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24th August 2009,
Gefitinib▼ is licensed for use in patients with locally advanced or metastatic non-small-cell lung cancer with activating mutations of the epidermal growth factor receptor tyrosine kinase. In a first-line study, IPASS, the primary endpoint of progression-free survival in the overall population was improved with gefitinib as compared to carboplatin-paclitaxel chemotherapy [HR 0.74; 95% CI 0.65–0.85]. Overall survival data is immature for this study. In a study involving pre-treated patients, INTEREST, gefitinib was non-inferior to docetaxel in terms of overall survival.
Level of evidence:
Level 2 (limited quality, patient-orientated evidence) according to the SORT criteria.
Action
In the absence of NICE guidance, local decision makers will need to plan with local pathologists, oncologists and Cancer Networks for the managed introduction of the mutation test and product. The immaturity of the data from the IPASS study, the non-inferiority of gefitinib when compared with docetaxel, and the lack of published health economic data might result in localities currently considering this to be a low priority within their commissioning plans. However, there are limited management options for patients with locally advanced or metastatic non-small-cell lung cancer with EGFR-TK mutation-positive tumours. Such patients usually have a poor prognosis and commissioners, providers and patients might wish to commission testing for the mutation with a view to making gefitinib available for this indication ahead of NICE guidance.
Update 29th September 2009
“AstraZeneca is partnering with various laboratories (including NHS facilities) to offer the NHS access to EGFR mutation testing as a service to medicine. ABPI guidelines on providing such a service precludes the company from having access to the results, and the company cannot maintain a patient database. The service is available until June 2010 when NICE guidance is anticipated. The company advocate that all patients newly diagnosed with NSCLC should be tested in order for clinicians to identify their mutation status and select the appropriate treatment.
The company has agreed a single fixed payment access scheme to be submitted to NICE in September 2009. It is anticipated that this scheme will be implemented mid-September 2009. Once the scheme is implemented then the cost, outside of the scheme, for 30 days treatment with gefitinib 250mg once daily will be £2167.71 (NHS list price). Median duration of treatment with gefitinib in the IPASS study is 5.6 months.”
What is the background to this?
Gefitinib (Iressa®) has been approved by the EMEA as a once daily oral treatment for patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC) with activating mutations of epidermal growth factor receptor tyrosine kinase (EGFR-TK). The manufacturer, AstraZeneca, is planning to market the product in the UK in September 2009. The successful application was based on three phase 3 trials (ISEL, INTEREST and IPASS), supported by additional studies.
The IPASS study evaluated, in a selected Asian patient population, the epidermal growth factor receptor (EGFR) status in tumours and tested the hypothesis that gefitinib would be active against this genetic marker in first-line treatment. The ISEL study involved treatment-refractory patients, of which 20% were of Asian origin. 22% of patients in the INTEREST study were also Asian. The low number of first-line non-Asian patients with EGFR activating mutations was a concern to the EMEA who have asked for a follow-up study to be done in a Caucasian population. It is known that Asian patients have a higher incidence of EGFR mutation-positive tumours.
The original anticipated marketing authorisation for gefitinib was for second-line treatment of locally advanced or metastatic NSCLC. However, during the regulatory process, data were submitted which caused the licensing authority to grant the licence for the specific indication of treatment of patients with activating mutations of EGFR-TK. A NICE appraisal for the second-line option was planned but, with the change in indication, the manufacturer intends to focus its efforts on first-line treatment of advanced NSCLC for patients with EGFR-TK mutation-positive tumours. Therefore, the manufacturer did not provide an evidence submission and the appraisal was terminated.
NICE guidance on gefitinib for first-line use is anticipated in June 2010. They have suggested that, should NHS organisations wish to consider the drug for patients with an activating mutation of EGFR-TK, then in the interim they should follow the advice set out by the Department of Health for the approach to be adopted in the absence of NICE guidance.
What does the IPASS study claim?
Gefitinib is superior to dual chemotherapy with carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among non-smokers or former light smokers in patients of Asian origin. The hazard ratio (HR) for progression or death was 0.74, 95% confidence interval (CI) 0.65 to 0.85. Treatment effect was not consistent over time, favouring chemotherapy for the first 6 months and gefitinib for the remaining 16 months.
The overall benefit was driven primarily by the subgroup of patients with an EGFR mutation. The authors of the paper suggest that EGFR mutation status should be determined before the initial treatment of pulmonary adenocarcinoma.
How does this relate to other studies?
The INTEREST study was a randomised, open-label trial of gefitinib versus docetaxel in 1466 patients with locally advanced or metastatic NSCLC who had been pre-treated with platinum. Approximately 35% of the study population were female, 22% were of Asian origin and 20% were non-smokers. Adenocarcinoma was diagnosed in 54% of patients.
The primary endpoint was overall survival (OS): assessing non-inferiority for the overall population and superiority in patients with high EGFR-gene-copy number. This latter information was available for 85 of the gefitinib group and 89 of the docetaxel patients, as tissue collection was not mandatory.
Gefitinib would be deemed to be non-inferior to docetaxel if the upper end of the 96% CI for the HR of gefitinib versus docetaxel was less than 1.154. Non-inferiority was proven, as the result was a HR of 1.020 (96% CI 0.905 to 1.150). Median OS was 7.6 months for gefitinib patients and 8.0 months in the docetaxel group. Superiority of gefitinib over docetaxel in patients with high EGFR-gene-copy number was not proven.
