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Keywords:

  • gefitinib;
  • lung adenocarcinoma;
  • cost-effectiveness;
  • economic evaluation;
  • Asia;
  • epidermal growth factor receptor

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND:

Epidermal growth factor receptor (EGFR) testing and first-line therapy with gefitinib for patients with activating mutations is quickly becoming the standard option for the treatment of advanced lung adenocarcinoma. Yet, to date, little is known about the cost-effectiveness of this approach.

METHODS:

A decision-analytic model was developed to determine the cost-effectiveness of EGFR testing and first-line treatment with gefitinib for those patients who harbor activating mutations versus standard care, which includes first-line treatment with chemotherapy followed by gefitinib as second-line treatment. The model uses clinical and outcomes data from randomized clinical trials and societal costs from Singapore cancer centers. Health effects were expressed as quality-adjusted life-years. All costs and cost-effectiveness ratios were expressed in 2010 Singapore dollars. Sensitivity and different scenarios analyses were conducted.

RESULTS:

EGFR testing and first-line treatment with gefitinib is a dominant strategy (with lower costs and greater effectiveness) compared with standard care. Because the primary savings result from not providing gefitinib to those who are not likely to benefit, this finding holds regardless of the prevalence of activating mutations. In a secondary analysis, first-line treatment with gefitinib was also dominant when compared with first-line chemotherapy in patients with activating EGFR mutations.

CONCLUSIONS:

This strategy can be considered a new standard of care and should be of great interest for health care payers and decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs. Cancer 2012;. © 2011 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Lung cancer is a major health problem. In 2008, there were an estimated 1.61 million cases and 1.38 million deaths because of the disease worldwide.1 Approximately 80% of all patients have nonsmall cell lung cancer (NSCLC), most of whom now have adenocarcinoma of the lung. Platinum-containing chemotherapy doublets increase overall survival and improve the quality of life of patients with advanced and metastatic NSCLC. Until 7 years ago, chemotherapy was the only systemic treatment method available, and clinical trial results had reached a plateau, with a median overall survival of 10 to 12 months.2-4

In 2002 in Japan and 2003 in the United States, gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), became the first clinically available drug in its class after phase 2 trials in chemotherapy-refractory patients demonstrated objective radiologic responses and symptomatic improvement.5, 6 A confirmatory international randomized trial, the Iressa Survival Evaluation in Lung Cancer trial (known as ISEL), failed to show an improvement in overall survival compared with placebo. Subset analysis, however, did show increased survival for Asian patients who received gefitinib.7, 8 Subsequent randomized controlled trials have showed that gefitinib is at least equivalent to docetaxel in the management of pretreated patients with advanced NSCLC,9, 10 and it is now recognized that activating EGFR mutations are the best predictor of response outcomes with EGFR TKIs, and that these mutations are more prevalent in Asians, nonsmokers, and women.

Recently, treatment with gefitinib has been compared with platinum-based doublet chemotherapy in the first-line treatment of lung adenocarcinoma in Asian patients who were never or light smokers and in patients whose tumors harbored activating EGFR mutations.11-14 In these clinical trials median overall survival, which ranged from 20 to 30 months, was similar across treatment groups, as patients were likely to cross over to chemotherapy or gefitinib upon progression. However, patients with activating EGFR mutations who received the EGFR TKI as first-line therapy had better response rates, longer progression-free-survival, and better quality of life than those who received chemotherapy.

