponding improvement in 1-year survival (RR 0.98; 0.90-1.07; 

P=0.66- new agent) (RR, 0.91;0.82-1.01; P=0.07).75 The meta-analysis by Hotta et al. found 

superior survival with platinum-based combinations containing cisplatin over those containing 

carboplatin plus the same agent (HR= 1.106; 95% CI: 1.005-1.218; P=0.039).74 It also found a 

greater objective response rate when using cisplatin over carboplatin (OR= 1.38; 95% CI: 1.14-

1.67; P=0.001). In the meta-analysis by Ardizzoni et al, there was a greater mortality risk in those 

treated with carboplatin compared to those treated with cisplatin in patients with nonsquamous 

histology (HR=1.12; 95% CI: 1.01-1.23).73

Literature Relevant to this Sub-question Not Included in the CCO Review

We found one additional trial.64 It compared vinorelbine plus cisplatin and paclitaxel plus 

carboplatin finding no significant difference between the two regimens in median survival 

8.1 (6.7-9.6) months for the cisplatin containing regimen compared to 8.6 (7.2-10.7) for the 

carboplatin containing regimen. The overall response rates were 28 and 25%, respectively. 

However, the difference in second agents in the doublet precludes reaching a conclusion about 

differences between carboplatin and cisplatin.

Summary of Key Sub-question 1.5

One new trial does not alter the conclusion by the CCO that cisplatin combinations may have a 

slight advantage over carboplatin combinations in terms of survival and response rate. However, 

carboplatin generally has a milder toxicity than cisplatin (GRADE=moderate).

Key Sub-question 1.6. Does triplet chemotherapy consisting of a platinum 

agent plus a new agent improve clinical outcomes compared with doublet 

chemotherapy consisting of a platinum agent plus a new agent? 

The review by the CCO identified updated guidelines published by the ACCP in 2007 which 

contained a meta-analysis of 28 trials and 12 additional RCTs where the addition of a third 

chemotherapeutic agent failed to show superiority over conventional doublets.76 Though they 

found that response rates did improve, this was at the cost of substantially increased toxicity 

with the triplets, leading to a recommendation of the two-drug combination. In addition to the 

trials analyzed for the ACCP guidelines, the CCO found six additional trials investigating triplet 

regimens, none of which found a difference in median or 1-year survival with toxicity generally 

more frequent with the triplet regimens.77-82

New Literature Since 2007 Relevant to this Sub-question

We identified a systematic review not in the review by the CCO that was relevant to this 

question.24 Azim and colleagues identified six trials including 1,932 patients who received either 

third generation triplet therapy or standard doublet therapy. Pooled analyses showed that triplet 

therapy resulted in a statistically significant increase in response rate (pooled OR=1.33, 95% 
19

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

CI: 1.50-2.23), however overall survival was improved by less than six weeks (42.8 vs. 37.4 

weeks) and this was not statistically significant. Patients receiving triplet therapy had statistically 

significantly more grade III/IV toxicities than patients receiving doublet therapy. The authors 

concluded that triplet therapy “is associated with higher tumor response rate at the expense of 

increased toxicity.”24

We found four new trials,83, 84 one of which was included in the review by Azim and colleagues.84

The first trial randomized 433 patients into 4 arms of treatment- gemcitabine-cisplatin, 

gemcitabine-vinorelbine, gemcitabine-ifosfamide-cisplatin or gemcitabine-ifosfamidevinorelbine.83 They found no benefit with the addition of ifosfamide to a gemcitabine based 

doublet. Overall survival was 10.4 (9.4-12.2) months for the doublet and 10.3 (9.2-11.8) months 

for the triplet and the response rate was 29% (23-35) for the doublet and 26% (21-33) for 

the triplet. The second trial had 433 patients randomly assigned to gemcitabine-vinorelbine, 

gemcitabine-paclitaxel, gemcitabine-vinorelbine-cisplatin, gemcitabine-paclitaxel-cisplatin.84

They found an increase in the response rate with triplets over doublets, 48% (42-54) vs. 35% 

(32-38). However, there was no benefit in overall survival with triplets having a median OS of 

10.7 months and doublets having an overall survival of 10.5 months (P=0.379).

We also found one trial that compared a platinum-based triplet (paclitaxel, carboplatin, 

gemcitabine) versus a nonplatinum doublet (gemcitabine + vinorelbine). There were no 

statistically significant differences in overall survival between groups (10.7 vs. 10.3 months), 

and certain toxicities were greater in the triplet therapy group.85 Another “triplet vs. doublet” 

study compared a nonplatinum triplet (vinorelbine, gemcitabine, docetaxel) to carboplatin plus 

paclitaxel and showed no statistically significantly difference in overall survival (13.6 vs. 14.1 

months), with toxicity greater in the platinum doublet treated patients.86

Summary of Key Sub-question 1.6

New trials continue to support the conclusion by the CCO that triplet cytotoxic therapy might 

have some slight advantages in terms of response rate but at an increased risk of toxicity 

(GRADE=high).

Key Sub-question 1.7. Does the addition of targeted therapy to doublet 

chemotherapy consisting of a platinum agent plus a new agent improve 

outcomes compared with doublet chemotherapy consisting of a platinum agent 

and a new agent?

The review by the CCO identified eight trials of adding targeted therapy to conventional 

chemotherapy. They found that aprinocarsen did not improve outcomes in patients with advanced 

disease. Four trials of the tyrosine kinase inhibitors (TKI) failed to show an improvement in 

survival or response. However erlotinib was shown to significantly increase survival when a 

particular subgroup of 116 patients, who had never smoked, received the drug. When combined 

with paclitaxel and carboplatin, this subgroup had a median survival of 22.5 months compared 

with 10.1 months for placebo patients (P=0.01). In another subgroup study of only 18 patients, 

the Tarceva Lung Cancer Investigation trial, erlotinib led to significantly longer progressionfree survival compared to placebo (7.9 months versus 5.4 months, P=0.02). Two of the trials 

looked at addition of bevacizumab. The first added bevacizumab to paclitaxel and carboplatin in 
20

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

a population restricted to those with Eastern Cooperative Oncology Group (ECOG) performance 

scores of 0-1, no brain metastases, nonsquamous cell histology, no hemoptysis and no history of 

bleeding diathesis or coagulopathy. In these 878 patients median survival increased by 2 months 

in the bevacizumab group (12.3 versus 10.3 months, HR= 0.79, 95% CI: 0.67-0.92; P=0.003) 

in addition to an improvement in response rate (35 vs. 15%, P<0.001). The second trial added 

bevacizumab to gemcitabine and cisplatin and found some improvement in response and a very 

modest improvement in progression-free survival, but no difference in overall survival. There 

were two trials adding cetuximab. The first added cetuximab to cisplatin and vinorelbine in 

1125 patients whose tumors were immunohistochemically positive for epidermal growth factor 

receptor (EGFR) expression. There was improved survival with cetuximab (HR=0.871; 95% CI: 

0.762-0.996; median 11.3 vs. 10.1 months). Response rates were also improved with cetuximab 

(36 vs. 29%, P=0.01). The other trial, which added cetuximab to carboplatin and taxane, did not 

show improvement in survival, or progression-free survival. 

New Literature Since 2007 Relevant to this Sub-question

Our update search identified an additional 10 trials relevant to this sub-question.87-96 Details of 

these trials, in addition to the eight contained in the review by the CCO, are presented in Table 

F4. Two of the new trials were of the agent PF-3512676. The first of these two trials, of 839 

patients, did not find an improvement in OS or PFS and, in fact was halted based on efficacy, 

futility, and increased toxicity.92 The other study of this agent had similar findings in 828 patients 

and was therefore also halted.90 There was one study of endostar which enrolled 126 patients and 

found improvement in the overall response rate of 39.3% in the treatment group versus 23.0% 

in the control group (p=0.078).89 However, there was no significant difference in the overall 

survival (17.6 vs. 15.8 months, p=0.696). There were two reports of bevacizumab. One of these 

had 1043 patients and was included in the review by the CCO,95 and the other was the Asian 

subset of that population, consisting of 105 patients.93 In the overall sample, as noted above, 

an improvement in progression-free survival was found. However this did not translate into an 

improvement in overall survival, which was about 13 months in each group. 95 In the study of 

the Asian subset, however, bevacizumab at a dose of 7.5 mg/kg improved the overall survival 

in Asian patients compared to placebo (HR=0.46, 95% CI: 0.22-0.97).93 The other agents failed 

to show positive results. One trial of sorafenib found no clinical benefit and, in fact, was halted 

after an interim analysis found higher mortality in patients with squamous cell histology taking 

sorafenib than those in the placebo group.96 Another study that was halted examined cediranib.88

That trial was halted to review imbalances in assigned causes of death. A trial of cetuximab found 

a slight improvement in overall survival but this was not statistically significant, 9.69 months 

with cetuximab vs. 8.38 months with standard chemotherapy alone, (HR= 0.890, 95% CI: 0.754-

1.051; p=.169).91 There were two trials of bexarotene with chemotherapy.87, 94 The first looked 

at 612 patients and found little difference in overall survival (8.5 vs. 9.2 months) or overall 

response (19.3 vs. 23.5%, p=.24).87 However, when they examined a subpopulation of those with 

hypertriglyceridemia, they found that those with hypertriglyceridemia had significantly longer 

median survival than control patients (12.4 vs. 9.2 months; log-rank, P=.014). The other trial 

was of 623 patients and found the same, no significant difference (OS: 8.7 vs. 9.9 months, P=.3, 

ORR: 16.7 vs. 24.4%, P=.0224) except in those with hypertriglyceridemia (OS 12.3 months).94

As both of these results were post-hoc subgroup analyses, their results should be interpreted with 

caution.
21

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Table F4. Targeted Agents (adapted from Goffin)

Study Comparison Survival (95% CI), p Value Overall Response 

Reference Nrand/Neval (95% CI), p Value a Agents Nrand/Nevala Median (mo) 1-yr %

Gatzemeier et al.97 1172/1159 EGC

GC

580

579

 9.9 (NR) 

10.1 (NR) 

41 (NR)

42 (NR) 

31.5

29.9

Giaccone et al.98 1093/— GCGe500 mg/d

GCGe250 mg/d

GC

365

365

363

9.9 (NR) p = 0.4560b

9.9 (NR) 

10.9 (NR)

43 (NR)

41 (NR)

44 (NR)

50.3 (NR) ps = ns

51.2 (NR)

47.2 (NR)

Herbst et al.99 1079/— PECb

PCb

539

540

10.6 (NR)

10.5 (NR)

46.9 (NR)c

43.8 (NR)

21.5 (NR) p = 0.36

19.3 (NR)

Herbst et al.100 1037/— PG e500 mg/dCb

PG e250 mg/dCb

PCb

347

345

345

8.7 (NR)

9.8 (NR)

9.9 (NR)

37 (NR) p = 0.64a

41 (NR)

42 (NR)

30.0 (NR) ps = ns

30.4 (NR)

28.7 (NR)

Sandler et al.101 878/850 PCb

PCb + B

444/433

434/417

10.3 (NR)d

12.3 (NR)

44 (NR)

51 (NR)

15 (NR) p < 0.001

35 (NR)

Reck et al.102 1043/— GC

GC + B7.5 mg/kg

GC + B15 mg/kg

347

345

351

6.1 NR

6.7 NR

6.5 NR

NR

NR

NR

20 (NR)

34 (NR)

30 (NR)

Paz-Ares et al.103 670/— GC

GC + Ap

328

342

10.4 (8.6-12.2)

10.0 (8.4-10.8)

44.9 (NR)e

41.8 (NR)

35.0 (NR) p = 0.12

28.9 (NR)

Pirker et al.104 1125/— C + V + Ce

C + V

557

568

11.3 (0.762) 

p = 0.044

10.1 (0.996)

47 (NR)

42 (NR)

36 p = 0.010

29 (NR)

Manegold92 839 GC+PF-3512676

GC

416

423

11.0, p=0.98

10.7

47.0

45.7

32.2

31

Gaafar 105 173 Ge

Pl

86

87

10.9,(0.60-1.15)

p=0.2

9.4

NR

NR

NR

NR

Hirsh90 828 PCb+PF-3512676

PCb

408

420

10.0 (0.81-1.12), 

p=.56

9.8

40.4,p=.73

41.6

28,p=.08

23

Han89 126 PCb+ ES

PCb + Pl

63

63

17.6(13.4-21.7)

p=0.696

15.8(9.4-22.9)

61.7,

p=0.462

55.1

39.3, p=0.078

23.0

Mok93

Asian subset of Reck, 

below

1043/105 GC+B7.5mg

GC+B15mg

GC+Pl

38

34

33

improved, but no 

details

NR 48.5

27.6

10.3

Reck, 200995 1043 GC+B7.5mg

GC+B15mg

GC+Pl

345

351

347

13.6(0.86-1.23)

p=0.761

13.4

13.1 (0.78-1.11)

p=0.420

NR 37.8,p<.0001

34.6,p<0.0002

21.6

Scagliotti96 926 PCb+S

PCb 

464

462

10.7 (9.1-13.9)

10.6 (9.6-12.0)

terminated when 

analysis concluded 

study unlikely to 

reach endpoint

Lynch91 676 Ct+TxCb

TxCb

338

338

9.69(0.754-1.051)

p=.1685

8.38

NR 25.7 (21.2-30.7)

p=.0066

17.2 (13.3-21.6)

Takeda 106 604/603 Platinum doublet 

chemotherapy

Ge (after 3 cycles 

of chemotherapy)

301

302

12.9 (0.72-1.03), 

p=.11

13.7

NR 29.3,p=.20

34.2

Goss88 296/251 PCb+Pl

PCb + Cd

126

125

study halted to review 

imbalances in assigned 

causes of death

NR 38,p<.0001

16

Blumenschein87 612 BxCbP

CbP

306

306

8.5

9.2

NR 19.3,p=.24

23.5

Ramlau94 623 CV

CVBx

312

311

9.9,p=.3

8.7

NR 24.4,p=.0224

16.7

*New entries are shaded.

a Neval only reported when analysis was not intention-to-treat. b

 Log rank comparison of three arms.

c Hazard ratio of overall survival for PECb vs. PCb was 0.995 (0.86 –1.16), p = 0.95.

d HR for death = 0.79 (0.67– 0.92), p = 0.003.

e

 Hazard ratio of overall survival for GC vs. GC = Ap was 1.05 (0.88 –1.25), p = 0.61.

