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

FDA Drug Approval Summary: Gefitinib (ZD1839) (Iressa®) Tablets Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 This material is protected by U.S. Copyright law. The ® Unauthorized reproduction is prohibited. For reprints contact: Reprints@AlphaMedPress.com Oncologist 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 Key Words. Gefitinib · Iressa · Non-small cell lung cancer, metastatic · Third-line treatment ABSTRACT combination with either gemcitabine plus cisplatin (n = On May 5, 2003, gefitinib (Iressa , ZD1839) 250-mg 1,093) or carboplatin plus paclitaxel (n = 1,037). Results tablets received accelerated approval by the U.S. Food and from those studies showed no benefit (response rate, time Drug Administration as monotherapy treatment for to progression, or survival) from adding gefitinib to patients with locally advanced or metastatic non-small cell chemotherapy. Consequently, gefinitib is only recom- lung cancer (NSCLC) after failure of both platinum-based mended for use as monotherapy. Common adverse and docetaxel chemotherapies. Information provided in events associated with gefitinib treatment included diar- this summary includes efficacy and safety results of rele- rhea, rash, acne, dry skin, nausea, and vomiting. Most vant clinical trials. Effectiveness was demonstrated in a toxicities were Common Toxicity Criteria grade 1 or 2. randomized, double-blind, phase II, multicenter trial com- Interstitial lung disease (ILD) has been observed in paring two oral doses of gefitinib (250 mg/day versus 500 patients receiving gefitinib. Worldwide, the incidence of mg/day). Two hundred sixteen patients were enrolled. The ILD is about 1% (2% in the Japanese postmarketing 142 patients who were refractory to or intolerant of a plat- experience and about 0.3% in a U.S. expanded access inum and docetaxel comprised the evaluable population program). Approximately one-third of the cases were for the efficacy analysis. A partial tumor response fatal. Physicians should promptly evaluate new or wors- occurred in 14% (9 of 66) of patients receiving gefitinib ening pulmonary symptoms. If ILD is confirmed, appro- 250 mg/day and in 8% (6 of 76) of patients receiving gefi- priate management includes discontinuation of gefitinib. tinib 500 mg/day. The overall objective response rate for Gefitinib was approved under accelerated approval reg- both doses combined was 10.6% (15 of 142 patients) (95% ulations on the basis of a surrogate end point response confidence interval 6.0%-16.8%). Responses were more rate. No controlled gefitinib trials, to date, demonstrate a frequent in females and in nonsmokers. The median dura- clinical benefit, such as improvement in disease-related tion of response was 7.0 months (range 4.6-18.6+ months). symptoms or greater survival. Accelerated approval reg- Other submitted data included the results of two ulations require the sponsor to conduct further studies to large trials conducted in chemotherapy-naive, stage III verify that gefitinib therapy produces such a benefit. The and IV NSCLC patients. Patients were randomized to Oncologist 2003;8:303-306 receive gefitinib (250 mg or 500 mg daily) or placebo, in INTRODUCTION new class of oral drugs that inhibits intracellular tyrosine Gefitinib (Iressa , ZD1839; Astra Zeneca, Inc.; London, kinase (TK) activity including that of the epidermal UK; http://www.astrazeneca.com) (Fig. 1) is a member of a growth factor receptor (EGFR)-TK. Gefitinib binds at the 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@cder.fda.gov Received May 19, 2003; accepted for publication June 20, 2003. ©AlphaMed Press 1083-7159/2003/$12.00/0 The Oncologist 2003;8:303-306 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 Cohen, Williams, Sridhara et al. 304 STUDY DESIGN The sponsor submitted two trials in previously treated NSCLC patients. The first trial was in the third-line treatment O N C1 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 progres- sion within 90 days of the last chemotherapy. The trial was a MeO 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 Figure 1. Molecular structure of gefitinib. one or two previous chemotherapy regimens, at least one ATP site of the tyrosine kinase region, a region that is having contained a platinum, and provides supportive evi- highly conserved across the various transmembrane tyrosine dence of gefitinib safety. Two hundred sixteen patients at 30 kinases. The maximum plasma concentrations resulting U.S. medical centers were entered in the third-line treatment from clinically relevant gefitinib doses are 0.5-1 μM or trial. One hundred forty-two patients with documented fail- more, similar to or greater than the 50% inhibitory concen- ure of platinum and docetaxel were evaluable