On the basis of the evidence described above, the American Society of Clinical Oncology recently published a provisional clinical opinion recommending EGFR mutation testing before treatment with EGFR TKIs in the management of patients with advanced lung cancer for whom such therapy is being considered.15 Although there are clear clinical benefits to providing gefitinib as first-line therapy for individuals with activating EGFR mutations, identifying those patients requires EGFR mutation testing for all patients with lung adenocarcinoma. Given that there are no health improvements for those who test negative, it is not clear whether the additional benefits of gefitinib as first-line therapy for patients with activating EGFR mutations are worth the additional mutation testing costs. To address this question, we developed a decision-analytic model to determine the cost-effectiveness of EGFR mutation testing and first-line treatment with gefitinib followed by second-line chemotherapy for patients who have activating EGFR mutations, and chemotherapy followed by best supportive care for those who do not. We compare this strategy to standard practice, which includes no EGFR mutation testing, first-line treatment with chemotherapy, and second-line treatment with gefitinib. This is the default treatment protocol in most countries where gefitinib is available (personal communication to the authors from Asian oncology experts contacted in Singapore, Hong Kong, South Korea, and Japan).

Because of the higher prevalence of EGFR mutation among Asians, we hypothesize that mutation testing and treatment with gefitinib is likely to be cost-effective as a first-line treatment in Asia. We also assessed the cost-effectiveness of first-line versus second-line treatment with gefitinib in a subset of patients with activating EGFR mutations. This secondary analysis allows for testing the cost-effectiveness of early treatment with gefitinib, when the quality of life benefits are likely to be greatest. Sensitivity analyses were conducted, and several different scenarios, including the use of pemetrexed, bevacizumab, and cetuximab, were assessed.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

To conduct the analyses, we developed a decision-analytic model using TreeAge Pro 2009 (TreeAge Software, Williamstown, Mass). The model shown in Figure 1 first considers whether EGFR testing occurs. If testing does not occur, the model assumes that individuals receive chemotherapy as first-line treatment. Upon progression, they receive gefitinib as second-line treatment until the cancer further progresses. They then go on to receive best supportive care (BSC). This decision rule is independent of EGFR mutation status, which in this arm is not revealed to the clinician or patient.

thumbnail image

Figure 1. Tree diagram shows primary analysis of the cost-effectiveness of epidermal growth factor receptor (EGFR) testing and gefitinib as first-line treatment for patients who are EGFR positive. BSC, best supportive care.

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In the EGFR mutation testing arm, a second branch separates those who test positive for activating EGFR mutations. In the base case, we assumed that 60% of individuals test positive for the EGFR mutation based on results of the IPASS trial.11 Individuals with activating EGFR mutations receive gefitinib as first-line treatment, chemotherapy as second-line treatment after initial progression, and BSC after further progression. Individuals found not to have activating mutations receive chemotherapy followed by BSC. We assumed that although patients might receive further third-line and/or fourth-line chemotherapies in the BSC, these would be evenly distributed across both arms and would therefore not bear importance in the incremental costs and benefits incurred to the testing arm.

Time spent in each treatment state is based on data from 3 clinical trials, weighted by the number of participants in each trial.11, 12, 14 Length of time in first-line treatment is based on median progression-free survival time. Given that overall survival is likely to be the same for those who receive gefitinib as first-line or second-line treatment (as there were no differences in overall survival in the abovementioned trials), we assumed that the length of time spent in a particular treatment state does not vary by whether it is first-line or second-line (ie, for those with a positive mutation, time spent in a treatment state after receiving gefitinib was assumed to be the same whether the treatment was first-line or second-line). Time spent in BSC is estimated as the difference between median total survival and time spent in each of the other treatment states.

Quality-adjusted life-years (QALYs) for each treatment state are estimated using health utility values adapted from available literature16, 17 and adjusted according to the rates of complications for diarrhea, fatigue, febrile neutropenia, hair loss, nausea/vomiting, neutropenia, and rash, as reported in 3 clinical trials.11, 12, 14 The average baseline QALY weight including decrements for complications for first-line treatment is 0.61 for chemotherapy. It is 0.67 for first-line treatment with gefitinib in those who test positive and 0.61 for those who test negative. The average QALY weight for the second-line treatment state with chemotherapy was 0.41; for those treated with gefitinib who test positive for activating mutations it was 0.47, and it was 0.41 for those who test negative. We assumed the same QALY weight of 0.41 during periods of BSC. We also assumed this QALY weight in the no testing branch during the second-line treatment state for individuals receiving second-line gefitinib who were negative for the EGFR mutation. For the base-case analysis, we assumed that gefitinib only provides a quality-of-life benefit in those with activating EGFR mutations.