Ap, aprinocarsen; B, bevacizumab; C, cisplatin; Cb, carboplatin; Ce, cetuximab; CI, confidence interval; E, erlotinib; G, gemcitabine; Ge, gefitinib; Neval, 

number of patients evaluable; Nrand, number of patients randomized; NR, not reported; P, paclitaxel; V, Vinorelbine; Pl, placebo; ES, endostar; S, sorafenib; 

Ct, cetuximab; Tx, taxane; Cd, cediranib; Bx, bexarotene
22

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Key Sub-question 1.7.1 Does targeted monotherapy improve outcomes in selected 

patient populations? 

We also identified seven publications (from six trials) that assessed the use of targeted monotherapy 

compared to conventional chemotherapy, primarily in the population of patients with the EGFR gene 

mutation. We consider this to be related but distinct to the above discussion regarding the addition of 

targeted therapy to conventional chemotherapy, and therefore have created a new key sub-question for 

this topic. These studies, which compared gefitinib to carboplatin-paclitaxel in a general population 

and then performed a subgroup analysis on patients with the EGFR mutation,107, 108 gefitinib vs. 

chemotherapy in patients selected for EGFR gene mutations,109, 110 gefitinib vs. chemotherapy in a 

general population and then performed a subgroup analysis on patients with EGFR mutations,111 and 

erlotinib vs. chemotherapy in patients selected for EGFR gene mutations,112, 113 consistently show large 

differences in progression-free survival favoring targeted monotherapy, such as10.1 months vs. 5.4 

months(Table F5). Overall survival also tended to favor groups treated with targeted monotherapy 

as opposed to chemotherapy treatment, but this has not reached statistical significance, and two trials 

favored chemotherapy over targeted monotherapy, however neither of these contradictory findings 

reached statistically significance either.111, 113 One of these trials was consistent with the support for 

targeted monotherapy compared to chemotherapy within a subgroup analysis of patients with EGFR 

mutations.111 Other than rash and aminotransferase elevation, erlotinib and gefitinib were also in 

general better tolerated than cytotoxic chemotherapy. 

Table F5. Targeted Monotherapy

Study Comparison Progression Free Survival 

(95% CI), p Value

Overall Response (95% 

Reference Nrand/Neval CI), p Value a Agents Nrand/Nevala

Mok, 2009108 1217/1177 Ge

CbP

609/597

608/550

Hazard ratio favoring treatment with 

gefitinib = 0.74 (95% CI 0.65-0.85)

Hazard ratio favoring 

treatment with gefitinib = 

0.91 (95% CI, 0.76-1.10)

Maemondo, 2010109

All patients had EGFR 

mutations

230/224 Ge

CbP

115/114

115/110

Hazard ratio favoring treatment with 

gefitinib = 0.30, 95% CI (0.22-0.41)

2 year survival

Ge 61.4%

CbP 46.7%

(p=0.31)

Mitsudomi, 2010110

All patients had EGFR 

mutations

177/172 Ge

CD

86/88

86/89

Hazard ratio favoring treatment with 

gefitinib = 0.49 (95% CI 0.34-0.71), 

p=0.0001

Hazard ratio favoring 

treatment with gefitinib = 

0.61 (95% CI 0.28-1.34)

Zhou, 2011112

All patients had EGFR 

mutations

165/154 E

CbP

83/82

82/72

Hazard ratio favoring treatment with 

erlotinib = 0.16 (95% CI 0.10-0.26)

NR

Han, 2012111

Total population 

EGFR mutation 

subgroup

313/309

--/96

Ge

GC

Ge

GC

309/159

309/150

--/53

--/43

Hazard ratio favoring treatment with 

gefitinib = 0.83 (95% CI 0.66-1.06), 

p=0.138

Hazard ratio favoring treatment with 

gefitinib = 0.544 (95% CI 0.27-1.10)

Hazard ratio showed 

no clinically important 

difference: 1.07 (95% CI 

0.82-1.40), p=.604

Hazard ratio showed 

no clinically important 

difference: 0.96 (95% CI 

0.46-2.00)

Rosell, 2012113

All patients had EGFR 

mutations

173/173 E

CD or CG

86/86

87/87

Hazard ratio favoring treatment with 

erlotinib = 0.37 (95% CI 0.25-0.54), 

p<0.0001

ratio showed no clinically 

important difference: 1.04 

(95% CI 0.65-1.67), p=0.87

a Neval only reported when analysis was not intention-to-treat.

 Ge, gefitinib; Cb, carboplatin; P, paclitaxel; E, erlotinib; C, cisplatin; D, Docetaxel; G, gemcitabine

One additional trial is relevant to this topic. Gridelli and colleagues compared a strategy of using 

erlotinib as first-line therapy in unselected patients with advanced NSCLC, followed by cisplatin 

and gemcitabine at the first sign of progression, versus the opposite strategy of initial therapy of 
23

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

cisplatin and gemcitabine followed by erlotinib given at the first sign of progression.114 Among 

nearly 800 patients, the erlotinib first strategy was significantly worse in terms of overall survival.

As part of an update search, we identified two recently published meta-analyses of tyrosine 

kinase inhibitors.13, 22 One meta-analysis was of monotherapy with either erlotinib or gefitinib 

compared to cytotoxic therapy in patients with advanced NSCLC and EGFR mutations.13

It included six trials, all of which are included in Table F5. The pooled analysis showed a 

statistically significant benefit for progression-free survival (HR=0.37; 95% CI: 0.27-0.52), and a 

nonstatistically significant benefit in overall survival (HR=0.94; 95%CI: 0.77-1.15). The second 

meta-analysis was restricted to gefitinib, and included studies of it as monotherapy, combined 

with systemic chemotherapy, and then given after systemic chemotherapy (only one trial of 

this).22 The monotherapy portion included four trials, three of which are included in Table F5, 

and also found improvement in progression-free survival for patients with EGFR mutations.

Summary of Key Sub-question 1.7

New trials of a number of novel targeted agents have so far failed to find results equivalent 

to the increases in progression-free survival seen with erlotinib (mostly in patients who have 

never smoked) and bevacizumab (in an Asian population subgroup analysis) in the CCO review 

(GRADE=moderate).

Erlotinib or gefitinib monotherapy is in general superior in terms of beneficial outcomes and 

adverse events than cytotoxic chemotherapy in patients with EGFR mutations (GRADE=high). 

Key Sub-question 1.8. Is a single new agent superior to best supportive care?

We did not update this key sub-question as our scope was the comparative effectiveness between 

drugs.

Key Sub-question 1.9. Is a single new agent superior to single-agent or doublet 

therapy including older agents?

The CCO review focused on cytotoxic “new agents” such as vinorelbine and irinotecan and 

not targeted therapies. As an earlier conclusion had already established doublet therapy as the 

treatment of choice, we did not update this key sub-question.

Key Sub-question 1.10. Which single new agent is most effective?

The CCO review focused on the single agent cytotoxic agents gemcitabine, vinorelbine, 

paclitaxel, and docetaxel. Since an earlier conclusion had established doublet therapy as the 

treatment of choice, we did not update this key sub-question.

Key Sub-question 1.11. What is the optimal administration, duration, and timing of 

chemotherapy for advanced nsclc?

We did not update this key sub-question as it did not assess comparative effectiveness of agents 

and therefore did not fit the scope of key question #1 for this current review.
24

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Key Sub-question 1.12. Is a Doublet Regimen Better than a Single Agent for the 

Elderly Population?

In the systematic review by the CCO, six trials were identified as being relevant to the treatment 

of elderly patients with NSCLC.2 These trials compared a variety of different regimens, including 

singlet vs. singlet, singlet vs. doublet, and singlet vs. best supportive care. The CCO original key 

question was refined by our TEP to focus solely on singlet vs. doublet therapy in elderly patients. 

Four trials in the CCO review compared singlet versus doublet therapy. Two of the trials reported 

modestly improved overall survival in the doublet-treated patients, and the other two reported 

no differences. The CCO review concluded that using a single new agent was superior to best 

supportive care in patients > 70 years of age; doublet therapy could be considered in those that 

could tolerate combination therapy or platinum agents; and that no trial that had been dedicated to 

assessing platinum agents in the elderly population has been completed. For patients > 70 years, 

survival was similar to that in younger patients, even though the elderly experienced more frequent 

leucopenia. There was a lack of data regarding the use of chemotherapy in patients >80 years of age 

and, therefore, chemotherapy should be used cautiously in that population.

New Literature Since 2007 Relevant to this Sub-question

We identified four new trials that compared single agents to doublet regimens in the elderly 

population.108, 113, 115, 116 The first two trials were focused on elderly patients.108, 113The second two 

trials examined the elderly as a subpopulation.115, 116

The first trial focused specifically on the elderly population, comparing treatment with docetaxel 

to treatment with both docetaxel and gemcitabine.116 Three hundred and fifty patients were 

randomized, with the median age of 74 years. ITT analysis showed median survival of 5.5 months 

in the group receiving the doublet chemotherapy, compared to 5.1 months in those receiving a 

single agent (P=.65). The median time-to-progression was longer in those receiving the doublet 

regimen (4.8 months) compared to those receiving a single agent (2.9 months; P=.004). 

The second trial compared individuals aged 70-89 receiving either the doublet regimen of 

carboplatin and paclitaxel or therapy with a single agent of vinorelbine or gemcitabine.115 The 

451 patients were randomly assigned to the two groups. Median overall survival was 10.3 

months for the doublet chemotherapy compared to 6.2 months for therapy with a single agent 

(HR 0.64, 95% CI 0.52-0.78; p<0.0001). One year survival was also greater in the doublet group 

with 44.5% (95% CI 37.9-50.9) alive at one year compared to 25.5% in the single agent group 

(95% CI 19.9-31.3). There were greater toxic effects in the doublet chemotherapy group but this 

was still considered a superior regimen to single agent therapy.

The first subgroup trial assessed elderly patients within a group of adults treated for NSCLC 

compared erlotinib to standard chemotherapy of cisplatin or carboplatin plus docetaxel or 

gemcitabine.113 The study was halted after interim analysis revealed that the study had met its 

primary endpoint. In the final analysis, the median progression-free survival for those treated 

with erlotinib was 9.7 months (95% CI 8.4-12.3) compared to 5.2 months for those treated with 

the doublet regimen (95% CI 4.5-5.8) (HR 0.37, 95% CI 0.25-0.54; p<0.0001). A multivariable 

analysis of progression-free survival found that age was not a significant factor. 
25

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Another subgroup study assessed differences in progression-free survival in patients treated with 

gefitinib compared to carboplatin plus paclitaxel.108 They found that progression-free survival 

was longer in the gefitinib group but that this was affected by age. For those patients younger 

than 65, the hazard ratio was 0.81; 95% CI, 0.70 - 0.95, and for those patients 65 years or older, 

the hazard ratio was 0.58; 95% CI, 0.45-0.76; P<0.001. There was a statistically significant 

interaction between age and treatment effect (p=0.03). 

We add here one additional trial, which compared singlet vs. doublet therapy, although the mean 

age of patients was “elderly” (mean age = 63), and not all clinical experts would judge this 

study as relevant to the elderly population.117 This study compared docetaxel alone to docetaxel 

plus gemcitabine in 312 patients with stage IIIB or IV NSCLC. There was a slight, statistically 

significant advantage for overall survival in the doublet-treated group (9.4 months vs. 8.3 

months). There was a greater proportion of patients in the doublet-treated group with grade 2-4 

anemia, plus two treatment-related deaths.

Summary of Key Sub-question 1.12

With the exception of studies of gefitinib and erlotinib monotherapy (in patients with EGFR 

mutations), doublet chemotherapy probably has a slight benefit in terms of survival compared 

to singlet therapy, but causes more toxicity (GRADE=moderate). Also, there now has been one 

trial of platinum therapy in the elderly taken to completion that found a near-doubling of the 

proportion of patients alive at one year in the doublet therapy group compared to monotherapy. 

Key Sub-question 1.13. Toxicity of first-line systemic chemotherapy regimens

The CCO reported a summary of Grade 3 or 4 chemotherapy toxicities from 7 large trials of 

various agents. They cautioned that “comparisons between trials should be avoided and numbers 

are provided only to give a general sense of the toxicity of the regimens,” which we now repeat. 

To the table from the CCO we have added the Grade 3 or 4 toxicities from additional large trials 

of first line treatment, see Table F6.

