By Turna Ray
This article was posted May 27.
The UK's National Institute for Health and Clinical Excellence recommended this week that the National Health Service should pay for AstraZeneca's non-small cell lung cancer drug Iressa in the first-line treatment setting if patients test positive for epidermal growth factor receptor-tyrosine kinase mutations and if the drug developer provides the drug at a fixed price.
NICE's recommendation for NHS to pay for Iressa in EGFR mutation-positive patients marks the the second personalized medicine product to be funded in the UK after Herceptin was approved in 2002 for HER2-overexpressing breast cancer patients.
AstraZeneca and the UK's Department of Health have agreed upon a so-called patient access scheme in which Iressa will be available for first-line treatment of NSCLC at a single fixed cost of £12,200 ($17,560) per patient, "irrespective of the duration of treatment," NICE stated in its final determination of the cost-effectiveness of the treatment. "The manufacturer will not invoice the NHS until the third monthly pack of Iressa is supplied. This means that patients who need less than three months of treatment will not incur a charge."
The £12,200 per-patient fixed price includes the cost of the drug and pre-treatment EGFR testing. Testing is provided by several commercial and academic laboratories in the UK.
An AstraZeneca spokesperson said that NHS will pay for the test. NICE estimated the average cost of testing to be between £157.50 ($229.28) and £210 ($305.81) per test.
Due to a study showing Iressa to have low efficacy in the general NSCLC population, AstraZeneca in 2005 withdrew its application in the EU. The company re-applied for marketing approval in 2008 with efficacy data in EGFR-positive patients, and last year the drug was approved for marketing in Europe as a treatment for locally advanced or metastatic NSCLC patients whose tumors have EGFR mutations.
Before NICE issued its final cost-effectiveness determination on the treatment, the company struck an agreement with the NHS to make Iressa available to UK patients through a patient access scheme under which the company agreed to pay for genetic testing and to charge NHS a fixed price for each patient treated with Iressa (PGx Reporter 04/07/10).
The fixed price for Iressa "will include the entire cost of a course of treatment of Iressa until disease progression, irrespective of treatment duration, and will be reviewed after three years in line with the Pharmaceutical Price Regulation Scheme," according to NICE.
Since NHS has only once before paid for a personalized medicine product involving genetic testing, in the case of HER2 testing with Herceptin, NICE had concerns about the availability and accuracy of EGFR testing available in the country. Ultimately, the NICE review committee came to a decision to pay for genetic testing based on improved outcomes for EGFR mutation-positive patients treated with Iressa in the pivotal Iressa Pan Asian Study, or IPASS.
In recent years, NICE has made several controversial decisions against covering certain cancer drugs it has deemed too expensive. As a result, drug developers have increasingly been engaging in creative cost-sharing schemes in which the sponsor agrees to pay for treatment for patients who don't see a benefit and NHS pays for the drug only when it is effective. In the personalized medicine space, AstraZeneca's PAS with the NHS represents the first example of a risk-sharing arrangement involving genetic testing.
When in 2002, the NHS decided to pay for Herceptin in addition to paclitaxel as a treatment for advance breast cancer ─ which an NICE appraisal estimated would cost NHS £17 million annually including the cost of HER2 testing for approximately 20,000 women ─ no such deal was struck between UK's Department of Health and Genentech.
On the other side of the pond, AstraZeneca has not announced any plans to submit pharmacogenomic data to the US Food and Drug Administration, which may allow the company to market Iressa in EGFR mutation-positive NSCLC patients. In 2004, the FDA restricted any new patients from receiving the drug after clinical trial data showed the drug had limited efficacy in the general NSCLC population.
Due to the lack of broadly available EGFR testing in the UK, the review group was concerned that making EGFR-testing services operational throughout England and Wales might require "substantial investment in time and resources." However, the cost-savings associated with EGFR testing seemed to be worth the investment to expand access to testing.
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The committee estimated that the prevalence of the EGFR-TK mutation varies from 5 percent to 17 percent. Based on the average cost of EGFR mutation testing, the committee calculated an incremental cost-effectiveness ratio of between £27,457 ($39,943) to £49,323 ($71,753) per quality-adjusted life-year gained for Iressa compared with gemcitabine and carboplatin (based on six cycles of chemotherapy).
Doctors the review committee spoke to acknowledge that "EGFR-TK mutation testing is not routinely carried out in UK clinical practice at present because it has not been needed to date." However, the specialists felt that by funding Iressa for EGFR-positive patients, NHS would help spur test adoption.
"The committee was persuaded that the need for testing for the EGFR-TK mutation would not limit treatment and that it should be seen as analogous to testing for HER2, which has been successfully implemented in a short timeframe within the NHS," NICE said.