Costs for each type of treatment and for EGFR testing are based on a weighted average (weighted by number of patients seen) of payments from patients and/or government payers from 3 cancer centers in Singapore: Tan Tock Seng Hospital, Johns Hopkins Singapore International Medical Centre, and the National Cancer Centre Singapore. The model includes payments for chemotherapy (gemcitabine and carboplatin), gefitinib, laboratory tests, physician visits, and treatment complications. All costs are in 2010 Singapore dollars (SGD). Note: as of January 2011, 1.3 SGD equal 1 US dollar and 2.06 SGD equal 1 British pound (GBP). Because total survival time is relatively short, we do not discount future costs and benefits, although discounting by 3% or 5% percent had almost no effect on the results (data available upon request).

We ran several sets of sensitivity analyses to assess the robustness of our results. First, we conducted one-way sensitivity analyses where we both halved and doubled the value of each variable in the module in a sequential fashion to gauge its impact on the resulting cost-effectiveness ratios. We also examined how sensitive the results were to larger changes in the prevalence of activating EGFR mutations, and to EGFR mutation testing costs.

We also looked at different scenarios including the use of pemetrexed (as part of the induction platinum-containing doublet and as a maintenance treatment after initial chemotherapy), bevacizumab (in patients without contraindications), and cetuximab added to chemotherapy.

Finally, we calculated the incremental cost-effectiveness ratio (ICER) of gefitinib versus no gefitinib in the EGFR testing strategy in the treatment of patients with activating EGFR mutations and in the treatment of those without (in the latter case, we assumed an overall survival benefit similar to that of erlotinib in the BR.21 trial, with adjustments for patients without EGFR mutations based on the BR.21 biomarker study).18-20 Readers who might like to have a deeper understanding of the methods used in health economics research may choose to read the review article listed in the references.21

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Table 1 shows the values and data source for each of the model inputs. The primary analysis focused on determining the cost-effectiveness of EGFR mutation testing and first-line treatment with gefitinib followed by second-line chemotherapy for patients who have activating mutations, and chemotherapy followed by best supportive care for those who do not. Results show that this is a dominant strategy relative to no EGFR testing and first-line treatment with chemotherapy followed by second-line treatment with gefitinib in all patients. This results because, as shown in Table 2, QALYs increase by 0.04 and costs decrease by SGD 2400. The decrease in costs resulting from testing is driven by avoiding the costs of gefitinib in the population testing negative for the EGFR mutation, and as such if empiric treatment were attempted it would negate the cost savings. Because of the assumption that first-line or second-line treatments have the same length of time before progression, there is no difference in treatment costs between testing and no testing for the group that tests positive for the mutation (ie, both groups receive chemotherapy and gefitinib for the same expected length of time, just in reverse order). There is a cost associated with testing that accrues to all patients. This cost partially offsets the savings resulting from not providing gefitinib to the group testing negative for the mutation.

Table 1. Values of Input Variables
VariableValueSource
  • Abbreviations: BSA, Body surface area; BSC, best supportive care; EGFR, epidermal growth factor receptor; SGD, Singapore dollars.

  • a

    Includes cost of drugs, administration, outpatient visits, follow-up radiology scans, hospitalizations, and adverse events. Chemotherapy included gemcitabine and carboplatin. Gemcitabine was calculated at an average BSA of 1.6 and carboplatin with an average dose of 500 mg. BSC costs include treatment for malignant pleural effusion, palliative radiation, pain control, and hospice treatment based on Singapore data for utilization rates and costs.