Table F6. Summary of Grade 3 or 4 Chemotherapy Toxicity (% Patients) from Large, Selected

Trials in NSCLC (adapted from Goffin)

Regimen Dose (mg/m2) and Administration Schedule

[Reference]

Febrile 

Neutropenia 

Anemia Nausea/

Vomiting

Peripheral 

Neuropathy

Platelets Renal

Paclitaxel 100 over 1 hr days 1, 8, 15 every 4 weeks 

[Comella 2004118]

3 2 NR/0 0 0 0

Gemcitabine 1200 over 30 mins days 1, 8, 15 every 4 weeks 

[Comella 2004 118]

3 10 NR/3 2 10 2

Vinorelbine 30 days 1, 8 every 3 weeks [Gridelli 2003119] NR <4 <1 1 <1 0

Docetaxel 60 over 1hr, day 1 every 3 weeks [Kudoh 2006120] 12.5 3.4 10.2 0 0 NR

Cisplatin/Vinorelbine 100 day 1/25 days 1, 8, 15, 22 every 4 

weeks [Fossella 200350]

5 24 16/16 4 (Sensory) 4 NR

Cisplatin/Vinorelbine 80 day 8/30 days 1 and 8 [Georgoulias 

2005121]

NR 6 15‡ NR 6 3

Cisplatin/Paclitaxel 75 day 2/135 (24 hour) day 1 every 3 

weeks [Schiller 200245]

16 13 25/24 5 6 3*

Cisplatin/Docetaxel 75 day 1/75 day 1 every 3 weeks 

[Fossella 200350]

5 7# 10/8 4 (Sensory) 3 NR

Cisplatin/Docetaxel 75 day 1/75 day 1 every 3 weeks 

[Schiller 200245]

11 15 24/21 5 3 3*
26

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Regimen Dose (mg/m2) and Administration Schedule

[Reference]

Febrile 

Neutropenia 

Anemia Nausea/

Vomiting

Peripheral 

Neuropathy

Platelets Renal

Cisplatin/Gemcitabine 100 day 1/1000 days 1, 8, 15 every 4 

weeks [Schiller 200245]

4† 28† 37/35 9 50† 9*†

Carboplatin/Paclitaxel AUC 6 day 1/225 (3 hour) day 1 

every 3 weeks [Schiller 200245]

4† 10 9†/8† 10 10 1*

Carboplatin/Paclitaxel AUC 6 day 1/200 (3 hour) day 1 

every 3 weeks [Kosmidis 2002122]

1 5 4 8 2 0

Carboplatin/Docetaxel AUC 6 day 1/75 day 1 every 3 weeks 

[Fossella 200350]

4 10# 6/4# 1 (Sensory) 7 NR

Gemcitabine/Docetaxel 1000 days 1 and 8/100 day 8 

[Georgoulias 2005121]

NR 2 2‡ NR 4 0

Gemcitabine/Paclitaxel 1000 day 1, 8/200 (3 hour) day 1 

every 3 weeks [Kosmidis 2002122]

2 2 7 6 1 1

Carboplatin/Paclitaxel AUC=6; 200 mg/m2 [Sandler 2006101] 1.8 0.9 NR NR 0.2 NR

Carboplatin/Paclitaxel/Bevacizumab AUC=6; 200 mg/m2

 15 

mg/kg/daily [Sandler 2006101]

4.0 0 NR NR 1.6 NR

Cisplatin/Gemcitabine [Reck 2009102] NR 13 4 NR 23 NR

Cisplatin/gemcitabine/ bevacizumab 4.5 mg/kg [Reck 

2009102]

NR 10 7 NR 27 NR

Cisplatin/gemcitabine/bevacizumab 15 mg/kg [Reck 2009102] NR 10 9 NR 23 NR

New entries are shaded.

Abbreviations: AUC = area under curve; hr = hour; mg=milligrams; m2

= meters squared; min = minutes; NR = not reported; NSCLC = nonsmall cell lung cancer.

*Grades 3, 4, and 5 renal toxicity.

† Toxicity was significantly different than for the trial comparator regimen, cisplatin-paclitaxel (p=0.05).[Schiller 2002]

‡ Toxicity was significantly different between the two regimens, gemcitabine-docetaxel and cisplatin-vinorelbine (p<0.001).[Georgoulias 2005]

#

 Toxicity was significantly different than for the trial comparator regimen, cisplatin-vinorelbine (p<0.01). [Fossella 2003]

KEY QUESTION 2. For patients with metastatic NSCLC what is the 

comparative effectiveness of the different recommended (e.g. NCCN 

guidelines) second line chemotherapy regimens?

“Second-line therapy,” by definition in this review, means active therapy. It has already been 

established that docetaxel monotherapy resulted in improved overall survival when compared to 

best supportive care. For example, more than a decade ago Shepherd and colleagues randomized 

104 patients to either docetaxel at 75mg/m2 or 100mg/m2 or best supportive care (BSC).123 The 

median overall survival was longer in the docetaxel groups with 7.0 months compared to the 4.6 

months in the BSC group. The difference was more significant when comparing the docetaxel 

75mg/m2 to the BSC with the median survival of 7.5 months compared to the 4.6 months of 

BSC (P=.010) One-year survival was also increased in the docetaxel 75mg/m2 group with 37% 

versus 11% in the BSC group (p=.003).

There was no single systematic review of second-line therapy that was both comprehensive and 

high quality, thus we found no equivalent to the review by the CCO. Therefore our synthesis of 

the second-line therapy first discusses the existing systematic reviews, and then the trials. 

Existing Systematic Reviews

There were seven systematic reviews, details of which can be found in Table S1.

The first three reviews were done by Qi and colleagues.124-126 The first of these consisted of five 

RCTs comparing pemetrexed doublets versus pemetrexed alone.124 The two other trials by Qi 
27

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

and colleagues included drugs that do not have FDA approval (enzastaurin and matuximab).125,126

Futhermore, the authors pooled data across studies that included a very heterogeneous group of 

drugs, including cytotoxic therapies and targeted therapies. We did not judge this pooling to be 

clinically sensible and hence concluded this meta-analysis was not relevant to clinical practice. 

Similarly, the second review by Qi and colleagues assesses the efficacy of vandetanib in a 

pooled analysis of heterogeneous comparators, and we likewise did not judge this as clinically 

meaningful.125

The third review consisted of eight RCTs comparing docetaxel- based doublets with docetaxel 

as a single agent.126 These trials resulted in 2,126 patients for analysis. Meta-analysis showed no 

difference in overall survival (HR=0.93; 95% CI: 0.80-1.07, P=0.308) but did show a difference 

in overall response rate (OR=1.42, 95% CI: 1.13-1.80, P=0.03). In addition, 1-year survival was 

not significantly improved (OR=1.09, 95% CI: 0.92-1.28, P=0.328). 

The next review was by Yang and colleagues and included four RCTs.127 Two of these compared 

bevacizumab plus carboplatin and paclitaxel to carboplatin plus paclitaxel alone, one compared 

bevacizumab with chemotherapy to bevacizumab with erlotinib or chemotherapy alone, and the 

last compared cisplatin plus gemcitabine with either placebo or bevacizumab. Only one of these 

trials studied treatment exclusively as second-line therapy,128 one trial included both untreated 

and recurrent nonsquamous cell disease,102 and the other two studied bevacizumab as part of first 

line treatment.101, 129 These four studies combined treated 2101 patients. Meta-analysis found that 

tumor response rate might not be increased with low-dose bevacizumab (7.5mg/kg) (RR= 1.19, 

p=0.68) but was with high-dose treatment (15mg/kg) (RR=1.69, p=0.002). The one year survival 

rate was not increased with either low (RR=1.02, p=0.82) or high doses (RR=1.09, p=0.07). The 

2 year survival rate was increased by the higher dose regimen but at a cost of greater toxicity. In 

the one study of bevacizumab as part of second line treatment,128 the addition of bevacizumab to 

second line treatment with docetaxel or pemetrexed resulted in improvements in progression-free 

survival and overall survival, with hazard ratios of 0.66 to 0.78, although these improvements 

were not statistically significant. In this study, adding erlotinib to the bevacizumab therapy 

did not result in additional improvement. No study demonstrated that continuing bevacizumab 

beyond first line chemotherapy, either alone or with another agent, offers superior overall 

survival to stopping bevacizumab at the time of discontinuation of first line cytotoxic therapy.

The fifth systematic review by Mountzios and colleages included four trials of erlotinib versus 

placebo, erlotinib and gemcitabine-cisplatin, erlotinib and carboplatin-paclitaxel, and erlotinib 

and bevacizumab.20 This review covered the use of erlotinib as first line, second line, and 

maintenance therapy. Regarding second-line therapy, assessment of overall survival found a 

modest absolute gain of 2 months (overall survival of 6.7 months vs. 4.7 months, HR = 0.70, p < 

0.001) in the BR.21 trial.130 This led to FDA (11/2004) and EMA (10/2005) approval of erlotinib 

for the treatment of chemotherapy-resistant patients. 

The final two systematic reviews were by Di Maio and colleagues. The first was an individual 

patient data meta-analysis of docetaxel administered weekly or once every three weeks as 

second-line therapy in patients with NSCLC.131 A total of 865 patients were included, 81 

percent were performance status 0 or 1, 91 percent had received platinum therapy. There was 

no difference in median survival (27.4 weeks vs. 26.1 weeks), and fewer episodes of severe 
28

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

and febrile neutropenia in patients receiving weekly docetaxel. The second systematic review 

included the data from six trials comparing single agent and doublet chemotherapy.132 Overall 

survival was not significantly different with the median of 37.3 weeks with doublets and 34.7 

weeks with single agent (P=.32). The response rate was 15.1% with the doublets and 7.3% with a 

single agent (P=.0004). There were more toxic effects from the doublet, compared to single agent 

therapy. 

The conclusions from the seven systematic reviews can be summarized as:

• doublet second line cytotoxic therapy might offer slight benefits in progression-free 

survival and response rate, not overall survival, but at a cost of increased toxicity;

• erlotinib produces modest increases in overall survival; and

• in one phase II study, the addition of bevacizumab to second line treatment resulted in 

improvements in survival that were not statistically significant.
29

all Cell Lung Cancer Evidence-based Synthesis Program

atic Reviews Published Since 2010

What was compared

Outcomes Reported

Overall Survival PConclusions per abstract:

rogression-free 

Survival

Overall 

Response Rate

Adverse Events

Other 

Outcomes 

Reported

Studies included:

First Author, Year Title. Journal

and something vs. pemetrexed alone

X X X X

Pemetrexed based doublet therapy didn’t gain any benefit in survival but significantly improved progression free survival and overall response competed with single agent pemetrexed. More adverse events in doublet group.

010 Phase II, double-blinded, randomized study of enzastaurin plus pemetrexed as second

n patients with advanced non-small cell lung cancer. J Thorac Oncol

1 Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell 

a randomized, double-blind phase III trial. J Clin Oncol

010 A randomized phase II study of bortezomib and pemetrexed, in combination or 

ents with previously treated advanced non-small-cell lung cancer. Lung Cancer

0 Pemetrexed with or without matuzumab as second-line treatment for patients with 

V non-small cell lung cancer. J Thorac Oncol

andomized phase II and pharmacogenetic study of pemetrexed compared with pemetrexed 

tin in pretreated patients with advanced non-small cell lung cancer. J Clin Oncol

s. Pemetrexed, Erlotinib, Docetaxel

X X X X

Vandetanib offered a clinically meaningful and statistically significant improvement in progression free survival and overall response rate in patients with advanced NSCLC but did not benefit overall survival.

Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with 

n-small-cell lung cancer (ZODIAC): a double-blind, randomized, phase 3 trial. Lancet Oncol

Phase III trial of vandetanib compared with erlotinib in patients with previously treated 

n-small-cell lung cancer. J Clin Oncol

1 Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung 

domized, double-blind phase III trial. J Clin Oncol

07 Randomized, placebo-controlled phase II study of vandetanib plus II study of vandetanib 

l in previously treated non-small-cell lung cancer. J Clin Oncol

ngle vs. doublet treatment

X X X X

1 year survival

Docetaxel-based doublet therapy did not gain any benefit in survival but significantly improved progression free survival and better overall response rate. However more grade 3/4 neutropenia, thrombocytopenia, and diarrhea were observed in the docetaxel-based doublet group.

Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with 

n-small-cell lung cancer (ZODIAC): a double-blind, randomized, phase 3 trial. Lancet Oncol

07 Randomized, placebo-controlled phase II study of vandetanib plus docetaxel in previously 

mall-cell lung cancer. J Clin Oncol

 Weekly docetaxel vs. docetaxel-based combination chemotherapy as second-line treatment 

non-small-cell lung cancer patients. The DISTAL-2 randomized trial. Lung Cancer

005 Comparison of docetaxel and docetaxel-irinotecan combination as second-line 

y in advanced non-small-cell lung cancer; a randomized phase II trial. Ann Oncol

 Phase II trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for 

l lung cancer: results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol 

A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel 

as second line treatment for patients with advanced/metastatic non-small cell lung cancer. 

05 A randomized phase II trial of docetaxel vs. docetaxel and irinotecan in patients with stage 

mall-cell lung cancer who failed first-line treatment. Br J Cancer

0 A randomized phase II study of a combination of docetaxel and S-1 versus docetaxel 

 in patients with non-small cell lung cancer previously treated with platinum-based 

y: results of Okayama Lung Cancer Study Group (OLCSG) Trial 0503. J Thorac Oncol
30

all Cell Lung Cancer Evidence-based Synthesis Program

What was compared

Outcomes Reported

Overall Survival PConclusions per abstract:

rogression-free 

Survival

Overall 

Response Rate

Adverse Events

Other 

Outcomes 

Reported

Studies included:

First Author, Year Title. Journal

b vs. various other agents in first or second-line therapy

X X X

1st year survival, 2nd year survival, tumor response rate, treatmentrelated deaths

Low-dose bevacizumab may significantly improve PFS in patients with unresectable NSCLC, whereas high-dose bevacizumab may increase 2-year overall survival rates, prolong PFS and improve tumor response rate but at the cost of higher treatment related death.