for the primary tration values of other intracellular transmembrane tyrosine- efficacy analysis. specific protein kinases. Therefore, gefitinib cytotoxicity Patient demographics and disease characteristics of the eli- could be the result of inhibition of downstream signal pro- gible treatment population are summarized in Table 1. teins or ATP-dependent kinases other than EGFR-TK. Approximately 75% of the eligible study patients had adeno- Gefitinib is extensively metabolized in the liver by the carcinoma histology (either alone or mixed with squamous cell cytochrome P450 3A4 enzyme. Over a 10-day period, histology). Thirty-two percent of patients receiving gefitinib approximately 86% of an orally administered radioactive 250 mg/day had never smoked. The median time from lung dose is recovered in the feces with less than 4% of the dose cancer diagnosis to study randomization was 19.6 months. in the urine. Following daily oral administration, steady- Among the 142 evaluable patients, there were 15 partial state plasma levels are reached in 10 days and are twofold responses. Response rates and durations are summarized higher than those achieved following single doses. in Table 2. Partial responses occurred in 9 of 66 patients In preclinical studies, the antiproliferative activity of receiving gefitinib 250 mg/day and in 6 of 76 patients gefitinib, alone or in combination with cytotoxic drugs, was receiving gefitinib 500 mg/day. The response rate was sim- investigated in human ovarian (OVCAR-3), breast (MCF- ilar in the 74 study patients not evaluable for the primary 10A ras; ZR-75-1), and colon (GEO) cancer cell lines, efficacy analysis (9.5%). which express EGFR and transforming growth factor alpha. Exploratory analyses of response rates in different sub- Gefitinib inhibited colony-forming ability in a concen- groups of patients were performed (Table 3). Due to small tration-dependent manner. Combining gefitinib with platins sample sizes, the results lack precision, as evidenced by the (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, wide confidence limits of the estimates. Responding docetaxel), topoisomerase inhibitors (doxorubicin, etopo- patients were predominantly female (11/15) and had adeno- side, topotecan), or the antimetabolite raltitrexed resulted in carcinoma (12/15). Response rates did not vary with World a markedly greater apoptotic cell death than that induced by Health Organization (WHO) performance status (0-1 ver- single-agent treatment. In studies with colon cancer (GEO) sus 2) or number of prior therapies (2 versus 3 versus 4). xenografts, combined treatment with gefitinib and cyto- While disease-related symptom improvement and quality toxic agents produced tumor growth arrest and extended the of life (QOL) were evaluated in both trials, the meaningful- survival of tumor-bearing animals. ness of that evaluation is questionable. Because Iressa 250 The submitted new drug application (NDA) sought mg/day and 500 mg/day had comparable efficacy results, accelerated approval for gefitinib as monotherapy for there was no comparator regimen for the QOL or symptom- patients receiving third-line treatment for locally advanced or relief analysis. Methodologic issues exist, including the metastatic non-small cell lung cancer (NSCLC). At present, absence of blinding, the censoring of early progressors, and there are four cisplatin-containing doublets (docetaxel, gem- the use of concomitant medications that might have con- citabine, paclitaxel, vinorelbine) and single-agent vinorel- tributed to symptom relief. Therefore, QOL and symptom bine approved for the first-line treatment of this patient results are not presented here. population. Docetaxel is approved for second-line therapy. Two large trials were conducted in chemotherapy- Third-line treatment is an unmet need. naive, stage III and IV NSCLC patients. Two thousand one Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 305 FDA Drug Approval: Gefitinib hundred thirty patients were randomized to receive gefi- Table 1. Demographics and disease characteristics, third-line treatment population tinib (250 mg or 500 mg daily) or placebo in combination Gefitinib dose with platinum-based chemotherapy regimens. The Characteristics chemotherapy regimens given in those first-line trials were 250 mg/day 500 mg/day gemcitabine plus cisplatin (n = 1,093) and carboplatin plus n* (%) n (%) Age group paclitaxel (n = 1,037). Results from those studies showed 18-64 years43(65) 43(57) no benefit (response rate, time to progression, or survival) 64-74 years19(29) 30(39) from adding gefitinib to chemotherapy. 