  • b

    Time in BSC is total survival time minus chemotherapy and/or gefitinib under the particular testing scenario (eg, for EGFR individuals undergoing testing, BSC is 12.0 months equal to 27.8 − 9.8 − 6.0).

Costs, 2010 SGD
 Cost of gefitinib for patients with activating EGFR mutationsa$34,900Data from Tan Tock Seng Hospital, Johns Hopkins Singapore International Medical Centre, and the National Cancer Centre Singapore
 Cost of gefitinib for patients without activating EGFR mutationsa$5700
 Cost of chemotherapy for patients with and without activating EGFR mutations$20,700
 Fixed BSC cost$1500As above
 Monthly variable cost of BSC$120As above
 Cost of EGFR test$380
Time in each treatment state, mo
 Patients with activating EGFR mutations
  Total survival timeb27.8References 11, 12, 14
  Time in treatment state under chemotherapy6.0
  Time in treatment state under gefitinib9.8
 Patients without activating EGFR mutations
  Total survival time12.5Reference 11
  Time in treatment state under chemotherapy6.0
  Time in treatment state under gefitinib2.1
Health utilities by treatment state
 Chemotherapy first line0.61Baseline and decrement values from references 15 and 16; rates of complications from references 11, 12, and 14
 Gefitinib first line, EGFR+0.67
 Gefitinib first line, EGFR0.61
 Chemotherapy second line0.41
 Gefitinib second line, EGFR+0.47
 Gefitinib second line, EGFR0.41
 BSC0.41References 15 and 16
 Proportion of positive EGFR mutation tests0.60Reference 11
Table 2. Costs and QALYs Associated With Each Treatment Arm
ArmCostIncremental CostQALYsIncremental QALYs
  1. Abbreviations: EGFR, epidermal growth factor receptor; QALY, quality-adjusted life-year.

Standard treatment (no EGFR testing followed by first-line chemotherapy and gefitinib in the second line)$47,1000.87
EGFR testing followed by first-line gefitinib for EGFR+ and second-line chemotherapy$44,700−$2,4000.910.04

Although the cost savings accrue to the group testing negative for activating mutations, the increase in QALYs is driven entirely by the group testing positive. Because the health utilities associated with chemotherapy after progression and BSC are both 0.41, there is no change in QALYs associated with the 2 treatments for the population without the EGFR mutation. However, testing allows the EGFR mutation group to receive gefitinib as a first-line treatment when quality of life is relatively high (ie, they receive 0.67 QALYs for 9.78 months and then 0.41 QALYs for 6.0 months compared with 0.61 QALYs for 6.0 months followed by 0.47 QALYs for 9.78 months). As a result, QALYs improve by 0.06 when we compare first-line treatment with gefitinib versus first-line treatment with chemotherapy in patients with activating EGFR mutations. At an equal cost, this means that treatment with gefitinib in the first-line is also dominant over chemotherapy in patients with activating EGFR mutations in this paper's secondary analysis.

Sensitivity Analysis and Different Scenarios

To explore the robustness of our principal finding, we conducted 1-way sensitivity analyses where each of the 22 variables in the model were halved and doubled. In 33 of 44 cases, and when EGFR mutation testing costs were varied, we found that EGFR mutation testing and first-line treatment with gefitinib for patients who have activating EGFR mutations and chemotherapy for those who do not remained a dominant strategy relative to standard practice. For the remaining 11 cases, Figure 2 presents the ICERs relative to no testing and first-line treatment with chemotherapy and second-line treatment with gefitinib. Note that in each of these scenarios, the case for EGFR mutation testing and first-line treatment with gefitinib for those who test positive becomes less compelling (ie, no longer a dominant strategy). However, it still may be a cost-effective treatment option depending on the cutoff value that policymakers use to determine cost-effectiveness.

thumbnail image

Figure 2. Results of 1-way sensitivity analysis show effect on incremental cost-effectiveness ratio (ICER). Base case represents EGFR testing and gefitinib as first-line treatment if patient is EGFR mutation positive. Black bars represent doubling the value of the input variable; gray bars represent halving the value. This figure only shows the 25% of cases in the sensitivity analysis in which the ICER did not favor strategy 2. chem, chemotherapy; EGFR, epidermal growth factor receptor; gef, gefitinib; prog, progression; QALY, quality-adjusted life-years; ttbsc, time from first progression to best supportive care; ttprog, time to first progression.

