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The Oncologist, Vol. 8, No. 4, 303–306, August 2003
© 2003 AlphaMed Press

FDA COMMENTARY

FDA Drug Approval Summary: Gefitinib (ZD1839) (Iressa®) Tablets

Martin H. Cohen, Grant A. Williams, Rajeshwari Sridhara, Gang Chen, Richard Pazdur

Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA

Correspondence: Martin H. Cohen, M.D., U.S. Food and Drug Administration, HFD-150, 5600 Fishers Lane, Rockville, Maryland 20857, USA. Fax: 301-594-0499; e-mail: cohenma{at}cder.fda.gov


   ABSTRACT
Top
 Abstract
Introduction
 Study Design
 Safety
 Pulmonary Toxicity
 Conclusions
 
On May 5, 2003, gefitinib (Iressa®, ZD1839) 250-mg tablets received accelerated approval by the U.S. Food and Drug Administration as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes efficacy and safety results of relevant clinical trials. Effectiveness was demonstrated in a randomized, double-blind, phase II, multicenter trial comparing two oral doses of gefitinib (250 mg/day versus 500 mg/day). Two hundred sixteen patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving gefitinib 250 mg/day and in 8% (6 of 76) of patients receiving gefitinib 500 mg/day. The overall objective response rate for both doses combined was 10.6% (15 of 142 patients) (95% confidence 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 submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV NSCLC patients. Patients were randomized to receive gefitinib (250 mg or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1,093) or carboplatin plus paclitaxel (n = 1,037). Results from those studies showed no benefit (response rate, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Most toxicities were Common Toxicity Criteria grade 1 or 2. Interstitial lung disease (ILD) has been observed in patients receiving gefitinib. Worldwide, the incidence of ILD is about 1% (2% in the Japanese postmarketing experience and about 0.3% in a U.S. expanded access program). Approximately one-third of the cases were fatal. Physicians should promptly evaluate new or worsening pulmonary symptoms. If ILD is confirmed, appropriate management includes discontinuation of gefitinib. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point response rate. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or greater survival. Accelerated approval regulations require the sponsor to conduct further studies to verify that gefitinib therapy produces such a benefit.

Key Words. Gefitinib • Iressa® • Non-small cell lung cancer, metastatic • Third-line treatment


   INTRODUCTION
Top
 Abstract
 Introduction
Study Design
 Safety
 Pulmonary Toxicity
 Conclusions
 
Gefitinib (Iressa®, ZD1839; Astra Zeneca, Inc.; London, UK; http://www.astrazeneca.com) (Fig. 1Go) is a member of a new class of oral drugs that inhibits intracellular tyrosine kinase (TK) activity including that of the epidermal growth factor receptor (EGFR)-TK. Gefitinib binds at the ATP site of the tyrosine kinase region, a region that is highly conserved across the various transmembrane tyrosine kinases. The maximum plasma concentrations resulting from clinically relevant gefitinib doses are 0.5–1 µM or more, similar to or greater than the 50% inhibitory concentration values of other intracellular transmembrane tyrosine-specific protein kinases. Therefore, gefitinib cytotoxicity could be the result of inhibition of downstream signal proteins or ATP-dependent kinases other than EGFR-TK.



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  		Figure 1. Molecular structure of gefitinib.

 
Gefitinib is extensively metabolized in the liver by the cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces with less than 4% of the dose in the urine. Following daily oral administration, steady-state plasma levels are reached in 10 days and are twofold higher than those achieved following single doses.

In preclinical studies, the antiproliferative activity of gefitinib, alone or in combination with cytotoxic drugs, was investigated in human ovarian (OVCAR-3), breast (MCF- 10A ras; ZR-75-1), and colon (GEO) cancer cell lines, which express EGFR and transforming growth factor alpha. Gefitinib inhibited colony-forming ability in a concentration-dependent manner. Combining gefitinib with platins (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, docetaxel), topoisomerase inhibitors (doxorubicin, etoposide, topotecan), or the antimetabolite raltitrexed resulted in a markedly greater apoptotic cell death than that induced by single-agent treatment. In studies with colon cancer (GEO) xenografts, combined treatment with gefitinib and cytotoxic agents produced tumor growth arrest and extended the survival of tumor-bearing animals.

The submitted new drug application (NDA) sought accelerated approval for gefitinib as monotherapy for patients receiving third-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC). At present, there are four cisplatin-containing doublets (docetaxel, gemcitabine, paclitaxel, vinorelbine) and single-agent vinorelbine approved for the first-line treatment of this patient population. Docetaxel is approved for second-line therapy. Third-line treatment is an unmet need.


   STUDY DESIGN
Top
 Abstract
 Introduction
 Study Design
Safety
 Pulmonary Toxicity
 Conclusions
 
The sponsor submitted two trials in previously treated NSCLC patients. The first trial was in the third-line treatment of NSCLC and provided the primary evidence supporting approval. Failure of prior platinum and docetaxel had to have been the result of treatment intolerance or disease progression within 90 days of the last chemotherapy. The trial was a randomized, double-blind, phase II, multicenter comparison of two doses of gefitinib tablets (250 mg/day versus 500 mg/day). The second trial enrolled patients who had failed one or two previous chemotherapy regimens, at least one having contained a platinum, and provides supportive evidence of gefitinib safety. Two hundred sixteen patients at 30 U.S. medical centers were entered in the third-line treatment trial. One hundred forty-two patients with documented failure of platinum and docetaxel were evaluable for the primary efficacy analysis.

Patient demographics and disease characteristics of the eligible treatment population are summarized in Table 1Go. Approximately 75% of the eligible study patients had adenocarcinoma histology (either alone or mixed with squamous cell histology). Thirty-two percent of patients receiving gefitinib 250 mg/day had never smoked. The median time from lung cancer diagnosis to study randomization was 19.6 months.