75 years and older 4 (6) 3 (4) Sex SAFETY Male 38 (58) 41 (54) Drug-related adverse events occurring with incidences Female 28 (42) 35 (46) ≥5% in either the 250-mg or 500-mg dose group are sum- Race marized in Table 4. The most common adverse reactions Caucasian 61 (92) 68 (89) were diarrhea, rash, and acne. Treatment-related delays and African-American 1 (2) 2 (3) dose reductions occurred more often in the 500 mg/day Asian 1 (2) 2 (3) dose group than in the 250 mg/day group (dose delays: 26% Hispanic 0 (0) 3 (4) Other 3 (5) 1 (1) and 15%, respectively; dose reductions: 10% and 1%, respectively). Most toxicities were Common Toxicity Smoking history Criteria grade 1 or 2. There did not seem to be substantially Yes (previous or current smoker) 45 (68) 62 (82) different toxicities for different age groups. The small num- No (never smoked) 21 (32) 14 (18) bers of patients >75 years of age (11 in the 250 mg/day Baseline WHO performance status group and 10 in the 500 mg/day group) make it difficult to 0 14 (21) 9 (12) draw conclusions concerning this group. 1 36 (55) 53 (70) 2 15 (23) 14 (18) Not recorded 1 (2) 0 (0) PULMONARY TOXICITY Tumor histology Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib. ILD is a complex Squamous9(14) 11(14) Adenocarcinoma 47(71) 50(66) disease, described by investigators using different terms. Undifferentiated 6(9) 4(5) (The sponsor captured cases by a collection of 24 MedDRA Large cell1(2) 2(3) [Medical Dictionary for Regulatory Affairs] terms.) The U.S. Squamous and adenocarcinoma 3 (5) 7 (9) Not recorded 0 (0) 2 (3) Food and Drug Administration (FDA) performed a detailed analysis of the sponsor’s drug safety database. This included Current disease status 50,005 patients (including 18,960 from marketed use in Locally advanced 11 (17) 5 (7) Metastatic 55 (83) 71 (93) Japan). Four hundred eight cases of ILD (324 from Japan and 84 from the U.S./rest of the world) were identified. The *total n of patients = 66 median time to onset of ILD was 24 days in the Japan group total n of patients = 76 and 42 days in the U.S. group. Worldwide, the incidence of Table 2. Response rates and duration in the third-line treatment of NSCLC Evaluable patients † ‡ 250 mg/day* (%) 500 mg/day (%) Combined (%) Objective response rate 13.6 7.9 10.6 95% CI 6.4-24.3 3.0-16.4 6.0-16.8 Median response duration (months) 8.9 4.5 7.0 Range 4.6-18.6+ 4.4-7.6 4.4-18.6+ *total n of patients = 66 total n of patients = 76 total n of patients = 142 +indicates data collection is ongoing; CI = confidence interval Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 Cohen, Williams, Sridhara et al. 306 Table 3. Retrospective subgroup analysis of response rates in the third-line treatment of NSCLC Subgroup n of patients in subgroup Response rate 95% CI Females63 17.5% 9.1%-29.1% Males79 5.1% 1.4%-12.5% Nonsmokers 34 29.4% 14.6%-46.3% Smokers108 4.6% 1.5%-10.6% Male smokers 65 3.1% 0.4%-10.7% CI = confidence interval have a greater rate of mortality. In the randomized studies Table 4. Drug-related adverse events with an incidence of ≥5% of gefitinib combined with chemotherapy, the ILD rate was † ‡ Drug-related adverse event* 250 mg/day n (%) 500 mg/day n (%) about 1%, but the rate was similar in the gefitinib and con- Diarrhea 49 (48) 76 (67) trol (chemotherapy plus placebo) arms. In the event of pul- Rash 44 (43) 61 (54) monary symptoms (dyspnea, cough, fever), gefitinib Acne 25 (25) 37 (33) therapy should be interrupted, and a prompt investigation of Dry skin 13 (13) 30 (26) these symptoms should occur. If interstitial lung disease is Nausea 13 (13) 20 (18) confirmed, gefitinib should be discontinued and the patient Vomiting 12 (12) 10 (9) treated appropriately. Pruritus8(8) 10(9) Asymptomatic increases in liver transaminases have Anorexia 7(7) 11(10) been observed in gefitinib-treated patients; therefore, peri- Asthenia 6 (6) 5 (4) odic liver function testing (transaminases, bilirubin, and Weight loss 3 (3) 6 (5) alkaline phosphatase) should be considered. Discontinuation of gefitinib should be considered if changes are severe. *Each patient may have had more than one drug-related adverse event. total n of patients = 102 CONCLUSIONS total n of patients = 114 The accelerated approval regulations allow approval of cancer drugs based on a surrogate end point when the drug ILD associated with gefitinib treatment was about 1% (2% in provides a benefit over available therapy. Gefitinib the Japanese postmarketing experience and about 0.3% in received accelerated approval based on an objective approximately 23,000 patients treated with gefitinib in a U.S. response rate of 10.6%, with a median response duration of expanded-access program). Approximately one-third of the 7 months, in the third-line treatment of NSCLC, a setting cases were fatal. Patients often presented with the acute onset where no therapy has demonstrated efficacy. Under the of dyspnea, with or without cough or low-grade fever. accelerated approval