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United States Food and Drug Administration Drug Approval Summary: Gefitinib (ZD1839; Iressa) Tablets

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United States Food and Drug Administration Drug Approval Summary: Gefitinib (ZD1839; Iressa) Tablets 1212 Vol. 10, 1212–1218, February 15, 2004 Clinical Cancer Research Report from the FDA United States Food and Drug Administration Drug Approval Summary: Gefitinib (ZD1839; Iressa) Tablets Martin H. Cohen, Grant A. Williams, ticenter trial comparing two oral doses of gefitinib (250 Rajeshwari Sridhara, Gang Chen, versus 500 mg/day). A total of 216 patients were enrolled. W. David McGuinn, Jr., David Morse, The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population Sophia Abraham, Atiqur Rahman, Chenyi Liang, for the efficacy analysis. A partial tumor response occurred Richard Lostritto, Amy Baird, and in 14% (9 of 66) of patients receiving 250 mg/day gefitinib Richard Pazdur and in 8% (6 of 76) of patients receiving 500 mg/day ge- Division of Oncology Drug Products, Center for Drug Evaluation and fitinib. The overall objective response rate (RR) for both Research, United States Food and Drug Administration, Rockville, doses combined was 10.6% (15 of 142 patients; 95% confi- Maryland dence interval, 6.0–16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6–18.6؉ months). Other Abstract submitted data included the results of two large trials con- On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg ducted in chemotherapy-naive, stage III and IV non-small tablets (AstraZeneca Inc.) received accelerated approval by cell lung cancer patients. Patients were randomized to re- the United States Food and Drug Administration as mono- ceive gefitinib (250 or 500 mg daily) or placebo, in combi- or (1093 ؍ therapy for patients with locally advanced or metastatic nation with either gemcitabine plus cisplatin (n Results from this .(1037 ؍ non-small cell lung cancer after failure of both platinum- carboplatin plus paclitaxel (n based and docetaxel chemotherapies. Information provided study showed no benefit (RR, time to progression, or sur- in this summary includes chemistry manufacturing and con- vival) from adding gefitinib to chemotherapy. Consequently, trols, clinical pharmacology, and clinical trial efficacy and gefinitib is only recommended for use as monotherapy. safety results. Gefitinib is an anilinoquinazoline compound Common adverse events associated with gefitinib treatment with the chemical name 4-quinazolinamine,N-(3-chloro-4- included diarrhea, rash, acne, dry skin, nausea, and vomit- flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has ing. Interstitial lung disease has been observed in patients the molecular formula C H ClFN O . Gefitinib is often 22 24 4 3 receiving gefitinib. Worldwide, the incidence of interstitial referred to as a “specific” or “selective” inhibitor of epider- lung disease was about 1% (2% in the Japanese post- mal growth factor receptor. Studies demonstrate, however, marketing experience and about 0.3% in a United States that gefitinib inhibits the activity of other intracellular expanded access program). Approximately one-third of the transmembrane tyrosine-specific protein kinases at concen- cases have been fatal. Gefitinib was approved under accel- trations similar to those at which it inhibits the epidermal erated approval regulations on the basis of a surrogate end growth factor signal. Maximum plasma concentrations re- point, RR. No controlled gefitinib trials, to date, demon- ␮ sulting from clinically relevant doses are 0.5–1 M or more, strate a clinical benefit, such as improvement in disease- well within the IC values of several tyrosine kinases. No 50 related symptoms or increased survival. Accelerated ap- clinical studies have been performed that demonstrate a proval regulations require the sponsor to conduct additional correlation between epidermal growth factor receptor ex- studies to verify that gefitinib therapy produces such benefit. pression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed through- out the body. Gefitinib is extensively metabolized in the liver Introduction by cytochrome P450 3A4 enzyme. Over a 10-day period, Gefitinib (Iressa; ZD1839) is a member of a new class of approximately 86% of an orally administered radioactive oral drugs that inhibit receptor tyrosine kinases (TKs) including dose is recovered in the feces, with <4% of the dose in the the epidermal growth factor receptor (EGFR)-TK; however, the urine. After daily oral administration, steady-state plasma precise anticancer mechanism of action has not been estab- levels are reached in 10 days and are 2-fold higher than lished. The submitted New Drug Application sought accelerated those achieved after single doses. Gefitinib effectiveness