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As shown in Figure 2, the largest (ie, least cost-effective) ICERs result from doubling the time to first progression for chemotherapy in the mutation-positive population, halving the time to first progression for gefitinib in the mutation-positive population, or doubling the time from first progression to BSC for chemotherapy in the mutation-positive population. These cases result in cost-effectiveness ratios well beyond conventional thresholds. This results because doubling the time to first progression for chemotherapy in the mutation-positive population significantly increases the costs of not testing by SGD 12,000, but also increases QALYs in the no testing arm by nearly 0.06. Halving the time to first progression for gefitinib cuts the cost of treatment, but it also reduces QALYs by nearly 0.06 for the treatment group, leading to a positive ICER. Doubling the time from first progression to BSC for chemotherapy has no effect on QALYs, because for the mutation-positive group second-line chemotherapy and BSC have the same QALY value (0.41). However, it increases costs of treatment by nearly 30%, which leads to a large increase in the ICER. Halving or doubling EGFR mutation testing costs did not change the dominance of the testing arm.

When the percentage of individuals who test positive for the mutation decreases by 50% to 0.3, testing remains dominant. This results because savings increase to SGD 4520 as gefitinib is not given to an even greater percentage of patients who test negative, and incremental QALYs remain positive but at a lower level of nearly 0.02. In Western populations, with a predicted activating EGFR mutation prevalence of approximately 10%, the base case savings are roughly SGD 5900 from avoiding the use of gefitinib in patients without mutations. In fact, the ICER only becomes positive when the proportion of individuals who test positive for the mutation increases to 95%. This counterintuitive finding results because as the prevalence of individuals with activating mutations increases, the potential savings from not giving gefitinib to those who are less likely to benefit decreases. (See below for results on the cost-effectiveness of treatment with gefitinib in patients without activating mutations.)

In different scenarios, the addition of pemetrexed as part of the platinum-containing doublet and/or as a maintenance treatment after initial chemotherapy, or the use of bevacizumab (in patients without contraindications) or cetuximab added to chemotherapy, increased the cost and overall QALYs but did not alter the incremental benefits and costs associated with mutation testing and treatment with gefitinib. This results from the authors assumption, based on expert opinion in Asia, where most patients with activating EGFR mutations are treated, that—given the lack of level I data from adequately powered randomized clinical trials—patients who receive gefitinib as first-line treatment are eligible to take further treatment based on the best available evidence for first-line treatment in other clinical trials (ie, this implies that pemetrexed-based initial and maintenance treatments, bevacizumab, or cetuximab would be added to both the first-line treatment for patients without testing and without activating mutations and to the second-line treatment of patients with activating mutations who receive first-line gefitinib, therefore canceling out any added benefits and costs).

In a scenario comparing EGFR testing and first-line gefitinib for patients who harbor activating mutations (as described above for the testing strategy) versus no testing and chemotherapy alone (without gefitinib in the second line), we calculated incremental costs and QALYs to be SGD 20,600 and 0.27, respectively, leading to an ICER of SGD 77,160 per QALY gained. Finally, gefitinib was not cost-effective in the treatment of individuals without mutations; with overall survival improvements ranging from 1.32 to 2 months, the ICER for gefitinib versus no gefitinib in second-line treatment was between SGD 129,000 and SGD 196,000 per QALY gained.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