Phase II study of efficacy and safety of bevacizumab in comparison with chemotherapy or 

pared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung 

 Oncol

4 Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with 

nd paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung 

 Oncol

 Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J 

hase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line 

onsquamous non-small-cell lung cancer: AVAil. J Clin Oncol

placebo; TALENT-erlotinib + platinum-based doublet (gemcitabine/cisplatin), 

rlotinib + carboplatin/paclitaxel), ATLAS-erlotinib + bevacizumab

X X X X

Risk of death

Despite the modest absolute gain in OS (2 months), the [Shepherd] study demonstrated a 30% reduction in the risk of death in this heavily pre-treated group of patients. On the basis of these results, erlotinib received both FDA and EMA approval in November 2004 and October 2005, respectively, for the treatment of chemotherapy-resistant patients with advanced NSCLC. Based on the results of the SATURN and ATLAS studies, the use of erlotinib as maintenance therapy is becoming a treatment option for patients with good performance status (PS) who respond to first-line chemotherapy.

05 Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med

2004 Determinants of tumor response and survival with erlotinib in patients with non

ng cancer. J Clin Oncol

 Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy 

ompared with chemotherapy alone for treatment of recurrent or refractory non small-cell 

J Clin Oncol

2008 A phase III, multicenter, placebo-controlled, double-blind, randomized, clinical 

ate the efficacy of bevacizumab (Avastin) in combination with erlotinib (Tarceva) 

th erlotinib alone for treatment of advanced non-small cell lung cancer (NSCLC) after 

ndard first line chemotherapy (BETA). J Thorac Oncol

ombination

X X X X

Doublet chemotherapy as second-line treatment of advanced NSCLC significantly increases response rate and progression-free survival, but is more toxic and does not improve overall survival compared to single-agent.

9 Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment 

l-cell lung cancer: Results of a Japan Clinical Oncology Group trial (JCOG0104). Ann 

 2004 Irinotecan plus gemcitabine vs. irinotecan for the second-line treatment of 

 advanced non-small-cell cancer pretreated with docetaxel and cisplatin: A multicentre, 

phase II study. Br J Cancer

 2005 Second-line treatment with irinotecan plus cisplatin vs. cisplatin of patients 

ed non-small-cell lung cancer pretreated with taxanes and gemcitabine: A multicenter 

phase II study. Br J Cancer

05 A randomized phase II trial of docetaxel vs. docetaxel and irinotecan in patients with 

 non-small-cell lung cancer who failed first-line treatment. Br J Cancer

9 Weekly docetaxel vs. docetaxel-based combination chemotherapy as second-line 

f advanced non-small-cell lung cancer patients: The DISTAL-2 randomized trial. Lung 

A randomized phase II study of pemetrexed (P) versus pemetrexed-carboplatin (PC) as 

reatment for patients (pts) with advanced non-small-cell lung cancer (NSCLC)- NVALT 

ol
31

all Cell Lung Cancer Evidence-based Synthesis Program

What was compared

Outcomes Reported

Overall Survival PConclusions per abstract:

rogression-free 

Survival

Overall 

Response Rate

Adverse Events

Other 

Outcomes 

Reported

Studies included:

First Author, Year Title. Journal

Weekly vs. Once every three weeks

X X X

Weekly docetaxel shows similar efficacy compared to docetaxel administered once every three weeks, and represents an alternative for second line treatment of advanced NSCLC.

4 A randomized clinical trial of two docetaxel regimens (weekly vs. 3 week) in the 

reatment of non-small-cell lung cancer: The DISTAL 01 study. Br J Cancer

5 Phase II randomized trial comparing docetaxel given every 3 weeks with weekly 

econd-line therapy in patients with advanced non-small-cell lung cancer (NSCLC). Ann 

05 Phase III study of second-line chemotherapy for advanced non-small-cell lung cancer 

compared with 3-weekly docetaxel. J Clin Oncol

ase II randomized trial of tri-weekly versus day 1 and 8 weekly docetaxel as a second

t of advanced non-small cell lung cancer. Jpn J Clin Oncol

 Randomized phase III study of 3-weekly versus weekly docetaxel in pretreated 

n-small-cell lung cancer: A Spanish Lung Cancer Group trial. Ann Oncol
32

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Clinical Trials Published Since 2006

We identified 20 trials, six of which were also included in the systematic reviews above.133-138

Table S2 shows the overlap between trials and systematic reviews. 

Trials Included in Existing Systematic Reviews

Two of the trials, by Gebbia and colleagues133 and Takeda and colleagues,134 were included in the 

review by Di Maio and colleagues discussed previously. 132 One trial by Herbst and colleagues136

was in the review by Yang and colleagues, 127 also discussed previously. The remaining three 

trials were only included in reviews by Qi and colleagues, which were not discussed in detail in 

the prior section.We therefore summarize these three trials here.

The first trial135 was included in Qi and colleagues (2012).126 In this RCT, patients who had been 

pretreated with front-line platinum-free regimens were randomized to receive either docetaxelcarboplatin or docetaxel alone. There was no significant difference in overall survival between 

the two groups with 10.27 (95% CI: 7.07-13.47) months achieved in the combination arm and 

7.70 (95% CI: 3.39-12.01) months in the docetaxel alone arm (p=0.550). The response rate was 

similar 10.4% for the combination versus 7.7% (p=0.764). Likewise, the one-year survival rate 

was similar 43.8% versus 40.3%.

The next trial137 was included in the systematic reviews by Qi and colleagues (2011)125 and Qi 

and colleagues (2012).124 In this study, 534 patients were randomized to receive vandetanib 

added to pemetrexed or pemetrexed plus placebo. There was no significant difference in overall 

survival. Median overall survival was 10.5 months for vandetanib and 9.2 months for placebo 

(HR=0.86; 97.54% CI, 0.65-1.13; p=.219). There were statistically significant improvements in 

overall response rate with 19% in the vandetanib group and 8% in the placebo group (p<.001). 

Vandetanib is not currently approved for use in the United States.

The last of the trials138 was found in Qi and colleagues (2011).125 In this trial 1,240 patients 

were randomized to receive vandetanib or erlotinib. There was no significant difference in the 

superiority analysis as the median overall survival was 6.9 months for vandetanib and 7.8 months 

with erlotinib (HR=1.01; p=.830). Likewise, the overall response rate was 12% in both arms 

(two-sided P=.98). A preplanned non-inferiority analysis supported non-inferiority, defined as 

whether vandetanib “retained at least 50%” of the efficacy of erlotinib. 
33

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Table S2. Second Line Trials Appearing in a Systematic Review

First Author, Year Title. Journal

Systematic 

Reviews 

Including this 

Trial*

Single versus Double 

Gebbia, 2009133Weekly docetaxel vs. docetaxel-based combination chemotherapy as second-line treatments of advanced 

non-small-cell lung cancer patients: The DISTAL-2 randomized trial. Lung Cancer

Di Maio (2009)132

Qi (2012)126

Takeda, 2009134 Phase III trial of docetaxel plus gemcitabine versus docetaxel in second-line treatment for non-small-cell 

lung cancer: Results of a Japan Clinical Oncology Group trial (JCOG0104). Ann Oncol

Di Maio (2009)132

Qi (2012)126

Pallis, 2010135 A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as 

second line treatment for patients with advanced/metastatic non-small cell lung cancer. BMC Cancer

Qi (2012)126

New Agent

Herbst, 2010136 Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-smallcell lung cancer (ZODIAC): a double-blind, randomized, phase 3 trial. Lancet OncolQi (2012)126

Qi (2011)125

Yang (2010) 127

De Boer, 2011137 Vandetanib plus pemetrexed for the second-line treatment of advanced non-small-cell lung cancer: a 

randomized, double-blind phase III trial. J Clin Oncol

Qi (2011)125

Qi (2012) 124

Natale, 2011138 Phase III trial of vandetanib compared with erlotinib in patients with previously treated advanced nonsmall-cell lung cancer. J Clin OncolQi (2011)125

* The systematic review by Mountzios and colleagues in this second line section did not overlap with any trials identified by our search or TEP, and is 

thus not included in this table

The remaining 15 trials were not found in any of the systematic reviews.123, 139-153 Table S3 has 

the details of these trials. We discuss these here in the order in which they emerged into clinical 

practice: docetaxel, followed by pemetrexed, then tyrosine kinase inhibitors (TKI), and finally 

newer agents.

Docetaxel 

We identified one new trial of docetaxel. Fossella and coleagues 373 patients were randomized to 

receive either docetaxel 100mg/ m2, docetaxel 75mg/m2 versus a regimen of either vinorelbine 

or ifosfamide.151 Overall survival was not significantly different between the three groups, 

5.5 months for docetaxel 100mg/m2, 5.7 months for docetaxel 75mg/m2 and 5.6 months for 

vinorelbine/ifosfamide. However, the 1-year survival was significantly greater with docetaxel 

75mg 32% (95% CI: 23-40) than with vinorelbine/ ifosfamide 19% (12-26). The overall response 

rates for both of the docetaxel arms were significantly higher than that of the vinorelbine/

ifosfamide arm with 10.8% for docetaxel 100mg/m2, 6.7% for docetaxel 75mg/m2 and 0.8% 

with vinorelbine/ifosfamide (p=.001 and p=.036, respectively). 

Pemetrexed

Cullen et al, randomized 588 patients to either standard or high-dose pemetrexed.145 The goal 

was to accrue 600 patients, however accrual was terminated after an interim analysis indicated a 

low probability of improved survival and numerically greater toxicity in the higher dose arm. Of 

the patients randomized, there was no statistically significant difference between the two groups 

in median survival reaching 6.7 months with the lower dose and 6.9 months with the higher 

dose (HR=1.0132, 95% CI: 0.837-1.226). Likewise there was no significant difference in overall 

response with 7.1% in the lower dose and 4.3% in the higher dose (P=0.1616). 
34

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

TKI versus Cytotoxic Therapy

There were six trials comparing TKI to cytotoxic therapy.139-144, 152 Ciuleanu et al, included 424 

patients who were randomized to receive either erlotonib or chemotherapy.139 About two-thirds of 

patients were positive for EGFR mutations. Median overall survival was 5.3 months (4.0-6.0) in 

the erlotinib group and 5.5 months (4.4-7.1) with chemotherapy (HR=0.96, 95% CI: 0.78-1.19; 

log-rank p=0.73). The response rate was also similar between the 2 groups with a RR of 7.9% 

(4.6-12.5) in the erlotinib group and 6.3% (3.5-10.4) in the chemotherapy group. The one-year 

survival was 26% (19-32) in the erlotinib group versus 24% (18-30) in the chemotherapy group. 

Maruyama and colleagues randomized 489 patients to receive either gefitinib or docetaxel.140

Patients were enrolled irrespective of EGFR receptor mutation status. There was no significant 

difference in overall survival, which was 11.5 months (95% CI: 9.8-14.0) in the gefitinib arm and 

14.0 months (95% CI: 11.7-16.5)in the docetaxel arm (P=.330). However, for ORR gefitinib was 

statistically superior to docetaxel (22.5% v 12.8%, odds ratio, 2.14; 95% CI: 1.21-3.78; P=.009).

Sekine and colleagues assessed quality of life outcomes in the preceding study reported by Maruyama 

and colleagues.142 This studied evaluated the quality of life differences between these two regimens 

and found gefitinib to have statistically significant benefits over docetaxel. The Functional Assessment 

of Cancer Therapy-Lung analysis was 23% for gefitinib versus 14% for docetaxel (P=0.023). The 

Trial Outcome Index was 21% vs 9% (P=0.002). There was no significant differences between 

treatments in Lung Cancer Subscale improvement rates (23% vs 20%, P=0.562). This study is the 

quality of life assessment outcome of a trial by Maruyama and colleagues, discussed above.140

Kim and colleagues randomized 1466 patients to either gefitinib or docetaxel.141 Patients were 

enrolled irrespective of EGFR mutation status. Median overall survival was 7.6 months in the 

gefitinib group and 8.0 months in the docetaxel group. One-year survival was 32% for gefitinib 

and 34% for docetaxel. 

Lee and colleagues randomized 161 patients to either gefitinib or docetaxel.143 Patients were 

enrolled irrespective of EGFR mutation status. The overall survival was 14.1 months for gefitinib 

and 12.2 months for docetaxel (HR=0.870, 95% CI: 0.613-1.236, 2-sided p=0.4370). The 

objective response rate was statistically superior in the gefitinib group (28.1%) compared to the 

docetaxel group (7.6%) (P=0.0007). 

Lastly, during peer review an abstract presented at the 2012 ASCO Annual Meeting was 

identified.152 This study randomized 221 patients to erlotinib or docetaxel; all patients had wild 

type EGFR status. At a median follow-up of 20 months, progression-free survival favored 

treatment with docetaxel. Overall survival was not yet analyzed. We await full publication of 

these results, which will provide more complete analyses.

TKI As an Addition to Cytotoxic Therapy

This study of pemetrexed was added during peer review.153 The study has been presented at the 

the 2011 ASCO Annual Meeting, but full publication is still pending. This was a phase II study in 

which 165 patients were randomized to receive either pemetrexed or pemetrexed plus erlotinib. 

The median progression-free survival was 2.9 months versus 3.2 months favoring combination 

therapy (HR=0.63, 95% CI 0.44-0.90). Overall survival also favored combination therapy (11.8 
35

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

months vs. 7.8 months, HR=0.68, 95% CI 0.47-0.98). We await full publication of these results, 

which will provide more complete analyses, and confirmation in a phase III study.