AstraZeneca has launched a website to inform healthcare providers and doctors in the UK about EGFR testing that lists several labs conducting such analyses, including the University of Birmingham, University Hospital of Wales, Royal Devon & Exeter NHS Foundation Trust, Lab21, and Source Bioscience Healthcare. Lab21 uses the EGFR Mutation Test Kit manufactured by Qiagen subsidiary DxS.
The NICE review panel was also concerned about a scenario in which patients wrongly identified by genetic testing as being EGFR positive might receive Iressa as opposed to more effective standard chemotherapy and subsequently experience negative outcomes in the form of decreased survival. "The accuracy of the amplification-refractory mutation system test for identifying EGFR-TK mutations is very high, but the power of the test result to predict a good response to treatment with [Iressa] is lower," the review committee pointed out, adding that AstraZeneca did not include the performance characteristics of EGFR tests in its clinical effectiveness and cost effectiveness modeling.
According to DxS, its EGFR Mutation Test Kit can detect copies of 29 somatic mutations in the EGFR gene even if mutations comprise 1 percent of the sample. The RT-PCR-based platform has a limit of detection of 10 copies or below.
Upon speaking to clinical specialists, however, NICE felt more comfortable with the low probability that patients would be incorrectly identified since the EGFR-TK mutation test "is qualitative rather than quantitative and shows either the presence or absence of an EGFR-TK mutation."
Finally, in deciding to provide genetic testing to all patients eligible for Iressa treatment, NICE interviewed doctors who said that even though EGFR-mutation positive patients were more likely to be Asian women who never smoked and had tumors on the glandular structures of the lungs, they felt uncomfortable limiting testing to patients solely based on ethnicity or clinical factors.
The committee heard from the clinical specialists who said that "although EGFR-TK mutation-positive patients were more likely to have certain characteristics … they would not feel comfortable limiting testing to these patients," NICE noted in its review documents. "The committee accepted the views of the clinical specialists that testing should be carried out on all eligible patients irrespective of gender, ethnicity, and smoking status to ensure that all eligible patients who could benefit would be identified."
For NICE's review of the clinical effectiveness of Iressa in EGFR mutation-positive NSCLC patients, AstraZeneca submitted data from the IPASS study, a randomized-controlled trial of East Asian patients who have never smoked or have been light smokers with locally advanced or metastatic NSCLC.
Patients enrolled in the study had not previously received chemotherapy, or biological or immunological treatment, and were randomized to receive 250 mg of Iressa once daily or paclitaxel immediately followed by carboplatin in three weekly cycles.
Although the overall IPASS study involved 1,217 patients, in its submission to NICE, AstraZeneca focused on a sub-group of 261 EGFR mutation-positive patients, representing 21 percent of the study population. The majority of the patients in the sub-analysis were women (80.8 percent) and never smokers (94.3 percent).
In this subset, progression-free survival in patients receiving Iressa was statistically significantly longer than for patients in the chemotherapy arm. Median progression-free survival was 9.5 months for patients taking Iressa versus 6.3 months given paclitaxel/carboplantin. Additionally, the objective tumor response rate was statistically significantly higher for patients randomized to receive Iressa (71.2 percent) compared with patients randomized to receive paclitaxel/carboplatin (47.3 percent).
However, when it came to overall survival, there was no statistically significant difference between the two arms.
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Additionally, EGFR mutation-positive patients on Iressa had a better quality of life and statistically significant improvement in disease symptoms compared to those receiving chemotherapy. Patients on Iressa in this subgroup also took longer to worsen in terms of disease symptoms than the comparator arm (median range 11.3 to 16.6 months for Iressa and 2.9 to 3.0 months for paclitaxel and carboplatin).
Upon reviewing the evidence, the review group decided that "the trial provided convincing evidence of the efficacy and benefits to health-related quality of life of Iressa in EGFR-TK mutation-positive patients compared with paclitaxel and carboplatin."
However, the group expressed concern over the lack of blinding in determining progression-free survival in the IPASS study. It also noted that hazard ratios for this outcome were inappropriately calculated using the Cox proportional hazards method and had 'major concerns" about the immaturity of overall survival data since interim analysis in the sponsor's submission was based on "relatively few deaths."
The group pointed out that "confounding may have occurred in IPASS because of crossover of treatment after disease progression. Therefore, any changes in overall survival may not result from the treatment to which trial participants were originally assigned."
According to AstraZenca's own cost-effectiveness analysis, Iressa is the second-most cost-effective treatment in EGFR mutation positive patients with locally advanced or metastatic NSCLC. Based on a threshold of £30,000 per quality-adjusted life-year gained, treatment with vinorelbine and cisplatin was most cost-effective.
Current standard of care in NSCLC in England and Wales is platinum-based chemotherapy.