The primary focus of this paper was to determine the cost-effectiveness of EGFR mutation testing and first-line treatment with gefitinib followed by second-line chemotherapy for patients who have activating EGFR mutations, and chemotherapy followed by best supportive care for those who do not. This strategy was compared with a standard practice that includes no testing, first-line treatment with chemotherapy, and second-line treatment with gefitinib. Our results suggest that EGFR mutation testing and guided targeted therapy are a dominant strategy relative to standard practice. It has both lower costs and greater effectiveness. This finding is driven partly by the small gain in QALYs that the group with activating EGFR mutations accrues from receiving gefitinib in the first line, but the larger driver of these results was the savings generated by not providing gefitinib to those patients who are much less likely to derive a clinical benefit because they do not harbor activating EGFR mutations. These savings dwarf the costs of EGFR mutation testing. Paradoxically, these results reveal that gefitinib becomes even more dominant as the proportion of those who test negative for the mutation increases. This results because, as noted above, costs are further reduced by not providing the drug to a greater proportion of individuals who would not be likely to benefit from it. With few exceptions, these conclusions were robust to large changes in key model parameters.

This analysis is subject to several limitations. First, we had to make assumptions about the length of time spent in each treatment state by extrapolating from clinical trial data and assuming that the time spent in first-line or second-line treatment with chemotherapy or gefitinib was equivalent to account for a similar overall survival. Second, the cost data are obtained from 3 specific Singapore oncology centers (which see nearly 60% of patients with cancer in the country) and may not be representative of other countries or hospitals. The acquisition costs for gefitinib in Asia vary little from country to country, however (author's personal communication). Moreover, as our one-way sensitivity analyses show, large variations in costs do not change the primary conclusion that testing and targeted therapy are a dominant strategy. Third, we made several assumptions about the quality of life values. These included greater health utility for gefitinib relative to chemotherapy because of its lower rate of adverse events and oral method of administration, the assumption that health utility values for BSC are equal to second-line chemotherapy, and other factors described in the Materials and Methods section. To the extent that these assumptions may be incorrect, our estimated ICERs may be biased. However, with few exceptions, the one-way sensitivity analyses show that our qualitative results are robust to halving and doubling these values. The exceptions result from halving or doubling the QALY values for specific health states (first-line chemotherapy and second-line gefitinib in mutation-positive persons lead to no effect on quality of life), and even under these circumstances, in most cases the cost-effectiveness of testing plus targeted therapy falls within usually accepted cost-effectiveness ranges. Fourth, because of a lack of available data, we were unable to model individual progressions through the course of the disease, which could potentially better capture some of the individual-level variation in treatment responses. As more detailed data emerge, the model can be updated, and individual-level complexity can be added. Fifth, the standard of care for treatment has moved to include pemetrexed, bevacizumab, and cetuximab in the first-line treatment and to include pemetrexed as a potential maintenance option after initial chemotherapy. The incremental costs and benefits of testing and treatment with gefitinib did not change, however, in the different scenarios with the addition of pemetrexed, bevacizumab, and cetuximab in our model.

Another caveat to this analysis is that our model specifically compares a standard practice, which includes no EGFR mutation testing, first-line treatment with chemotherapy, and second-line treatment with gefitinib, to EGFR testing and guided therapy based on the results of the test. We show that based on this comparison, testing and guided therapy are clearly a dominant strategy to this standard. However, recent research has challenged the cost-effectiveness of gefitinib overall. The United Kingdom's National Institute for Health and Clinical Excellence has made public the results of its Evidence Review Group assessment of the cost-effectiveness of first-line gefitinib versus chemotherapy in patients with advanced or metastatic nonsmall cell lung cancer.22 The ICER for treatment with gefitinib versus several chemotherapy options ranged from GBP 59,000 to 73,000 (SGD 121,500-144,000; US dollars [USD] 93,400-110,000) per QALY gained. This is much higher than the manufacturer's prior estimate of GBP 20,744 (SGD 42,800, USD 32,900) per QALY gained, and it is outside the usual limits considered acceptable for the British payer, although it would generally be considered cost-effective by the World Health Organization (for countries with GDP per capita equal to or greater than USD 36,600) and payers in the United States. In our model, using EGFR mutation testing to select patients for first-line therapy with gefitinib, we calculated an ICER of SGD 77,160 (USD 59,000), which was also higher than the manufacturer's initial estimate, but which would generally be considered cost-effective.