TKI Plus Bevacizumab versus TKI Alone

Herbst and colleagues randomized 636 patients to either bevacizumab plus erlotinib or erlotinib 

alone.144 Approximately 90 percent of patients had wild type EGFR receptor status. The overall 

survival did not differ between the two groups with the median overall survival of 9.3 months 

(IQR 4.1-21.6) in the bevacizumab arm compared to 9.2 months (IQR 3.8-20.2) in the erlotinib 

alone arm (HR=0.97, 95% CI: 0.80-1.18, p=0.7583). Objective response rate was much higher in 

the bevacizumab group (13% vs 6%). 

Various Other Agents

There were seven trials of various other agents or doses.123, 146-151, 153 Ready and colleagues randomized 

106 patients to either the proapoptotic agent AT-101 or placebo in combination with docetaxel.146

There was no significant difference in the median overall survival which was 7.8 months in the AT101 arm and 5.9 months in the placebo arm (HR=0.82, 95% CI: 0.5-1.3, p=0.21). According to an 

independent review, the response rate and median PFS were not different between the arms, with the 

PFS for the AT-101 group of 7.5 weeks and 7.1 weeks for placebo (HR=1.04, p=0.57).

Ramlau and colleagues randomized 829 patients to either oral topotecan or IV docetaxel.147 The 

median survival was higher with docetaxel at 30.7 weeks (95% CI: 28-34) compared to 27.9 

weeks (95% CI: 24-31) with topotecan (p=.0568). Overall response rate was 5% (95% CI: 3-7%) 

for both docetaxel and topotecan. One-year survival was 29% (24-33%) for docetaxel and 25% 

(21-29%) for topotecan.

Paz-Ares and colleagues randomized 849 patients to either paclitaxel poliglumex or docetaxel.148 The 

median survival was not different, at 6.9 months in each arm (HR 1.09, p=0.257). The 1-year survival 

was also similar with 25% in the paclitaxel poliglumex arm and 29% in the docetaxel arm (P=0.006). 

Hermes and colleagues randomized 220 patients to either irinotecan plus carboplatin or etoposide 

plus carboplatin.39, 154 Overall survival was better in the irinotecan group with a median survival of 8.5 

months compared with 7.1 months in the etoposide group (etoposide relative to irinotecan HR=1.41; 

95% CI: 1.06-1.87). The one-year survival rate was 34% for irinotecan and 24% for etoposide. 

Krzakowski and colleagues randomized 551 patients to either vinflunine or docetaxel.149 The 

median overall survival was 6.7 months (95% CI: 5.9-7.9) in the vinflunine group and 7.2 

months (6.0-8.5) in the docetaxel group (HR=0.973, 95% CI: 0.805-1.176). The overall response 

rate was 4.4% for vinflunine and 5.5% for docetaxel treatment. 

Finally, Schiller and colleagues randomized 150 patients to receive either pemetrexed alone, 

pemetrexed plus matuzumab 800mg/week, or pemetrexed plus matuzumab 1600mg/3 weeks.150

There was a trend for improved OS in patients receiving matuzumab weekly compared to the 

every 3 weeks group with the former of 12.4 months and the latter 5.9 months. This was also 

greater than the 7.9 months of the pemetrexed group. Pooling the matuzumab arms gave an ORR 

of 11% compared to 5% for pemetrexed alone. Of note, all responses, except for one patient in 

the pemetrexed group, occurred in patients whose tumors expressed EGFR. 
36

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Table S3. Trials Not Included in Existing Systematic Reviews

Author; Date Nrand

Comparison

Agents/ N Histology(%)**

EGFR mutation 

status (if 

relevant)

Median Survival,

months (95% CI),

p value

1-year survival 

% (95% CI), p

value

Overall Response,

% (95% CI), p

value

Docetaxel

Fossella, 2000151 373

D100mg/

m2/125

D75mg/

m2/125

V or I/123

A: 50

S: 27 NR

5.5

5.7

5.6

-

32(23-40)

19(12-26)

10.8

6.7, p=.001

0.8,p=.036

Pemetrexed

Cullen, 2008145 588

Pem 

(standard 

dose)/295

Pem (hi 

dose)/293 NR NR

6.7

6.9 NR

7.1

4.3, p=0.1616

TKI vs. Cytotoxic Therapy

Ciuleanu, 2012139 424

E/203

Chemo/221

A: 50

S: 37

68% EGFR 

positive

5.3 (4.0-6.0)

5.5 (4.4-7.1)

p=0.73

26 (19-32)

24 (18-30)

7.9(4.6-12.5)

6.3(3.5-10.4)

Maruyama, 2008140 489

Gf/245

D/244

A: 78

S: 16

Enrolled 

irrespective

11.5(9.8-14.0)

14.0(11.7-16.5)

p=.330 NR

22.5

12.8, p=.009

Sekine, 2009142 490

Gf/245

D/244

Same as Maruyama, 

above NR NR NR

Kim, 2008141 1466

Gf/733

D/733

A; 57

S; 25

57% EGFR 

mutation positive

7.6

8.0 NR

32

34

Lee, 2010143 161

Gf/82

D/79

A: 66

S: 21

Enrolled 

irrespective

14.1

12.2

p=0.4370 NR

28.1

7.6, p=0.0007

Garassino, 2012152 221

E/108

D/110 NR

100% EGFR 

wild-type NR NR NR

TKI as an Addition to Cytotoxic Therapy

Von Pawel, 2011153 165

Pem/83

Pem+E/76 Non-S: 100 NR

7.8 (5.3-10.4)

11.8 (8.2-16.7),

P=0.019 NR

10.8

17.1

TKI Plus Bevacizumab vs. TKI Alone

Herbst, 2011144 636

BE/319

E/317

A: 75

S: 4

90% EGFR wild 

type

9.3

9.2, p=0.7583 NR

13

6

Various

Ready, 2011146 106

D+AT-101/53

DPl/52

A: 30

S: 56 NR

7.8

5.9,p=0.21 NR NR

Ramlau, 2006147 829

T/414

D/415

A: 42

S: 41 NR

27.9weeks(24-31)

30.7weeks(28-34), 

p=.0568

25 (21-29)

29 (24-33)

5

5

Paz-Ares, 2008148 849

Px/427

D/422 NR NR

6.9

6.9,p=0.257

25

29,p=0.006 NR

Krzakowski, 

2010149 551

Vin/274

D/277

A; 43

S;35 NR

6.7(5.9-7.9)

7.2(6.0-8.5) NR

4.4

5.5

Hermes, 200839 220

Ir+Cb/105

Et+Cb/104 NR NR

8.5

7.1

p=0.02

34

24 NR

Schiller, 2010150 150

Pem/50

PemMat 

(weekly)/51

PemMat 

(q3weeks)/49

A: 51

S: 31

EGFR 

expression status 

detectable (88%) 

vs. nondetectable 

(11%) 

7.9

12.4

5.9 NR

5

11 (PemMat 

groups combined)

** A: Adenocarcinoma, S: squamous cell carcinoma

Nrand, number of patients randomized; NR, not reported; C, cisplatin; Cb, carboplatin; CI, confidence interval; D, docetaxel; Et, etoposide; G, 

gemcitabine; Ir, Irinotecan; P, paclitaxel; Vd, vindesine; MVP, mitomycin; Pem, pemetrexed; E, erlotinib; Gf, gefitinib; B, bevacizumab; Pl, 

placebo; BSC, best supportive care; T, topotecan; Ct, cetuximab; Vin, vinflunine; Mat, matuzumab; If, ifosfamide
37

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Summary of Second-line therapy Trials Not in Existing Systematic Reviews

The summary of these trials not included in existing systematic reviews is:

•	 Considering data from first line and maintenance therapy studies in addition to second 

line studies, there are sufficient data to support the conclusion that histology type 

influences the effectiveness of potential treatments. Pemetrexed is more effective 

in nonsquamous NSCLC, while docetaxel is more effective in squamous NSCLC 

(GRADE=moderate).

•	 Tyrosine kinase inhibitors, when used as second-line therapy in patients unselected for 

EGFR mutation status, produce overall survival similar to docetaxel (GRADE=strong).

•	 There is insufficient data to support effectiveness of other drugs, or drugs in 

combinations, in second-line therapy (GRADE=moderate).

•	 The above second line studies are typically undertaken after evidence of disease 

progression, and should be distinguished from mainenance therapy, which is undertaken 

when a patient has at least stable disease during treatment (typically four cycles).

Toxicity of Second Line or Maintenance Agents

Analogous to the presentation in first line threatment, we present here a summary of Grade 3 or 4 

toxicities from selected trials of second line agents, some of which are also used in maintenance 

therapy. As noted before, comparisons across trials should be avoided, and “numbers are 

provided only to give a general sense of the toxicity of the regimens.”2

TABLE S4. Summary of Grade 3 or 4 Chemotherapy Toxicity (% Patients) from Large, Selected

Trials of Maintenance or Second-line therapy

Regimen Dose (mg/m2) and Administration

Schedule [Reference]

Skin RashDiarrheaInfection/ InfestationHypertensionFatigueBleedingNauseaFebrile NeutropeniaNeutropenia

Erlotinib 150 mg/day [Cappuzzo 2010155] 9 2 1 NR NR NR NR NR NR

Erlotinib 110 mg/daily [Ciuleanu 2012139] 5 18 NR NR 3 NR 5 NR NR

Bevacizumab 15 mg/kg; erlotinib 150 mg/

daily [Herbst 2011144] NR NR NR 15 NR 3 NR NR NR

Pemetrexed 500 mg/m2

 [Cullen 2008145] 0.3 1.4 2.4 NR 3.1 NR 1.4 1.4 2.1

Abbreviations: AUC = area under curve; hr = hour; mg=milligrams; m2

= meters squared; min = minutes; NR = not 

reported; NSCLC = non-small cell lung cancer.

KEY QUESTION 3. For patients with metastatic NSCLC what is the 

benefit of maintenance therapy following first line chemotherapy 

regimens compared with no maintenance therapy? 

We identified three systematic reviews of maintenance therapy published since 2010.3, 20, 156 Details 

of these systematic reviews are in Table M1. The most comprehensive and best quality review was 

completed by Zhang and colleague.3

 It met 10 of the 11 AMSTAR criteria and identified eight trials 

with a total of 3,736 patients with nonprogressing NSCLC. Trials were of either a continuous or 

switch strategy and were compared to either placebo or observation. Of the nine trials, three employed 

a continuous maintenance strategy157-159 while six utilized a switch strategy.155, 159, 160, 161-164
38

all Cell Lung Cancer Evidence-based Synthesis Program

matic Reviews Published Since 2010

was compared

Trials included; Total 

Number of Patients

First Author, Year

Title. Journal*

Outcomes Reported

Conclusions per abstract:

Overall Survival Progression Free Survival

Overall Response Rate

Adverse Events

Other 

Outcomes 

Reported

fitinib vs.

 BSC or observation; 

placebo and BSC; 

d erlotinib vs. 

d placebo; 

ervation

8 trials; 3,736 ptsCapuzzo, 2010Perol,2010Ciuleanu,2009Brodowicz, 2006Belani, 2010Fidias, 2009Miller, 2009Kabbinavar, 2010Surmont, 2010 X X X

Maintenance therapy with either a continuous or a switch strategy significantly increases OS and PFS compared with placebo or observation. However, the benefits must be balanced against toxicity.

rlotinib vs. Placebo

5 trials; 3,634 ptsCapuzzo, 2010Herbst,2005Perol,2010Ciuleanu,2009Paz-Ares,2011 X X

Maintenance therapy with either erlotinib or pemetrexed has clinically and statistically significant advantage over placebo observation.

nib vs. Placebo;

b + bevacizumab vs. 

2 trials; 1,768 ptsCapuzzo, 2009Miller, 2009 X X X X

Risk of death

Based on the results of the SATURN and ATLAS studies, the use of erlotinib as maintenance therapy is becoming a treatment option for patients with good performance status who respond to first-line chemotherapy.

ess (total patients, included trials)

leanu 2009), totaling 1,552 patients, that are included in Zhang 2011.

Capuzzo 2010 and Miller 2009), totaling 1,768 patients, that are included in Zhang 2011.

 Review, for Table M1. 

 Final results from the IFCT-GFPC 0502 phase III study: maintenance therapy in advanced NSCLC with either gemcitabine (G) or erlotinib (E) versus observa

nduction chemotherapy (CT), with predefined second-line treatment [abstract]. Ann Oncol. 2010; 21 (suppl 8): viii 124.

, et al; SATURN investigators. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo controlled phase 

521 - 529.

C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, 

9): 1432- 1440.

mized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemo

t of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) [abstract LBA8002]. J Clin Oncol. 2009; 27 (suppl 1): 18S.

 BE, et al. Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemothera

ment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) [abstract 7526]. J Clin Oncol. 2010; 28 (suppl): 15S.

r M, et al; Central European Cooperative Oncology Group CECOG. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or 

small cell lung cancer: a phase III trial. Lung Cancer. 2006; 52 (2): 155 - 163.
39

all Cell Lung Cancer Evidence-based Synthesis Program

H, et al. Phase III study of maintenance gemcitabine (G) and best supportive care

rd combination therapy with gemcitabine-carboplatin (G-Cb) for patients with advanced non-small cell lung cancer (NSCLC) [abstract 7506]. J Clin Oncol. 

. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non small-cell lung can

 598.

GV, et al. A double-blind, randomized, placebo-controlled phase III intergroup study of gefitinib (G) in patients (pts) with advanced NSCLC, non-progressing 

therapy (EORTC 08021-ILCP 01/03) [abstract]. Ann Oncol. 2010; 21 (suppl 8): viii 124.

