Emerging Drug List GEFITINIB

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1 Generic (Trade Name): Manufacturer: Gefitinib (Iressa ) formerly referred to as ZD1839 AstraZeneca NO. 52 JANUARY 2004 Indication: Current Regulatory Status: Description: Current Treatment: Cost: Evidence: For the treatment of inoperable or recurrent non-small cell lung cancer (NSCLC). Gefitinib received marketing approval in Canada in December Gefitinib was approved in May 2003 by the Food and Drug Administration for marketing in the United States. Gefitinib is also marketed in Japan and Australia. 2 Regulatory reviews in Europe are underway. Gefitinib is undergoing phase III clinical trials for the treatment of head and neck cancer; and phase II clinical trials for the treatment of breast cancer and colorectal cancer. 3 Gefitinib is a synthetic anilinoquinazoline 4 that selectively inhibits the tyrosine kinase activity of epidermal growth factor receptor (EGFR). When stimulated, EGFR starts a cascade of signalling events that are implicated in cell proliferation and survival. 4 Antineoplastic agents used to treat NSCLC include vinorelbine, paclitaxel, docetaxel, gemcitabine, vinblastine, mitomycin, irinotecan and topotecan. 3 These agents are typically combined with platinum agents such as carboplatin and cisplatin. Chemotherapy for NSCLC can palliate symptoms and may provide a short-term survival benefit, but the effects on overall survival are small (median <2 months). 3 There is no established price for gefitinib in Canada. In Australia, the price for one month of therapy (250 mg daily) is approximately C$4,070 (A$1=C$0.904). 5 In the US, the cost of gefitinib (250 mg daily) is approximately US$1,168 per month. In Japan, it is approximately US$2,200 per month. 6,7 It is estimated that annual sales of gefitinib in the US will reach US$600 million in Gefitinib s efficacy against NSCLC was evaluated in four phase I trials (dose finding trials) and in two phase II trials (IDEAL 1 and IDEAL 2). 3,9 The IDEAL (Iressa dose evaluation in advanced lung cancer) trials were double-blind, randomized, parallel group, noncomparative, multicentre clinical trials in patients with metastatic or locally advanced NSCLC. In the IDEAL 1 trial, patients had previously received one or two chemotherapy regimens (at least one being a platinum-based regimen). In IDEAL 2, most patients were refractory or intolerant of two or more previous chemotherapy regimens containing a platinum agent and docetaxel. 10,11 Patients were randomized to groups receiving 250 mg or 500 mg daily doses of gefitinib. A total of 210 patients were randomized in IDEAL 1 with 216 randomized in IDEAL 2. The primary objectives of these trials included the determination of objective radiographic response rates, safety profile and symptom improvement. Secondary objectives included finding the rates of disease control, progression-free survival rates and times to symptom progression.

2 Radiographic response rates, median survival rates, one-year survival rates and symptomatic improvement rates are summarized below: IDEAL mg 500 mg IDEAL mg 500 mg Radiographic Response Rate Median Survival Rate (months) One-year Survival Rate Symptomatic Improvement Gefitinib was also evaluated in combination with chemotherapy in the INTACT trials (Iressa NSCLC trial assessing combination treatment). 12,13 In INTACT 1, the chemotherapy involved cisplatin plus gemcitabine, while in the INTACT 2 trial, carboplatin plus paclitaxel were used. The two trials enrolled over 2,000 subjects. Once patients were enrolled, they were randomized to receive chemotherapy (six cycles) plus gefitinib 250 mg daily or 500 mg daily; or placebo. Once the chemotherapy cycles were completed, subjects continued on daily doses of gefitinib or placebo until disease progression. Neither trial produced positive results for gefitinib. One-year survival rates were 43%, 41% and 45% for gefitinib 250 mg, 500 mg and placebo respectively in INTACT 1; and 37%, 41% and 42% for gefitinib 250 mg, 500 mg and placebo in INTACT 2. There were no significant differences in symptom response or time to tumour progression with gefitinib plus chemotherapy versus chemotherapy alone. Smaller studies on gefitinib have been published. Cappuzzo et al. conducted a study in 63 patients with advanced or metastatic NSCLC to determine whether there was a correlation between HER2 gene expression and gefitinib efficacy. 14 Daily doses of 250 and 500 mg were assessed. This study did not demonstrate an association between gefitinib efficacy or toxicity and HER2 expression. A phase II trial evaluating the efficacy of gefitinib in treating recurrent or metastatic squamous cell carcinoma of the head and neck was recently published. 15 Enrolled patients had no more than one prior therapy for recurrent or metastatic disease. All patients received gefitinib 500 mg daily. Of the initial 52 patients, 47 were assessable for a response. The observed response rate was 10.6% and the disease control rate was 53%. The median time to disease progression was 3.4 months and the median survival time was 8.1 months. Adverse Effects: Gefitinib was generally well tolerated, with most adverse effects being mild and transient. 4 The most commonly reported adverse effects were skin reactions (i.e., rash, acne, dry skin, pruritus) and gastrointestinal effects (i.e., diarrhea, vomiting, nausea). In

