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

EXECUTIVE SUMMARY

BACKGROUND

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

Most patients with lung cancer are diagnosed when the cancer is already advanced (stage III or 

IV), and they are no longer candidates for surgical resection. Small cell lung cancer and nonsmall cell lung cancer (NSCLC) are treated as different diseases in terms of therapy. 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 NSCLC. 

The key questions were:

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?

METHODS

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

systematic reviews; 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 

relating to advanced non-small cell lung cancer and cost-effectiveness analyses. The second 

step was to identify relevant clinical trials, which we identified 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 both searches to peer-reviewed, English language literature. 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.

For systematic reviews and cost-effectiveness analyses to be included, they 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 III, 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. We 

did not exclude studies based solely on having assessed a drug not in current NCCN guidelines, 
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

as guidelines can change and in part do so in response to systematic reviews of evidence. To be 

included trials had to address first line, second line, or maintenance therapy for advanced nonsmall cell lung cancer. 

DATA SYNTHESIS

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

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

data pertinent to first-line therapy. This report was divided into sub-questions, into which we 

sorted the systematic reviews and trials identified by our search strategies. For Key Question 

#2 (second-line therapy), we created three evidence tables and narratively summarized the 

findings. The first evidence table presents data for the relevant systematic reviews, the second 

maps all relevant identified trials to the systematic reviews, and the final evidence table presents 

more detailed data for trials not included in the existing identified systematic reviews. For Key 

Question #3 (maintenance therapy), we identified a good quality, comprehensive recent review. 

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 

and the second presents data for relevant identified trials not included in the existing systematic 

reviews. For Key Question #4 (cost-effectiveness analyses), evidence table data are organized 

by therapy type. After obtaining input from our TEP, we focused on specific cost-effectiveness 

analyses of greatest interest.

PEER REVIEW

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

leadership. Reviewer comments were addressed and our responses were incorporated in the final 

report.

RESULTS

We screened 736 titles for systematic reviews and cost-effectiveness analyses and 820 titles 

for trials. We screened 88 potential systematic reviews and cost-effectiveness analyses in more 

detail. From these, we identified 55 articles for inclusion: 24 were relevant to Key Question 

#1, 6 were relevant to Key Question #2, 3 were relevant to Key Question #3, and 22 were costeffectiveness analyses relevant to Key Question #4. From the trial citations, 120 were potential 

includes after the title screen. Of the 60 meeting 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. Peer review identified ten additions, including four trials for Key Question #1, one systematic 

review and two trials for Key Question #2, and one update on a trial already included for Key 

Question #3, as well as one new trial.

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

•	 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. 

Summary of Key Question 2: Second-line therapy

The conclusions from the relevant 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).
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Treatment of Metastatic Non-Small Cell Lung Cancer Evidence-based Synthesis Program

• 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). 

ABBREVIATIONS TABLE

CI Confidence interval

HSR&D Health Services Research and Development Service

OR Odds ratio

P or p Probability

VA Veterans Affairs

VAMC VA Medical Center

NSCLC Non-small cell lung cancer

ECOG Eastern Cooperative Oncology Group

EGFR Epidermal growth factor receptor

ASCO American Society of Clinical Oncology

TKI Tyrosine Kinase Inhibitors