regulations, the sponsor will be Symptoms often became severe within a short time and required to conduct further studies to verify that gefitinib required hospitalization. therapy is associated with clinical benefit in NSCLC. The ILD occurred in patients who received prior radiation recommended gefitinib dose is 250 mg/day because the 500 therapy (31% of reported cases), prior chemotherapy (57% mg/day dose was more toxic yet not more effective. of reported cases), and no previous therapy. Patients with The views expressed herein are the result of indepen- concurrent idiopathic pulmonary fibrosis whose condition dent work and do not necessarily represent the views and worsened while receiving gefitinib have been observed to findings of the U.S. FDA. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Oncologist Oxford University Press

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

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Publisher
Oxford University Press
Copyright
Copyright © 2022 Oxford University Press
ISSN
1083-7159
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1549-490X
DOI
10.1634/theoncologist.8-4-303
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Abstract

Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 This material is protected by U.S. Copyright law. The ® Unauthorized reproduction is prohibited. For reprints contact: Reprints@AlphaMedPress.com Oncologist 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 Key Words. Gefitinib · Iressa · Non-small cell lung cancer, metastatic · Third-line treatment ABSTRACT combination with either gemcitabine plus cisplatin (n = On May 5, 2003, gefitinib (Iressa , ZD1839) 250-mg 1,093) or carboplatin plus paclitaxel (n = 1,037). Results tablets received accelerated approval by the U.S. Food and from those studies showed no benefit (response rate, time Drug Administration as monotherapy treatment for to progression, or survival) from adding gefitinib to patients with locally advanced or metastatic non-small cell chemotherapy. Consequently, gefinitib is only recom- lung cancer (NSCLC) after failure of both platinum-based mended for use as monotherapy. Common adverse and docetaxel chemotherapies. Information provided in events associated with gefitinib treatment included diar- this summary includes efficacy and safety results of rele- rhea, rash, acne, dry skin, nausea, and vomiting. Most vant clinical trials. Effectiveness was demonstrated in a toxicities were Common Toxicity Criteria grade 1 or 2. randomized, double-blind, phase II, multicenter trial com- Interstitial lung disease (ILD) has been observed in paring two oral doses of gefitinib (250 mg/day versus 500 patients receiving gefitinib. Worldwide, the incidence of mg/day). Two hundred sixteen patients were enrolled. The ILD is about 1% (2% in the Japanese postmarketing 142 patients who were refractory to or intolerant of a plat- experience and about 0.3% in a U.S. expanded access inum and docetaxel comprised the evaluable population program). Approximately one-third of the cases were for the efficacy analysis. A partial tumor response fatal. Physicians should promptly evaluate new or wors- occurred in 14% (9 of 66) of patients receiving gefitinib ening pulmonary symptoms. If ILD is confirmed, appro- 250 mg/day and in 8% (6 of 76) of patients receiving gefi- priate management includes discontinuation of gefitinib. tinib 500 mg/day. The overall objective response rate for Gefitinib was approved under accelerated approval reg- both doses combined was 10.6% (15 of 142 patients) (95% ulations on the basis of a surrogate end point response confidence interval 6.0%-16.8%). Responses were more rate. No controlled gefitinib trials, to date, demonstrate a frequent in females and in nonsmokers. The median dura- clinical benefit, such as improvement in disease-related tion of response was 7.0 months (range 4.6-18.6+ months). symptoms or greater survival. Accelerated approval reg- Other submitted data included the results of two ulations require the sponsor to conduct further studies to large trials conducted in chemotherapy-naive, stage III verify that gefitinib therapy produces such a benefit. The and IV NSCLC patients. Patients were randomized to Oncologist 2003;8:303-306 receive gefitinib (250 mg or 500 mg daily) or placebo, in INTRODUCTION new class of oral drugs that inhibits intracellular tyrosine Gefitinib (Iressa , ZD1839; Astra Zeneca, Inc.; London, kinase (TK) activity including that of the epidermal UK; http://www.astrazeneca.com) (Fig. 1) is a member of a growth factor receptor (EGFR)-TK. Gefitinib binds at the 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@cder.fda.gov Received May 19, 2003; accepted for publication June 20, 2003. ©AlphaMed Press 1083-7159/2003/$12.00/0 The Oncologist 