, et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multi-centre, randomized, placebo-controlled phase 3 study. Lancet Oncol 

 al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung 

9.

C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomized, double-blind, 

-40

al. Maintenance with either gemcitabine or erlotinib versus observation with predefined second-line treatment after cisplatin–gemcitabine induction chemo

GFPC 0502 phase III study. J Clin Oncol 2010;28(Suppl):15s (abstr 7507)

M, et al. PARAMOUNT: Phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following 

splatin for advanced nonsquamous non-small cell lung cancer (NSCLC). J Clin Oncol 2011;29(Suppl):18s (abstr CRA7510) 

R, et al. Efficacy and safety of erlotinib as first-line maintenance in NSCLC following non-progression with chemotherapy: results from the phase III SATURN 

Conference on Lung Cancer IASCL 2009; 2009 Jul 31- Aug 4; San Francisco (CA).

 A randomized, double blind, placebo controlled, phase IIIb trial (ATLAS) comparing bevacizumab therapy with or without erlotinib, after completion of che

ine treatment of locally-advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) [abstract no. LBA8002]. J Clin Oncol 2009; 27: 18s.
40

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

In the trials examining continuous maintenance therapy, there was a trend towards benefits in 

the overall survival, however this did not quite reach statistical significance (HR=0.88; 95% CI: 

0.74-1.04; p=.15). There was no evidence of heterogeneity between the studies (p=.66, I2=0%). 

The first of these trials accrued 215 patients and continued patients on gemcitabine after an initial 

therapy of gemcitabine and cisplatin. Overall survival was 10.2 months in the maintenance group 

compared to 8.1 months in the best supportive care group (HR=0.79; 95% CI: 0.57-1.11).157

Another trial of 255 patients on gemcitabine following gemcitabine and cisplatin found overall 

survival to be 8 months in the maintenance group versus 9.3 months in the best supportive care 

group (HR=0.97; 95% CI: 0.72-1.30).158 The last of these trials accrued 309 patients, treating 

them with gemcitabine after gemcitabine and cisplatin and favored continued maintenance, 

though specific data were not reported.159

The six trials examining switch maintenance therapy found a clinically and statistically 

significant 15% improvement in OS when compared to the placebo or observation groups 

(HR=0.85; 95% CI: 0.79-0.92; p<.001). There was no evidence of heterogeneity (p=.77, I2=0%). 

There were two trials of cytotoxic agents. The first trial accrued 309 patients and treated patients 

with docetaxel after gemcitabine and carboplatin. The overall survival of the maintenance 

therapy group was 12.3 months compared to 9.7 months in the best supportive care group 

(HR=0.81, 95% CI: 0.63-1.03).165 The other trial included 663 patients treated with pemetrexed 

after platinum-doublet chemotherapy versus placebo and found overall survival to be 13.4 and 

10.6 months (HR=0.79, 95% CI: 0.65-0.95).164 There were four trials of molecular-targeted 

agents. Two trials were combined to give 768 patients treated with bevacizumab and either 

erlotinib or placebo after bevacizumab and platinum-doublet chemotherapy. The erlotinib group 

had an overall survival of 15.9 months versus 13.9 in the placebo group (HR=0.90, 95% CI: 

0.74-1.09; p=0.2686).161, 162 A trial of 889 patients receiving erlotinib or placebo after platinumdoublet chemotherapy found the overall survival to be 12 in the erlotinib group and 11 in the 

placebo group.155 Another study of erlotinib included 310 patients and compared it to observation 

following gemcitabine and cisplatin. The overall survival hazard ratio was 0.91 (95% CI: 0.80-

1.04) in favor of the maintenance therapy.159 The last of these studies included 173 patients 

treated with gefitinib or placebo after platinum-doublet chemotherapy and found an overall 

survival of 10.9 months in the treatment arm versus 9.4 months (HR=0.87, 95% CI: 0.80-0.95).163

Overall, these nine trials comprised 3,736 patients. When comparing continuous and switch 

maintenance therapies, the interaction test found no statistically significant difference in overall 

survival (HR=0.88 vs. 0.85; interaction p=0.78). This result was interpreted as meaning that there 

is no evidence to conclude superiority for either the continuous or the switch approach. Within 

the trials of switch maintenance, a subgroup analysis revealed that there was no statistically 

significant difference in overall survival between the cytotoxic and tyrosine kinase inhibitor 

agents. Again, the conclusion is that there is no evidence to support that one approach is superior 

to the other.

The other two systematic reviews were more targeted. The first review identified 5 trial including 

3,634 patients.156 Three of these trials were of erlotinib versus either placebo or gemcitabine. Two 

of the trials were of pemetrexed versus placebo. Two of the trials were included in the review 

by Zhang.155, 166 Both regimens led to significant improvement in overall survival compared with 

placebo or observation (erlotinib HR=0.90, 95% CI: 0.83-0.98; pemetrexed HR=0.79; 95% CI: 
41

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

0.65-0.95) and relative hazards ratio showed no significant difference between the two agents 

(HR=0.88; 95% CI: 0.71-1.08, p=0.22). These results are compatible with the conclusions of the 

review by Zhang and colleagues. However, pemetrexed was superior to erlotinib in the outcome 

of progression free survival. The other systematic review included the SATURN and ATLAS 

trials which studied erlotinib versus placebo and erlotinib and bevacizumab versus bevacizumab 

alone.20 There were 2 trials including 1768 patients. In the SATURN trial, patients in the 

erlotinib arm had a better response rate (12% vs 5%), PFS (12 vs. 11.1 weeks; HR=0.71; 95% 

CI: 0.62,0.82; p<0.0001) and better overall survival (12 vs. 11 months, HR=0.81, 95% CI: 0.70, 

0.95; p=0.0088). The ATLAS trial found an improvement in progression free survival of 4.76 

versus 3.75 months (HR=0.722; 95% CI: 0.592, 0.881; p<0.0012). 

Finally, we identified four additional trials.167-171 Details of these trials are presented in Table M2. 

The first was a quality of life assessment of the study by Ciuleanu, included in the systematic 

review by Zhang.168 This trial treated 663 patients with pemetrexed or placebo after platinumbased therapy. The primary outcome was time to worsening of symptoms and this was longer 

in the pemetrexed group for pain (HR=0.76, 95% CI: 0.59-0.99; p=0.041) and hemoptysis 

(HR=0.58, 95% CI: 0.34-0.97; p=0.038). The PARAMOUNT trial of pemetrexed versus 

placebo treated 539 patients who had undergone therapy with pemetrexed and cisplatin.167

Within the 359 patients treated with pemetrexed, there was a significant reduction in the 

risk of disease progression compared to the placebo group (HR=0.62, 95% CI: 0.49-0.79; 

p<0.0001). In addition, the median progression free survival in the pemetrexed group was 

4.1 months (95% CI: 3.2-4.6) versus 2.8 months (95% CI: 2.6-3.1) in the placebo group. The 

results of the PARAMOUNT trial were recently updated in abstract form at the 2012 ASCO 

Annual Meeting.171 Continuation maintenance therapy with pemetrexed resulted in a 22 percent 

reduction in the risk of death at a median follow-up of 12.5 months.The INFORM trial by Zhang 

and colleagues randomized Chinese patients with advanced NCSLC who had received four 

cycles of platinum-based doublet therapy to gefitinib pr placebo.170 Progression-free survival 

was approximately doubled from 2.6 to 4.8 months; there was no difference in overall survival. 

Adverse events, primarily rash, diarrhea, and liver function abnormalities, were much more 

common in patients taking gefitinib. Lastly, there was a trial of thalidomide versus placebo in 

722 patients who had been treated with gemcitabine and carboplatin.169 Thalidomide did not 

improve overall survival as the median duration in the placebo group was 8.9 months compared 

to 8.5 months in the thalidomide arm (HR=1.13, 95% CI: 0.97-1.32; p=.12). Unfortunately, 

the risk of thrombotic stroke was increased by 74% in the thalidomide group (HR=1.74, 95% 

CI: 1.20-2.52; p=.003). In addition survival was significantly worse in those patients who had 

nonsquamous histology. In summary, two of these trials reported benefits in additional outcomes 

for maintanence therapy with pemetrexed compared to placebo, while two other trials did not 

support any beneficial clinical effect for maintenance treatment with paclitaxel or thalidomide.
42

all Cell Lung Cancer Evidence-based Synthesis Program

ed in Existing Systematic Reviews

Maintenance following

Treatments being compared Outcomes Conclusions per abstract:

Four cycles of platinumbased induction therapy

Best supportive care plus placebo or pemetrexed (500 mg/m2 every 21 days)

QOL (Lung Cancer Symptom Scale)

Longer time to worsening was recorded for pain (hazard ratio [HR] 0.76, 95% CI: 0.59-0.99; p = 0.041) and haemoptysis (HR=0.58, 95% CI: 0.34-0.97, p = 0.038) with pemetrexed than with placebo; no other significant differences in analyses of time to worsening were noted. Additional longitudinal analyses showed a greater increase in loss of appetite in the pemetrexed group than in the placebo group (4.3 mm vs. 0.2 mm; p=0.028).Quality of life during maintenance therapy with pemetrexed is similar to placebo, except for a small increase in loss of appetite, and significantly delayed worsening of pain and haemoptysis. In view of the improvements in overall and progression-free survival noted with pemetrexed maintenance therapy, such treatment is an option for patients with advanced non-squamous NSCLC who have not progressed after platinum-based induction therapy.

Induction 

therapy with pemetrexed plus cisplatin

Best supportive care plus either placebo or maintenance with pemetrexed (500 mg/m2 every 21 days)

Progression-free survival; adverse eventsOverall survival

Among the 359 patients randomized to continuation maintenance with pemetrexed, there was a significant reduction in the risk of disease progression over the placebo group (HR=0.62, 95% CI: 0.49-0.79, p<0.0001). The median progression-free survival, measured from randomization, was 4.1 months (95% CI: 3.2-4.6) for pemetrexed and 2.8 months (2.6-3.1) for placebo.Continuation maintenance with pemetrexed is an effective and well tolerated treatment option for patients with advanced non-squamous NSCLC with good performance status who have not progressed after induction therapy with pemetrexed plus cisplatin.Continuation maintenance therapy with pemetrexed resulted in a 22 percent reduction in the risk of death at a median follow-up of 12.5 months.

Four cycles of platinum-based doublet therapy

Gefitinib (250 mg/day) or placebo

Overall survival, progression-free survival, adverse events

Progression-free survival was significantly longer with gefitinib (n=148) than placebo (n=148) (median progression-free survival of 4.8 months [95% CI: 3.2-8.5] vs. 2.6 months [95% CI: 1.6-2.8]; hazard ratio [HR]: 0.42, 95%CI: 0.33-0.55, p<0.0001). Adverse events occurred more frequently with gefitinib placebo. 

Gemcitabine 

and carboplatin every 3 weeks for 4 cycles

Thalidomide or 

placebo capsules (100-200 mg/daily) beginning at the start of chemotherapy and continuing for up to 2 years.

Overall survival, progression-free survival, response rate, grade 3/4 toxicity, and quality of life

The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI: 0.97-1.32; P=.12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI: 1.20-2.52; P=0.003).In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous history.
43

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Summary of Key Question 3: Maintenance Therapy

•	 Maintenance therapy improves overall survival (GRADE=High).

•	 Maintenance therapy with gefitinib significantly prolonged preogression-free survival 

compared with placebo in patients from east Asia with advanced NSCLC who achieved 

disease control after first-line chemotherapy (GRADE=high).

•	 There is insufficient evidence to reach conclusions regarding whether a continuous or a 

switch strategy is superior (GRADE=Very low). However, two drugs have been approved 

for switch therapy.

•	 Differences in survival in placebo-controlled trials of erlotinib or cytotoxic agents 

are sufficiently small that head-to-head comparisons will be required before strong 

conclusions can be reached about comparative effectiveness.

KEY QUESTION 4. What is the relative cost and cost-effectiveness of 

the different approaches in Key Questions 1-3? 

Our literature review identified one systematic review of cost-effectiveness analyses and 21 

cost-effectiveness analyses published since 2010. Of the latter, eight analyses concerned firstline therapy, seven analyses concerned second-line therapy, six analyses concerned maintenance 

therapy, and one concerned third line therapy. A single publication could deal with more than 

one kind of therapy. Eleven analyses assessed erlotinib, nine analyses assessed pemetrexed, 

five analyses assessed bevacizumab, five analyses assessed docetaxel, and a number of other 

agents were assessed less frequently (analyses could assess more than one agent). Four studies 

assessed cost-effectiveness from a US payor perspective, while the remainder used non-US payor 

perspectives. Almost all studies used life expectancy or quality-adjusted life years (QALYs) as 

the measure of outcome. Details about the 22 analyses are presented in Table CE1.

The systematic review by Bongers and colleagues was published in 2012 and searched PubMed, 

EMBASE, and the Health Economic Evaluations database from 2001 through October 2010. The 

authors identified 6 prior systematic reviews, six cost-effectiveness analyses, and 6 cost-utility 

analyses. Four assessments of first-line therapy were included, as were 6 assessments of secondline therapy. The authors noted numerous methodological weaknesses in the included studies. 

Their overall conclusions were:

•	 Due to the small number of studies, heterogeneity between studies and lack of a clear and 

consistent definition of best supportive care in each study, strong conclusions cannot be 

drawn

•	 The estimates of key parameters, model assumptions, and calculations in modeling 

studies were often poorly reported.