was approval for gefitinib as monotherapy for patients receiving demonstrated in a randomized, double-blind, Phase II, mul- third-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC). At present, four cisplatin-containing doublets (docetaxel, gemcitabine, paclitaxel, and vinorelbine) and single-agent vi- Received 11/12/03; accepted 11/18/03. norelbine are approved for the treatment of chemotherapy-naı¨ve Note: Dr. Chen is presently atJ&JPharmaceutical Research and NSCLC patients. Docetaxel is approved for second-line therapy. Development, 920, Route 202, Raritan, New Jersey 08869. Before gefitinib approval, third-line treatment was an unmet Requests for reprints: Martin H. Cohen, United States Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, MD 20857. need. Phone: (301) 594-5470; Fax: (301) 594-0499; E-mail: cohenma@cder. This application received Fast Track designation (allowing fda.gov. early submission and review of application components) and Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2004 American Association for Cancer Research. Clinical Cancer Research 1213 priority review status (with a 6 month review goal). The final ities, and major portions of these proteins have considerable Chemistry, Manufacturing and Controls section of the New sequence homology (2, 3). Drug Application was received on August 5, 2002. After safety Epidermal growth factor (EGF) binds to the extracellular reports of pulmonary toxicity became available from the Japa- domain of EGFR, a large single-pass transmembrane receptor nese post-marketing experience in October 2002, additional protein. When two receptor proteins in close proximity bind safety information was requested by the United States Food and EGF, an intracellular dimer is formed. The two components of Drug Administration. Supplemental information concerning in- the dimer autophosphorylate each other at multiple sites. This terstitial lung disease (ILD) was provided in submissions autophosphorylation step is essential for the initiation of kinase through January 2003, resulting in an adjusted approval goal activity in most TK receptors proteins except EGFR, for which date of May 5, 2003. it is possibly only facilitative (4). A complex menagerie of intracellular signaling proteins then bind and are, in turn, phos- Chemistry, Manufacturing, and Controls phorylated (5). These proteins initiate a cascade of signals Drug Substance. Gefitinib is an anilinoquinazoline com- within the cellular cytoskeleton and the nucleus that regulate pound with the chemical name 4-quinazolinamine,N-(3-chloro- cell division. Other receptor TKs control cell division or other 4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. The cell functions similarly. Cross-signaling among the downstream structural formula is represented in Fig. 1. signaling proteins is considerable. Gefitinib, a free base, has the molecular formula Many human tumors have high copy numbers of the EGFR and other receptor tyrosine-specific kinases on the cell surface. C22H24ClFN4O3. It is a white-colored powder. The molecule High copy number may result from overexpression at the tran- has pKa values of 5.4 and 7.2 and therefore ionizes progres- sively in solution as the pH falls. Gefitinib is sparingly soluble scription level or from a failure of the cell to attenuate the at pH 1 and is practically insoluble above pH 7, with the receptor signal by endocytosis (6). High copy number correlates solubility dropping sharply at pH 5. with a poor clinical prognosis. Inhibition of EGFR dimerization The proposed drug substance specifications were found to by transfected dominant negative mutants of EGFR, blockade of be adequate, and the test data were acceptable. The drug sub- EGFR expression with antisense nucleotides, or inhibition of the stance is stored at controlled room temperature. EGF signal with EGFR-specific antibodies can prevent EGF- Drug Product. Iressa (gefitinib) film-coated tablets con- stimulated cell division (7–9). These results led to the search for tain 250 mg of gefitinib/film-coated tablet. Twenty-four to 36 a small molecule EGFR inhibitor. months of stability data from the supportive drug product sta- Gefitinib Mechanism of Action. Ward et al. (10) de- bility batches were adequate to demonstrate the stability of drug fined the kinetics of the ATP-driven phosphorylation of tyrosine product tablets under International Conference on Harmoniza- by EGFR. They then selected likely inhibitors of EGFR based tion testing conditions. on structural similarities to ATP or tyrosine. The selected can- No significant degradation in chemical and physical prop- didate drug was 4-(3-chloroanilino)-quinazoline. This com- erties was observed in the drug product stability database. Based pound competitively inhibited ATP in
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