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Maher AR, Miake-Lye IM, Beroes JM, et al. Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost-Effectiveness [Internet]. Washington (DC): Department of Veterans Affairs (US); 2012 Oct.



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.

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 cost-effective, and the differences between erlotinib and docetaxel maintenance therapy were slight in another study (GRADE=low).


  • 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.


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 First-Line 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 0–1We 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/gemcitabinePemetrexed 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 survivalNew 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 patientsNew 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 RTWe did not look at evidence on radiation therapy.
New agent/nonplatinum combinations are reasonable alternatives if data show activity and tolerable toxicityNew 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 mutationsThis conclusion is strongly supported by new evidence.
Crizotinib is indicated as a first-line therapy in patients that are ALK positiveWe did not identify new evidence about crizotinib.


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.

Cover of Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost-Effectiveness
Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost-Effectiveness [Internet].
Maher AR, Miake-Lye IM, Beroes JM, et al.
Washington (DC): Department of Veterans Affairs (US); 2012 Oct.


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