•	 However, there was reasonable consensus between studies that gemcitabine-cisplatin 

is a cost-effective option for first-line treatment of non-small cell lung cancer, although 

pemetrexed-cisplatin appears more effective for non-squamous-cell carcinoma

•	 In second line treatment, docetaxel appears to be cost-effective compared with best 

supportive care, while erlotinib may be a cost-effective alternative compared to 

docetaxel. 
44

all Cell Lung Cancer Evidence-based Synthesis Program

Analyses Published Since 2010

h treatments are 

assessed?

Where are the data 

from?

Perspective of 

the analysis*

Outcome used

QUALYs Conclusions per abstract:

Life expectancy

Other

atin

Single study: J Clin Oncol 2005; 23 (suppl): Abstract 7138

Non-US payer X The addition of rh-endostatin to standard first-line chemotherapy is unlikely to be cost-effective

mab Single study: ECOG4599 US payer X Bevacizumab does not appear to be cost-effective when added to chemotherapy in patients with advanced NSCLC

mab Multiple studies Non-US payer X X BevCG (bevacizumab + cisplatin + gemcitabine) is more costly but associated with additional life years in Korea and Taiwan

b Single study: FLEX Non-US payer X

The addition of cetuximab to standard first-line chemotherapy in patients with epidermal growth factor receptor-expressing advanced NSCLC cannot be recommended to date, due to a high Incremental Cost-Effectiveness Ratio compared with other health care interventions

mab Multiple studies

Societal perspective is France, Germany, Italy, Spain

Progression free survival

Bevacizumab-based treatment can result in substantial cost savings in progression-free patients with metastatic NSCLC

mab, pemetrexed Multiple studies Non-US payer X

Clinical benefits with bevacizumab plus cisplatin and gemcitabine therapy are achieved at a lower monthly cost than pemetrexed plus gemcitabine doublet therapy

mab, pemetrexed Multiple studies Non-US payer X

Bevacizumab-based therapy can be considered as a cost-effective option when 

compared to chemotherapy treatments such as pemetrexed for the treatment of advanced NSCLC

in and paclitaxel Single study: Chang Mai Hospital Non-US payer X Carboplatin plus paclitaxel are not cost-effective at a threshold of 100,000 Baht (Thailand)

BR.21 trial database, Canada Non-US payer

Incremental cost-effectiveness ratio (2007 Canadian dollars to life-years gained)

With an incremental cost-effectiveness ratio of $94,638 per life-year gained, erlotinib treatment for patients with previously treated advanced non–small cell lung cancer is marginally cost-effective. The use of molecular predictors of benefit for targeted agents may help identify more or less cost-effective subgroups for treatment.

ed, docetaxel Non-US payer; Spain Pemetrexed as a second-line treatment option for patients with a predominantly non-squamous histology in NSCLC is a cost-effective alternative to docetaxel according to the € 30000/QALY threshold commonly accepted in Spain.

, pemetrexed, erlo- 

inib Single study: IN- TEREST Non-US payer X Gefitinib is a dominant cost-saving strategy compared with docetaxel
45

all Cell Lung Cancer Evidence-based Synthesis Program

h treatments are 

assessed?

Where are the data 

from?

Perspective of 

the analysis*

Outcome used

QUALYs Conclusions per abstract:

Life expectancy

Other

docetaxel Single study: Own institution data

Non-US payerPayor perspective is Canadian provincial health care system

X Erlotinib and docetaxel are statistically equivalent in terms of treatment cost and overall survival

, gefitinib 

 therapy is assessed Single study: INTEREST Non-US payer Canada cost perspective X Adverse events The modest increase in cost associated with gefitinib supports its use as an alternative to docetaxel as second-line treatment of advanced NSCLC particularly given the improvements in QoL, patient preference for oral therapy and better toxicity profile with gefitinib

, pemetrexed Single study: GFPC 05-06 Non-US payer X Adverse events Second line treatment for NSCLC is more cost-effective with docetaxel than with pemetrexed

docetaxel Multiple studies

Non-US payerFrom perspective of UK NHS, probably relevant to VA

X

In general, erlotinib appeared to generate similar overall survival, an increase in QALYs and a small reduction in NHS costs compared with docetaxel, due to lower adverse event and drug administration costs

Single study: SATURN Non-US payer X Erlotinib is a cost-effective treatment option when used as first line maintenance therapy

ed Multiple studies

Non-US payerPayor perspective is Swiss Health Care System

X Switch maintenance with pemetrexed inpatients with advanced nonsquamous- cell lung cancer is not cost-effective

pemetrexed Multiple studies Non-US payer X Adverse events

Erlotinib appears to be a cost-saving treatment alternative to pemetrexed, producing comparable survival benefits, based on indirect comparison at a lower cost

pemetrexed Multiple studies Non-US payer Adverse events Erlotinib maintenance therapy in patients with advanced NSCLC causes lower AE management costs then pemetrexed maintenance therapy

Single study: Own institution US payer Costs The overall budget impact to a health plan of expanding the use of erlotinib from the 2nd/3rd line advanced NSCLC setting to maintenance setting was relatively small

ed, bevacizumab, 

nsquamous NSCLC

Multiple studies US payer X

Compared with observation and other agents used and/or reimbursed for maintenance therapy in advanced NSCLC, pemetrexed may be considered costeffective, particularly in patients with nonsquamous cell histology

 therapy is assessed Single study: Local Data Non-US payer X X Erlotinib may be an effective and cost-effective third-line treatment for advanced NSCLC compared to best supportive care
46

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Our review identified 22 cost-effectiveness analyses published since 2010, of which four 

overlapped with the systematic review by Bongers and colleagues. We obtained additional 

information from our TEP to focus our assessment on the following key sub-questions:

First-line Therapy

• Which platinum-doublet is the most cost-effective therapy in squamous and in nonsquamous histology types?

• In non-squamous NSCLC, is the carboplatin-paclitaxel-bevacizumab option more costeffective than platinum-pemetrexed?

Second-line Therapy

• Which of the three approved agents (docetaxel, pemetrexed for non-squamous histology, 

or erlotinib) is more cost-effective? 

Maintenance Therapy

• Which approach is more cost-effective: switch maintenance with pemetrexed, 

continuation maintenance therapy with pemetrexed or erlotinib?

Key Sub-question 4.1. Which platinum-doublet is the most cost-effective therapy 

in squamous and in non-squamous histology types?

The review by Bongers and colleagues concluded that there was a “reasonable consensus” that 

gemcitabine + cisplatin was more cost-effective than other doublet options assessed.172 In the 

three studies used to reach this conclusion, the comparison options were paclitaxel-cisplatin, 

gemcitabine-paclitaxel, docetaxel-cisplatinum, vinorelbine-cisplatin, and pemetrexed-cisplatin. 

The payer perspectives were the Dutch health insurance system, the UK health care system, and 

a US payer. The study assessing pemetrexed (discussed in more detail, below) concluded that 

pemetrexed-cisplatin is more cost-effective than cisplatin-gemcitabine for patients with nonsquamous disease.

Our search identified eight cost-effectiveness analyses of first-line therapy, but two dealt 

with agents that were not of interest (rh endostatin173 and cetuximab174) and five dealt with 

bevacizumab (discussed below). Of the remaining two, one assessed the cost-effectiveness 

of cisplatin + etoposide compared to carboplatin + paclitaxel, using data from a single Thai 

hospital,175 and was judged by our TEP to be not of interest for this review. Thus, there are no 

new cost-effectiveness analyses since the review by Bongers and colleagues that are relevant 

to this key sub-question. However, Key Question 1 for this review, about first-line therapy, 

identified one high quality systematic review by the CCO that concluded that “a combination 

of a platinum agent plus a new agent continues to be the standard of care” and “as differences 

between regimens are small, toxicity and patient preference should help guide regiment choice.”2

However, the CCO does note the meta-analysis by Le Chevalier that reported a trend toward 

improved survival with gemcitabine combinations. Eight clinical trials published since that 

review was completed in aggregate reach the same conclusion – no particular combination has 

been shown to be consistently superior in terms of effectiveness outcomes. In the absence of 

clinically important differences in effectiveness, then differences in the costs of the agents, and 
47

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

possibly the cost of treating different treatment toxicities, will drive any differences in costeffectiveness. An addendum to the CCO review, restricted to pemetrexed, concluded that “data 

are compelling to recommend that pemetrexed should not be used in the treatment of squamous 

cell carcinomas for first line treatment” and “on the other hand, these data are not sufficiently 

compelling to recommend that pemetrexed be used preferentially over all other new agents in 

doublet therapy to treat adenocarcinoma in first line settings.”

Key Sub-question 4.2. In non-squamous NSCLC, is the carboplatin-paclitaxelbevacizumab option more cost-effective than platinum-pemetrexed?

This combination was not assessed in the review by Bongers and colleagues, but the costeffectiveness of bevacizumab was the subject of five recent cost-effectiveness analyses, although 

none were of exactly this comparison. Four of these analyses were supported by the maker of 

bevacizumab.176, 177, 178 , 179 All three concluded that bevacizumab was a cost-effective approach to 

care in the following situations: bevacizumab + cisplatin + gemcitabine compared to pemetrexed 

+ cisplatin in non-squamous cell histology, using an Italian payer perspective;178 bevacizumab 

+ cisplatin + gemcitabine compared to cisplatin + pemetrexed in non-squamous cell histology, 

using a Korean and Taiwanese health payer perspective;176 the same combination using the 

payer perspective of Italy and Germany;179 and an analysis that combined together the results 

of two trials, which compared the addition of bevacizumab to either cisplatin + gemcitabine or 

carboplatin + paclitaxel, and used a societal perspective including time off from work in France, 

Germany, Italy and Spain.177

The one non-industry funded analysis used a US payer perspective and compared the addition 

of bevacizumab to carboplatin + paclitaxel versus carboplatin + paclitaxel alone.180 Data about 

outcomes came from the ECOG 4599 trial. Costs came from Medicare data. The discount rate for 

future costs and QALYs was 3% per year. The main result was the incremental cost-effectiveness 

ratio (ICER). Numerous sensitivity analyses were performed. The principal result was that the 

ICER was $560,000 per QALY gained, or $309,000 per life-year gained, for the addition of 

bevacizumab to the carboplatin + paclitaxel treatment. The results were most sensitive to the 

time for survival without progression while on treatment and the number of bevacizumab cycles. 

In order to reach a value of $100,000 per QALY gained, the addition of bevacizumab would have 

to result in a mean overall survival advantage of 1.3 years (while holding other model parameters 

constant). Alternatively, in order to reach the same $100,000/QALY threshold, the acquisition 

cost of bevacizumab would have to drop to $885, all other model parameters being held constant. 

The overall conclusion of the authors was that “bevacizumab does not appear to be cost-effective 

when added to chemotherapy in patients with advanced NSCLC, based on approximate costeffectiveness thresholds that have been identified in the United States.”

Key Sub-question 4.3 Which of the three approved agents (docetaxel, pemetrexed 

for non-squamous histology, or erlotinib) is more cost-effective? 

The review by Bongers and colleagues concluded that “docetaxel appears to be cost-effective 

compared to best supportive care, while erlotinib may be a cost-effective alternative compared 

with docetaxel.”172 These conclusions were based on the results of 6 cost-effectiveness analyses, 

3 of them published in 2010 and this also included in our assessment.181-183 The other 3 analyses 

assessed the cost-effectiveness of docetaxel, in two of these docetaxel was compared to best 
48

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

supportive care and in one compared to pemetrexed and erlotinib. The two cost-effectiveness 

analyses comparing docetaxel with best supportive care both concluded that second line 

treatment with docetaxel had an incremental cost-effectiveness ratio well under conventional US 

thresholds for considering a treatment to be cost-effective: about $32,000 in one study and about 

$20,000 in the other. The third study assessed second line treatment with docetaxel, pemetrexed, 

and erlotinib. That analysis assumed that survival with all 3 treatments was equal, but that there 

was a very slight advantage in QALYs for erlotinib due to fewer adverse events. That, plus the 

oral administration of erlotinib, led to the finding that erlotinib second line treatment is more 

cost-effective than pemetrexed or docetaxel. It is unclear whether or not EGFR mutation status or 

cell histology was considered in this analysis.

Our search identified 7 cost-effectiveness analyses of second line treatment published since 2010. 

Of these, two analyses assessed erlotinib compared to docetaxel,181, 184 two analyses assessed the 

gefitinib compared to docetaxel using data from the INTEREST trial,185, 186 two analyses assessed 

pemetrexed versus docetaxel,183, 187 and one analysis assessed erlotinib compared to placebo using 

data from the BR.21 trial.182

The assessment of erlotinib compared to placebo used data from the BR.21 study and the actual 

resource use of the patients enrolled in the trial.182 Resources were converted into Canadian 

health care costs. Discounting was not used because median survival was only 1 year. The 

principal finding was the incremental cost-effectiveness ratio of adding erlotinib was $94,000 

(Canadian) for life-year gained. In sensitivity analyses, the main driver was the magnitude 

of the survival benefit. Particular subgroups had more favorable ICERs, corresponding to the 

increased effectiveness of erlotinib in these subgroups: never smoked = $39,000; EGFR protein 

expression positive = $64,000; EGFR gene copy number high = $33,000. The authors concluded 

that “erlotinib treatment is...marginally cost-effective. The use of molecular predictors of benefit 

for targeted agents may help identify more or less cost-effective subgroups for treatment.” The 

publication states that the analysis was supported by the University of Toronto.

