Boston, Mass., September 29, 2016 – The Institute for Clinical and Economic Review (ICER) has released an Evidence Report assessing the comparative clinical effectiveness and value of treatments for non-small cell lung cancer (NSCLC). A draft version of this report was open for a four-week public comment period. The updated Evidence Report reflects changes made based on comments received from patient groups, clinicians, the manufacturers of the drugs, and other stakeholders.

This assessment evaluates the health and economic outcomes of certain tyrosine kinase inhibitors (TKIs) and programmed death 1 (PD-1) agents in the treatment of advanced NSCLC. The effects of both classes of agents are evaluated in EGFR-positive (EGFR+) NSCLC, and PD-1 agents are evaluated in NSCLC without a driver mutation (EGFR-).

A key goal of ICER’s reports is to ensure that patients, providers, insurers, and policymakers have the information they need to support efforts to improve the quality and value of care. The report provides analyses of the clinical effectiveness and comparative value (including long-term cost-effectiveness and potential budget impact) of the drugs under study.

The results of these analyses were used to calculate a value-based price benchmark. Price benchmarks reflect estimates of how much better the interventions are at improving patient outcomes. In addition, ICER considers whether the introduction of these agents might pose challenges to health-system affordability and require policy discussions around steps that could be taken to manage their costs.

Highlights of the report’s findings, as well as a table of key terms, are included below :
Clinical Effectiveness

For patients with EGFR+ advanced NSCLC, the report found high certainty that TKI therapy is better tolerated than platinum-based chemotherapy and achieves at least equal gains in overall survival, and moderate certainty that TKI therapy provides a clinically meaningful overall survival benefit. The evidence was insufficient to distinguish between the TKI drugs reviewed.

For patients with EGFR- advanced NSCLC, the report found that a substantial minority of patients respond to second-line treatment with PD-1 immunotherapies, but for those who do respond there is high certainty of important gains in overall survival.

Evidence was found to be insufficient for first-line use of PD-1 immunotherapy in NSCLC as well as use following progression on TKI therapy; limited indirect evidence suggests that use of PD-1 immunotherapy in this latter setting may be inferior to chemotherapy with a platinum-based doublet. More information on the methodology for these ratings, the evidence, and uncertainties surrounding the evidence is available in the full report.

Comparative Value
The primary aim of the economic analysis was to estimate the long-term costs, outcomes, and cost-effectiveness of treatment for advanced NSCLC for two distinct populations:
  • First-line therapy with TKIs versus platinum-based chemotherapy for EGFR+ patients, and
  • Second-line therapy with PD-1 immunotherapy versus docetaxel in EGFR- patients who progressed on a first-line chemotherapy doublet.

Due to a lack of publicly available comparative evidence, we did not model second- or third-line PD-1 immunotherapy for EGFR+ patients or first-line PD-1 immunotherapy in patients without a driver mutation.

First-line therapy with TKIs 

  • Cost-effectiveness estimates were quite similar across the TKIs, ranging from $110,840 to $147,244 per quality-adjusted life year (QALY) gained.
  • Because we did not find adequate evidence to distinguish among the TKIs, we did not calculate a separate value-based price benchmark for each of these drugs, but instead calculated average percentage discounts (or premiums) across all three agents.
    • The average discount to achieve a cost-effectiveness threshold of $100,000/QALY would be approximately 21%.
    • A premium could be added to each drug’s list price to achieve $150,000/QALY; the average of these would represent an approximately 15% increase in price.

Second-line therapy with PD-1 immunotherapy

  • Cost-effectiveness estimates for PD-1 immunotherapies were:
    • $219,179 per QALY gained for atezolizumab,
    • $240,049 for pembrolizumab, and
    • $415,950 for nivolumab.
  • There is substantial uncertainty in these estimates, and the results are not directly comparable because of differences in labeled or expected indications for each drug as well as the type of assay used for PD-1/PD-L1 expression.
  • The ICER value-based price benchmark to achieve $100,000 to $150,000/QALY for atezolizumab represents a 47%-62% discount from the wholesale acquisition cost (WAC) list price. For pembrolizumab, the discount is 61%-73% to achieve these thresholds. The ICER value-based price benchmark for nivolumab is a 52%-65% discount from the WAC list price.

Key Terms 

EGFR stands for epidermal growth factor receptor. Some patients with NSCLC have mutations in their tumor that affects the EGFR. EGFR+ indicates that this mutation is present, while EGFR- indicates that it is not present. Whether a patient is EGFR+ or EGFR- can affect which treatments will work best for them.
PD-1 Immunotherapy
Tumor cells can produce substances that alter how the immune system responds to a tumor, such as by affecting a regulatory “checkpoint” or brake on the T cell response to the tumor, which allows the tumor to evade the immune system. Immunotherapy aimed at inhibiting such a checkpoint through the programmed death 1 (PD-1) receptor or its ligand, PD-L1, have demonstrated benefit in at least some patients with NSCLC. Several drugs that focus on this pathway are available; some are antibodies to PD-1 while others are antibodies to its ligand, PD-L1.  We use the term “PD-1 immunotherapy” to refer to both groups of antibodies.
 Tyrosine kinase inhibitors (TKIs) are once-daily oral medications typically used as a first-line treatment option for patients with EGFR+ NSCLC.

ICER is committed to a transparent public engagement process to ensure that all stakeholders have the opportunity to provide input to our reports. As noted above, after ICER’s Draft Evidence Report was released on August 19th, interested stakeholders had a four-week period to provide comments. ICER staff considered these comments and made revisions to the report as needed. The Evidence Report, as well as the accompanying voting questions, public comments, and ICER’s written response to comments, are available on the ICER website.

The Evidence Report will be the subject of the October 20th public meeting of the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC), during which the independent Council will vote on key questions raised in the report, and a policy roundtable will discuss recommendations to apply the evidence to policy and practice. During the meeting, a limited amount of time will be available for pre-registered stakeholders to provide a brief oral comment on the report. Requests to make an oral comment were accepted during the public comment period on the Draft Evidence Report.
About ICER

The Institute for Clinical and Economic Review (ICER) is an independent non-profit research institute that produces reports analyzing the evidence on the effectiveness and value of drugs and other medical services. ICER’s reports include evidence-based calculations of prices for new drugs that accurately reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall health care system.

ICER’s reports incorporate extensive input from all stakeholders and are the subject of public hearings through three core programs: the California Technology Assessment Forum (CTAF), the Midwest Comparative Effectiveness Public Advisory Council (Midwest CEPAC) and the New England Comparative Effectiveness Public Advisory Council (New England CEPAC). These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of health care. For more information about ICER, please visit ICER’s website.


Appendix 1: Therapies of interest included: 
TKIs for chemotherapy-naïve patients with an EGFR+ tumor:

  • Afatinib
  • Gefitinib
  • Erlotinib

PD-1 immunotherapy for patients without an EGFR+ tumor who are either chemotherapy-naïve or have progressed after first-line treatment with a platinum doublet, and patients who have an EGFR+ tumor that has progressed after first- or second-line treatment with a TKI:

  • Atezolizumab
  • Nivolumab
  • Pembrolizumab