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  		Table 1. Demographics and disease characteristics, third-line treatment population
 
Among the 142 evaluable patients, there were 15 partial responses. Response rates and durations are summarized in Table 2Go. Partial responses occurred in 9 of 66 patients receiving gefitinib 250 mg/day and in 6 of 76 patients receiving gefitinib 500 mg/day. The response rate was similar in the 74 study patients not evaluable for the primary efficacy analysis (9.5%).


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  		Table 2. Response rates and duration in the third-line treatment of NSCLC
 
Exploratory analyses of response rates in different subgroups of patients were performed (Table 3Go). Due to small sample sizes, the results lack precision, as evidenced by the wide confidence limits of the estimates. Responding patients were predominantly female (11/15) and had adenocarcinoma (12/15). Response rates did not vary with World Health Organization (WHO) performance status (0–1 versus 2) or number of prior therapies (2 versus 3 versus 4). While disease-related symptom improvement and quality of life (QOL) were evaluated in both trials, the meaningfulness of that evaluation is questionable. Because Iressa® 250 mg/day and 500 mg/day had comparable efficacy results, there was no comparator regimen for the QOL or symptom-relief analysis. Methodologic issues exist, including the absence of blinding, the censoring of early progressors, and the use of concomitant medications that might have contributed to symptom relief. Therefore, QOL and symptom results are not presented here.


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  		Table 3. Retrospective subgroup analysis of response rates in the third-line treatment of NSCLC
 
Two large trials were conducted in chemotherapy-naive, stage III and IV NSCLC patients. Two thousand one hundred thirty patients were randomized to receive gefitinib (250 mg or 500 mg daily) or placebo in combination with platinum-based chemotherapy regimens. The chemotherapy regimens given in those first-line trials were gemcitabine plus cisplatin (n = 1,093) and carboplatin plus paclitaxel (n = 1,037). Results from those studies showed no benefit (response rate, time to progression, or survival) from adding gefitinib to chemotherapy.


   SAFETY
Top
 Abstract
 Introduction
 Study Design
 Safety
Pulmonary Toxicity
 Conclusions
 
Drug-related adverse events occurring with incidences >=5% in either the 250-mg or 500-mg dose group are summarized in Table 4Go. The most common adverse reactions were diarrhea, rash, and acne. Treatment-related delays and dose reductions occurred more often in the 500 mg/day dose group than in the 250 mg/day group (dose delays: 26% and 15%, respectively; dose reductions: 10% and 1%, respectively). Most toxicities were Common Toxicity Criteria grade 1 or 2. There did not seem to be substantially different toxicities for different age groups. The small numbers of patients >75 years of age (11 in the 250 mg/day group and 10 in the 500 mg/day group) make it difficult to draw conclusions concerning this group.


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  		Table 4. Drug-related adverse events with an incidence of >=5%
 

   PULMONARY TOXICITY
Top
 Abstract
 Introduction
 Study Design
 Safety
 Pulmonary Toxicity
Conclusions
 
Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib. ILD is a complex disease, described by investigators using different terms. (The sponsor captured cases by a collection of 24 MedDRA [Medical Dictionary for Regulatory Affairs] terms.) The U.S. Food and Drug Administration (FDA) performed a detailed analysis of the sponsor’s drug safety database. This included 50,005 patients (including 18,960 from marketed use in Japan). Four hundred eight cases of ILD (324 from Japan and 84 from the U.S./rest of the world) were identified. The median time to onset of ILD was 24 days in the Japan group and 42 days in the U.S. group. Worldwide, the incidence of ILD associated with gefitinib treatment was about 1% (2% in the Japanese postmarketing experience and about 0.3% in approximately 23,000 patients treated with gefitinib in a U.S. expanded-access program). Approximately one-third of the cases were fatal. Patients often presented with the acute onset of dyspnea, with or without cough or low-grade fever. Symptoms often became severe within a short time and required hospitalization.

ILD occurred in patients who received prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported cases), and no previous therapy. Patients with concurrent idiopathic pulmonary fibrosis whose condition worsened while receiving gefitinib have been observed to have a greater rate of mortality. In the randomized studies of gefitinib combined with chemotherapy, the ILD rate was about 1%, but the rate was similar in the gefitinib and control (chemotherapy plus placebo) arms. In the event of pulmonary symptoms (dyspnea, cough, fever), gefitinib therapy should be interrupted, and a prompt investigation of these symptoms should occur. If interstitial lung disease is confirmed, gefitinib should be discontinued and the patient treated appropriately.

Asymptomatic increases in liver transaminases have been observed in gefitinib-treated patients; therefore, periodic liver function testing (transaminases, bilirubin, and alkaline phosphatase) should be considered. Discontinuation of gefitinib should be considered if changes are severe.


   CONCLUSIONS
Top
 Abstract
 Introduction
 Study Design
 Safety
 Pulmonary Toxicity
 Conclusions
 
The accelerated approval regulations allow approval of cancer drugs based on a surrogate end point when the drug provides a benefit over available therapy. Gefitinib received accelerated approval based on an objective response rate of 10.6%, with a median response duration of 7 months, in the third-line treatment of NSCLC, a setting where no therapy has demonstrated efficacy. Under the accelerated approval regulations, the sponsor will be required to conduct further studies to verify that gefitinib therapy is associated with clinical benefit in NSCLC. The recommended gefitinib dose is 250 mg/day because the 500 mg/day dose was more toxic yet not more effective.

The views expressed herein are the result of independent work and do not necessarily represent the views and findings of the U.S. FDA.

Received May 19, 2003; accepted for publication June 20, 2003.




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