The two analyses comparing erlotinib to docetaxel used different data sources and reached 

somewhat different conclusions. The first study was supported by the maker of erlotinib and 

used data from the BR.21 study to estimate the benefits of erlotinib and data from the TAX317 

study to estimate the benefits of docetaxel, and concluded that erlotinib had a small reduction in 

UK National Health Services costs relative to docetaxel.181 The second study was supported by 

the Canadian Center for Applied Research in Cancer Control and used observational data from 

patients treated in British Columbia.184 This study found that the difference in mean overall survival 

between patients treated with erlotinib or docetaxel was 1 day, and the mean difference in cost 

was less than $3000; neither difference was statistically significant. The authors concluded that 

“erlotinib and docetaxel are statistically equivalent in terms of treatment cost and overall survival.”

The two analyses of the comparing gefitinib to docetaxel both used data from the INTEREST

trial for their estimates of effectiveness. One study was supported by two hospitals in Toronto,185

while the other does not state how it was supported.186 The latter study used a Thai payer 

perspective and concluded the gefitinib is cost-saving compared to docetaxel. The former study 

used the Canadian health care system perspective, and found an increase in costs with gefitinib 

use ($5161 per patient). The main driver of cost was the cost of the drug. No incremental cost-
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

effectiveness ratio, in terms of life-years or QALYs, was presented. The authors concluded 

that “the modest increase in cost associated with gefitinib supports its use as an alternative to 

docetaxel as second-line treatment of advanced NSCLC.”

The two analyses comparing docetaxel to pemetrexed were both supported by the makers of 

the drugs in question. The analysis supported by the maker of docetaxel concluded that “second 

line treatment for NSCLC is more cost-effective with docetaxel that with pemetrexed.”187 The 

analysis supported by the maker of pemetrexed concluded that “pemetrexed as a second-line 

treatment option for patients with a predominantly non-squamous histology in NSCLC is a costeffective alternative to docetaxel.”183

Key Sub-question 4.4. Which approach is more cost-effective: switch 

maintenance with pemetrexed, continuation maintenance therapy with 

pemetrexed or erlotinib?

Only one cost-effectiveness analysis was included in the review by Bongers and colleagues, 

published in 2010, and we also include it in our assessment here.188 We identified 6 costeffectiveness analyses of maintenance therapy published since 2010. Of these, 2 analyses 

assessed erlotinib,189, 190 2 assessed pemetrexed,188, 191 and 2 assessed erlotinib compared to 

pemetrexed.192, 193 All but one study were supported by the manufacturers of either erlotinib 

or pemetrexed. The two studies of erlotinib funded by the makers of erlotinib concluded that 

“erlotinib is a cost-effective treatment option when used as first-line maintenance therapy for 

locally advanced or metastatic NSCLC”189 and “the overall budget impact to a health plan of 

expanding the use of erlotinib from the second/third line advanced NSCLC setting to include 

the maintenance setting was relatively small”.190 The one analysis supported by the maker of 

pemetrexed concluded that “compared with observation and other agents used and/or reimbursed 

for maintenance therapy in advanced NCSLC, pemetrexed may be considered cost-effective, 

particularly in patients with non-squamous cell histology.”188 The two analyses comparing 

erlotinib to pemetrexed, both of which were supported by the maker of erlotinib, concluded 

“erlotinib appears to be a cost-saving treatment alternative to pemetrexed, producing comparable 

survival benefits, based on indirect comparisons, at a lower cost”193 and “erlotinib maintenance 

therapy in patients with advanced NSCLC causes lower adverse event management costs than 

pemetrexed maintenance therapy indicating a potentially superior tolerability profile”.192

The one study that was not industry supported came from Swiss researchers and assessed the 

incremental cost-effectiveness ratio of adding pemetrexed to best supportive care, compared to 

best supportive care alone.191 Data came from the study by Ciuleanu.164 The model used a lifetime cost horizon using a Swiss health care perspective. No discount rate was used. The principal 

results were that the addition of pemetrexed resulted in an incremental cost-effectiveness ratio 

of 106,202 Euros/QALY (approximately $145,000/QALY). The results were most sensitive 

to assumptions about the utility of being in the stable disease state and then the costs of 

best supportive care in the pemetrexed-treated patients. The authors concluded that “switch 

maintenance therapy with pemetrexed in patients with advanced nonsquamous-cell lung cancer 

after standard first-line chemotherapy is not cost-effective.”191

Additional evidence to consider for this sub-question comes from that reported in Key Question 

3 in this report, about maintenance therapy. A systematic review and meta-analysis by Zhang 
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

and colleagues3 was unable to support clinically important differences between the switch 

and the continuous approach to maintenance therapy, and equally unable to support clinically 

important differences between switch therapy with cytotoxic agents and therapy with tyrosine 

kinase inhibitors. Of note, the number of original trials for assessment are small, and there are 

no published head-to-head comparisons of maintenance therapy with erlotinib compared to 

pemetrexed, meaning any conclusions must be made on indirect comparisons.

Summary of Key Question 4

There are a large number of published cost-effectiveness analyses, but approximately two-thirds 

of such studies are supported by the makers of the drugs being assessed. Invariably, studies 

supported by the makers concluded that their drug was cost-effective. Of the cost-effectiveness 

analyses not supported by industry, the addition of bevacizumab to first-line therapy was found 

in one study to be not cost-effective, erlotinib was found in one study to be marginally costeffective, and the differences between erlotinib and docetaxel maintenance therapy were slight in 

another study (GRADE=low). 
51

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

SUMMARY AND DISCUSSION

SUMMARY OF EVIDENCE BY KEY QUESTION

Key Question 1. First-line therapy

•	 Key Sub-question 1.1. New trials continue to support the conclusion by the CCO that 

any differences in survival between platinum-based doublets are modest (GRADE=High).

•	 Key Sub-question 1.2. This result continues to support the conclusions by the CCO that 

doublet chemotherapy including a platinum agent has a higher survival rate and a higher 

response rate than a single agent (GRADE=High).

•	 Key Sub-question 1.3. New trials continue to support the conclusion by Goffin and 

colleagues that any differences in outcomes between platinum-based agents are modest 

(GRADE=High).

•	 Key Sub-question 1.4. New trials continue to support the conclusion by the CCO that 

doublet chemotherapy including a platinum agent probably has a slight advantage over 

nonplatinum doublets (GRADE=moderate).

•	 Key Sub-question 1.5. One new trial does not alter the conclusion by the CCO that 

cisplatin combinations may have a slight advantage over carboplatin combinations in 

terms of survival and response rate. However, carboplatin generally has a milder toxicity 

than cisplatin (GRADE=moderate).

•	 Key Sub-question 1.6. New trials continue to support the review by the CCO that triplet 

cytotoxic therapy might have some slight advantages in terms of response rate but at an 

increased risk of toxicity (GRADE=High).

•	 Key Sub-question 1.7. New trials of a number of novel targeted agents have so far failed 

to find results equivalent to the increases in progression-free survival seen with erlotinib 

(mostly in patients who have never smoked) and bevacizumab (in an Asian population 

subgroup analysis) in the CCO review (GRADE=moderate).

•	 Key Sub-question 1.7.1 Erlotinib or gefitinib monotherapy is in general superior in terms 

of beneficial outcomes and adverse events than cytotoxic chemotherapy in patients with 

EGFR mutations (GRADE=high).

•	 Key Sub-question 1.12. With the exception of studies of gefitinib and erlotinib 

monotherapy (in patients with EGFR mutations), doublet chemotherapy probably has a 

slight benefit in terms of survival compared to singlet therapy, but causes more toxicity 

(GRADE=moderate). Also, there now has been one trial of platinum therapy in the 

elderly taken to completion that found a near-doubling of the proportion of patients alive 

at one year in the doublet therapy group compared to monotherapy. 
52

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

Summary of Key Question 2: Second-line therapy

The conclusions from the seven systematic reviews can be summarized as:

• doublet second line cytotoxic therapy might offer slight benefits in progression-free 

survival and response rate, not overall survival, but at a cost of increased toxicity;

• erlotinib produces modest increases in overall survival; and

• in one phase II study, the addition of bevacizumab to second line treatment resulted in 

improvements in survival that were not statistically significant.

The summary of these trials not included in existing systematic reviews is:

• Considering data from first line and maintenance therapy studies in addition to second 

line studies, there are sufficient data to support the conclusion that histology type 

influences the effectiveness of potential treatments. Pemetrexed is more effective 

in nonsquamous NSCLC, while docetaxel is more effective in squamous NSCLC 

(GRADE=moderate).

• Tyrosine kinase inhibitors, when used as second-line therapy in patients unselected for 

EGFR mutation status, produce overall survival similar to docetaxel (GRADE=strong).

• There is insufficient data to support effectiveness of other drugs, or drugs in 

combinations, in second-line therapy (GRADE=moderate).

• The above second line studies are typically undertaken after evidence of disease 

progression, and should be distinguished from mainenance therapy, which is undertaken 

when a patient has at least stable disease during treatment (typically four cycles).

Summary of Key Question 3: Maintenance Therapy

• Maintenance therapy improves overall survival (GRADE=high).

• Maintenance therapy with gefitinib significantly prolonged preogression-free survival 

compared with placebo in patients from east Asia with advanced NSCLC who 

achieved disease control after first-line chemotherapy (GRADE=high).

• There is insufficient evidence to reach conclusions regarding whether a continuous or a 

switch strategy is superior (GRADE=very low). However, two drugs have been approved 

for switch therapy.

• Differences in survival in placebo-controlled trials of erlotinib or cytotoxic agents 

are sufficiently small that head-to-head comparisons will be required before strong 

conclusions can be reached about comparative effectiveness.

Summary of Key Question 4: Cost-Effectiveness Analyses

There are a large number of published cost-effectiveness analyses, but approximately two-thirds 

of such studies are supported by the makers of the drugs being assessed. Invariably, studies 

supported by the makers concluded that their drug was cost-effective. Of the cost-effectiveness 

analyses not supported by industry, the addition of bevacizumab to first-line therapy was found 

in one study to be not cost-effective, erlotinib was found in one study to be marginally costeffective, and the differences between erlotinib and docetaxel maintenance therapy were slight in 

another study (GRADE=low). 
53

Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

LIMITATIONS

• Some comparisons of interest have not been studied in direct head-to-head studies, leaving

comparisons to be made using indirect methods. Such indirect methods are highly susceptible 

to bias and are less reliable when differences between agents are small, as in this review.

• There is a paucity of cost-effectiveness analyses by someone other than the maker of the drug.

SUMMARY 

Despite a great many new clinical trials published since 2007, evidence continues to support 

most of the NCCN guidelines as reported in the topic nomination brief. 

Topic Nomination Brief Statement about NCCN Guidelines for FirstLine Therapy of NSCLCNew Evidence

All chemotherapy regimens recommended on the NCCN website involve 

the use of cisplatin (or carboplatinum when cisplatinum is not tolerated).

Platinum doublets remain the standard of care. The exception 

would be EGFR mutation positive patients, for whom erlotinib or 

gefitinib monotherapy provides superior progression-free survival 

and fewer serious side effects. 

Bevacizumab +chemotherapy or chemotherapy alone for performance 

status (PS) 0-1 \

The addition of bevacizumab probably yields added benefit, but 

with increased cost and toxicity. One cost-effectiveness analysis 

estimated the incremental cost-effectiveness ratio of adding 

bevacizumab at $560,000 per QALY gained. 

Cetuximab + vinorelbine/cisplatin is also an option for PS 0-1 We identified only one new trial of cetuximab, in combination 

with standard chemotherapy, reporting no additional benefit. 

The guidelines note that there is superior efficacy and decreased toxicity 

with cisplatin/pemetrexed in patients with non-squamous histology when 

compared with cisplatin/gemcitabine 

Pemetrexed is clearly less active in squamous histology cancers. 

While not conclusively proven, data support the conclusion that 

pemetrexed is probably the preferable agent in non-squamous 

histology. They also note that there is superior efficacy for cisplatin/gemcitabine in 

patients with squamous pathology when compared to cisplatin/pemetrexed 

Two cytotoxic agents are recommended----the guidelines state that 3 

increases response rates but not survival 

New systematic reviews and new trials of triplet therapy report 

increases in response rate and toxicity compared to doublet 

therapy, but has not increased overall survival.

Single agent therapy or platinum based therapy are reasonable 

alternatives in PS 2 patients or elderly patients 

New studies suggest doublet therapy might slightly increase 

survival in elderly patients, but with increased toxicity.

In locally advanced NSCLC, concurrent chemotherapy and thoracic 

radiation (RT) is superior to RT alone and sequential chemo followed by 

RT 

We did not look at evidence on radiation therapy.

New agent/nonplatinum combinations are reasonable alternatives if data 

show activity and tolerable toxicity 

New evidence supports that differences between doublet therapies, 

whether platinum-based or otherwise, are modest. 

Erlotinib is indicated as a first-line therapy in patients with EGFR mutations This conclusion is strongly supported by new evidence. 

Crizotinib is indicated as a first-line therapy in patients that are ALK 

positive 

We did not identify new evidence about crizotinib. 

RECOMMENDATIONS FOR FUTURE RESEARCH

Since VA policy makers are greatly interested about cost-effectiveness in the VA setting a proper 

cost-effectiveness analysis, using VA data and adjusting the population characteristics for VA 

patient characteristics, is needed to reach strong conclusions about cost-effectiveness of these 

drugs in VA setting. Such a study should be possible by combining data from this review on 

effectiveness with data from VA databases on the number of patients being trated, how they are 

being treated, the resources used, and their outcomes. Sensitivity analysis can be used to estimate 

the degree to which baseline assumptions would need to change in order to reach different 

concusions about cost-effectiveness. 
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