The INTEREST trial had been expected to provide results that would allow the future selection of patients based on prognostic factors and it was also expected that patients with increased EGFR gene copy-number would do better on gefitinib [1]. However, this was not evident from the results.
The ISEL (Iressa Survival Evaluation in Lung Cancer) study (n=1,692) investigated the effects of gefitinib as second- or third-line treatment for patients with locally advanced or metastatic NSCLC. Patients were randomised to gefitinib 250mg per day or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. After a median follow-up of 7·2 months, median survival did not differ between the groups: for the overall population it was 5·6 months for gefitinib and 5·1 months for placebo; and for patients with adenocarcinoma: 6·3 months compared to 5·4 months.
According to the Summary of Product Characteristics, pooled data from the ISEL, INTEREST and IPASS trials (2,462 patients treated with gefitinib) show that adverse events occurring in more than 20% of patients were diarrhoea and skin reactions (rash, acne, pruritus etc.). Approximately 8% of patients had severe reactions. Interstitial lung disease, often severe, has been reported in 1.3% of patients. Cases with fatal outcomes have been seen. Although liver function test abnormalities were common, they were rarely associated with hepatitis.
Several appraisals of other agents for NSCLC are available on the NICE website and a clinical guideline on the management of lung cancer was issued in February 2005.
So what?
In 2003, there were 31,900 new diagnoses of lung cancer in England and Wales (an incidence of around 60 cases/100,000) [2]. A diagnosis of NSCLC is made in approximately 80% of cases. If we assume that 70–80% of these will be at an advanced stage then approximately 39 patients/100,000 population may require a biopsy and test for EGFR-mutation status. About 11–15% of these will be EGFR-mutation positive and eligible for gefitinib (AstraZeneca personal communication, April 2009), approximately 5–6 patients/100,000 population. However, the EGFR mutation test is not routinely performed and is available only in a small number of NHS centres at present. Commercial laboratories also offer the test. Cost estimates for the test seem to vary between £100 and £400 (Personal communication, Cancer Networks).
AstraZeneca is hoping to operate a Single Payment Access scheme for this drug which will include the cost of the EGFR-test. It remains uncertain how this will operate for patients who have the test and are mutation-negative.
The Iressa Pan-Asia Study (IPASS) details
Mok TS, Wu Y-L, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. Online first August 19th 2009. N Engl J Med 2009; 361: 1–11
Design: Phase 3, randomised open-label trial
Patients: Previously untreated adults in East Asia who had advanced pulmonary adenocarcinoma and of whom 94% had never smoked. Over 99% of participants were of Asian origin and 79% were women.
Intervention and comparison: Gefitinib 250mg orally daily (n=609) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6mg/ml/minute) plus paclitaxel (200mg/m2 body surface area) (n=608). Mean duration of treatment with gefitinib was 6.4 months (median 5.6; range, 0.1 to 22.8) and 3.4 months for dual chemotherapy (median 4.1; range, 0.7 to 5.8). Median follow-up period for analysis of PFS was 5.6 months.
Outcomes and results: The primary endpoint was progression-free survival (PFS). The study met its primary objective of demonstrating non-inferiority of gefitinib, and also showed its superiority, with regard to dual chemotherapy, in terms of PFS in the intention-to-treat population (ITT).
Published data is conflicting with PFS reported as better for patients receiving gefitinib (HR 0.74; 95% CI 0.65–0.85, P<0.001), yet the median PFS is reported as 5.7 months for gefitinib and 5.8 months for dual chemotherapy.
The 12-month rates of PFS were 24.9% for gefitinib and 6.7% with carboplatin-paclitaxel.
Secondary endpoints included overall survival (OS), tumour response and quality of Life (QoL). Overall survival data is immature at this stage in the trial and follow-up is ongoing, with completion due in 2010. Preliminary OS seems similar for the two treatments with a median of 18.6 versus 17.3 months, respectively (HR was 0.91; 95% CI 0.76–1.10).
Significantly more patients in the gefitinib group than in the dual chemotherapy group had a clinically-relevant improvement in QoL.
Correlating outcome with biomarkers was a pre-planned secondary analysis. Of the 437 patients evaluable for EGFR mutation status, 261(59.7%) were positive for a mutation. Such patients had a longer PFS with gefitinib than if they were receiving dual chemotherapy, HR 0.48; 95% CI 0.36–0.64, P<0.001. PFS was significantly shorter among patients receiving gefitinib than those receiving dual chemotherapy in the mutation-negative subgroup. Where the mutation status was unknown then PFS was similar to that for the overall population. Post-hoc analysis of OS in this sub-group favoured gefitinib in mutation-positive patients (HR 0.78) but the 95% CI crossed the point of no difference (0.50–1.20).
The most common adverse events were rash or acne and diarrhoea in the gefitinib group and neurotoxic effects, neutropenia, and alopecia in those receiving dual chemotherapy.
Sponsorship: AstraZeneca
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References
1. Cullen M and Thatcher N. Gefitinib or docetaxel in advanced non-small-cell lung cancer. Lancet 2008; 372:1785-6. Accessed from http://www.sciencedirect.com/science/article/B6T1B-4TYWC50-4/2/50dfb2c9d72f920d716fc46a1255e502?&zone=raall on 17.8.09
2. NICE. Gefitinib for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, Final scope July 2009. Accessed from http://www.nice.org.uk/nicemedia/pdf/LungNSCFLGefitinibFinalScope.pdf on 17.8.09