Finally, we also have to mention that in the base case we assumed that gefitinib did not benefit patients without activating mutations, even beyond first-line treatment. This assumption derives from the ISEL trial and may be criticized, as further studies have shown gefitinib to be equivalent to second-line chemotherapy in unselected populations.9, 10 In addition, it should be noted that this model assumes the amplification refractory mutation system (ARMS) is used as the test of choice for EGFR mutation testing. This stems from the findings that the response rate for EGFR mutation-negative patients in the IPASS study (which used ARMS) was 1.1%, as compared with 25.9% in the First-Signal study (which used direct sequencing, a technique that has lower sensitivity than ARMS). The clinical implications of a high false-negative rate are self-evident, and every effort should be made to use the most sensitive diagnostic tests available. Moreover, erlotinib, the other approved EGFR TKI currently in clinical use, does seem to improve survival in patients without activating mutations in the postchemotherapy and maintenance settings.18-20 Be that as it may, in our scenario analysis, gefitinib was not cost-effective in the treatment of patients without activating mutations, even when we assumed a clinical benefit similar to that of erlotinib in the BR21 trial, with an ICER falling between SGD 129,000 and 196,000 (USD 99,000 and 151,000) per QALY gained. These results are similar to those of an economic evaluation of the BR.21 trial showing that erlotinib was marginally cost-effective in Canada in the treatment of patients with advanced NSCLC after failure of first-line chemotherapy.23 We are currently working on a meta-analysis of retrospective studies and on an indirect comparison of randomized clinical trials as well as on economic models to assess the relative clinical and cost-effectiveness merits of treatment with erlotinib versus gefitinib (to be presented as a poster at the 14th World Conference on Lung Cancer in July 2011) in patients with NSCLC.

Although this is an area that warrants further research, our results clearly show that where the EGFR TKI is already incorporated into clinical practice, mutation testing and first-line therapy with gefitinib for patients with activating EGFR mutations and chemotherapy for those without is a dominant strategy compared with no testing followed by first-line chemotherapy and second-line gefitinib for all unselected patients with lung adenocarcinoma. Moreover, first-line treatment with gefitinib is also dominant when compared with chemotherapy in the initial treatment of patients with activating mutations. Gefitinib does not seem to be cost-effective in the treatment of patients without activating EGFR mutations. This strategy can be considered a new standard of care and should be of great interest for health care payers and other decision makers in an era in which our greatest challenge is to balance hard-won and incremental, yet small, improvements in patient outcomes with exponentially rising costs.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

This study was supported by a grant from AstraZeneca Pte Ltd, Singapore. It was conducted independently, and the company did not participate in developing the study or in reporting its results.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES
  • 1
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    Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol. 2003; 21: 2237-2246.
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    Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008; 372: 1809-1818.
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    Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362: 2380-2388.
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    Lee JS, Park K, Kim SW, et al. A randomized phase III study of gefitinib (IRESSATM) versus standard chemotherapy (gemcitabine plus cisplatin) as a first-line treatment for never-smokers with advanced or metastatic adenocarcinoma of the lung [abstract]. J Thorac Oncol. 2009; 9( suppl 1). Abstract PRS4.
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    Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2009; 11: 121-128.
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    Keedy VL, Temin S, Somerfield MR, et al. American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor (EGFR) mutation testing for patients with advanced non-small cell lung cancer considering first-line EGFR tyrosine kinase inhibitor therapy. J Clin Oncol. 2011; 29: 2121-2127.
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