3 the IDEAL 1 and IDEAL 2 trials, grade 3 or 4 adverse effects were reported in 8.7% and 6.9% of patients receiving 250 mg; and 30.2% and 17.5% of those receiving the 500 mg daily dose. 10,11 Safety concerns surfaced after the appearance of reports about deaths that were attributed to the use of gefitinib. In Japan, where gefitinib has been available the longest, of 23,500 patients taking the drug, 471 developed serious cases of pneumonia or other pulmonary adverse effects. The Japanese government revealed that 167 deaths were attributed to the use of gefitinib. 16,17 American oncologists questioned the association between severe pneumonia and gefitinib. Experts stated that pneumonitis, which was also reported with the use of irinotecan, another chemotherapy drug, was never reported in other countries. 18 They stated that in Japan, oncologists used a lot of radiation therapy, so the cases of pneumonia were likely cases of radiation-induced pneumonitis, which typically occurs three to six months after radiation therapy. 18 Commentary: Gefitinib is a drug in a new class of agents designed to inhibit the tyrosine kinase activity of EGFR. There is no direct evidence that this agent offers a therapeutic advantage compared to other agents or supportive care. Some experts note that the radiographic response rates and the 24% to 35% one-year survival rates observed in the IDEAL trials suggest that there is a benefit compared with historical controls and attribute this to use of the drug. Others note that the patients in the IDEAL trials do not represent a typical population of those with refractory advanced or metastatic disease. This is supported by the high prevalence of slow-growing adenocarcinomas (>60%) in these studies, the relatively long time from initial diagnosis to randomization (median in IDEAL 1, 12.1 months; median in IDEAL 2, 19.6 months) and the lack of multiple measurable lesions in responding patients. 19 Other trial design issues prevent the drawing of straightforward conclusions about gefitinib s effects. These include the absence of a suitable control group, the absence of blinding, the dropping out of patients with early disease progression and the inappropriate meaning of criteria used to evaluate the benefit leading to an improved quality of life. The associated and controversial pulmonary adverse effects and the increased incidence of death in Japan have not been reported in the US. Post-marketing surveillance is expected to be intense, however, now that gefitinib has been launched in Canada. With widespread uptake, the use of gefitinib could significantly increase the cost of managing NSCLC.

4 References: 1. Iressa. In: Notices of compliance. Ottawa: Therapeutic Products Directorate, Health Canada; Available: (accessed 2004 Jan 14). 2. Iressa (gefitinib, ZD1839). London: AstraZeneca International; Available: (accessed 2003 Sep 11). 3. Pipeline summary. London: AstraZeneca International; Available: (accessed 2003 Sep 11). 4. Culy CR, Faulds D. Gefitinib. Drugs 2002;62(15): Robotham J. Smokers pay heavy price - but who picks up the bill? Sydney Morning Herald 2003 May 8. Available: 6. Gefitinib (Iressa) for advanced non-small cell lung cancer. Med Lett Drugs Ther 2002;44(1138): Minutes of the DoD Pharmacy & Therapeutics Executive Council " " Interim Meeting, 14 July 2003 (Amended version (section 4B) approved by the DoD P&T Executive Council at their regularly scheduled meeting, 5 August 2003). Houston: Pharmacoeconomic Center, Dept. of Defense; Seidman R. Protecting pharmaceutical value [presentation]. Health Care Policy Conference V; 2003 Jul 9; Thousand Oaks (CA). Available: 9. Johnson DH. Gefitinib (Iressa) trials in non-small cell lung cancer. Lung Cancer 2003;41 Suppl 1:S Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, 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(12): Kris MG, Natale RB, Herbst RS, Lynch TJ, Prager D, Belani CP, et al. A phase II trial of ZD1839 ('Iressa') in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2) [abstract]. 38th Annual Meeting of the American Society of Clinical Oncology; 2003 May 18; Orlando (FL). Abstract no Available: PAGE,00.asp. 12. Johnson DH, Herbst R, Giaccone G, Schiller J, Natale RB, Miller V, et al. ZD1839 ("Iressa") in combination with paclitaxel & carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC): results from a phase III clinical trial (INTACT 2) [abstract]. Ann Oncol 2002;13 Suppl 5: Available: Giaccone G, Johnson DH, Manegold C, Scagliotti GV, Rosell R, Wolf M, et al. A Phase III clinical trial of ZD 1839 (Iressa) in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small cell lung cancer (INTACT 1) [abstract]. Ann Oncol 2002;13 Suppl 5:2-3. Available: Cappuzzo F, Gregorc V, Rossi E, Cancellieri A, Magrini E, Paties CT, et al. Gefitinib in pretreated nonsmall-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC. J Clin Oncol 2003;21(14): Cohen EE, Rosen F, Stadler WM, Recant W, Stenson K, Huo D, et al. Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2003;21(10): Iressa - more deaths reported in Japan; drug struggles for survival. DrugINTEL Newsletter 2003;1(4). Available:

5 17. Drugs of concern: Iressa. Wayne (PA): DrugIntel; Available: The safety of AstraZeneca's Iressa. Trends in Medicine 2002;Nov:1-4. Available: Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Drug review package. Iressa (gefitinib) tablets, company: AstraZeneca, application no.: , approval date: 5/5/2003. Medical review: part 1. Rockville (MD): The Center; Available: This series highlights medical technologies that are not yet in widespread use in Canada and that may have a significant impact on health care. The contents are based on information from early experience with the technology; however, further evidence may become available in the future. These summaries are not intended to replace professional medical advice. They are compiled as an information service for those involved in planning and providing health care in Canada. These summaries have not been externally peer reviewed. ISSN (online only)