2003;8:303-306 www.TheOncologist.com Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 Cohen, Williams, Sridhara et al. 304 STUDY DESIGN The sponsor submitted two trials in previously treated NSCLC patients. The first trial was in the third-line treatment O N C1 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 progres- sion within 90 days of the last chemotherapy. The trial was a MeO 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 Figure 1. Molecular structure of gefitinib. one or two previous chemotherapy regimens, at least one ATP site of the tyrosine kinase region, a region that is having contained a platinum, and provides supportive evi- highly conserved across the various transmembrane tyrosine dence of gefitinib safety. Two hundred sixteen patients at 30 kinases. The maximum plasma concentrations resulting U.S. medical centers were entered in the third-line treatment from clinically relevant gefitinib doses are 0.5-1 μM or trial. One hundred forty-two patients with documented fail- more, similar to or greater than the 50% inhibitory concen- ure of platinum and docetaxel were evaluable for the primary tration values of other intracellular transmembrane tyrosine- efficacy analysis. specific protein kinases. Therefore, gefitinib cytotoxicity Patient demographics and disease characteristics of the eli- could be the result of inhibition of downstream signal pro- gible treatment population are summarized in Table 1. teins or ATP-dependent kinases other than EGFR-TK. Approximately 75% of the eligible study patients had adeno- Gefitinib is extensively metabolized in the liver by the carcinoma histology (either alone or mixed with squamous cell cytochrome P450 3A4 enzyme. Over a 10-day period, histology). Thirty-two percent of patients receiving gefitinib approximately 86% of an orally administered radioactive 250 mg/day had never smoked. The median time from lung dose is recovered in the feces with less than 4% of the dose cancer diagnosis to study randomization was 19.6 months. in the urine. Following daily oral administration, steady- Among the 142 evaluable patients, there were 15 partial state plasma levels are reached in 10 days and are twofold responses. Response rates and durations are summarized higher than those achieved following single doses. in Table 2. Partial responses occurred in 9 of 66 patients In preclinical studies, the antiproliferative activity of receiving gefitinib 250 mg/day and in 6 of 76 patients gefitinib, alone or in combination with cytotoxic drugs, was receiving gefitinib 500 mg/day. The response rate was sim- investigated in human ovarian (OVCAR-3), breast (MCF- ilar in the 74 study patients not evaluable for the primary 10A ras; ZR-75-1), and colon (GEO) cancer cell lines, efficacy analysis (9.5%). which express EGFR and transforming growth factor alpha. Exploratory analyses of response rates in different sub- Gefitinib inhibited colony-forming ability in a concen- groups of patients were performed (Table 3). Due to small tration-dependent manner. Combining gefitinib with platins sample sizes, the results lack precision, as evidenced by the (cisplatin, oxaliplatin, carboplatin), taxanes (paclitaxel, wide confidence limits of the estimates. Responding docetaxel), topoisomerase inhibitors (doxorubicin, etopo- patients were predominantly female (11/15) and had adeno- side, topotecan), or the antimetabolite raltitrexed resulted in carcinoma (12/15). Response rates did not vary with World a markedly greater apoptotic cell death than that induced by Health Organization (WHO) performance status (0-1 ver- single-agent treatment. In studies with colon cancer (GEO) sus 2) or number of prior therapies (2 versus 3 versus 4). xenografts, combined treatment with gefitinib and cyto- While disease-related symptom improvement and quality toxic agents produced tumor growth arrest and extended the of life (QOL) were evaluated in both trials, the meaningful- survival of tumor-bearing animals. ness of that evaluation is questionable. Because Iressa 250 The submitted new drug application (NDA) sought mg/day and 500 mg/day had comparable efficacy results, accelerated approval for gefitinib as monotherapy for there was no comparator regimen for the QOL or symptom- patients receiving third-line treatment for locally advanced or relief analysis. Methodologic issues exist, including the metastatic non-small cell lung cancer (NSCLC). At present, absence of blinding, the censoring of early progressors, and there are four cisplatin-containing doublets (docetaxel, gem- the use of concomitant medications that might have con- citabine, paclitaxel, vinorelbine) and single-agent vinorel- tributed to symptom relief. Therefore, QOL and symptom bine approved for the first-line treatment of this patient results are not presented here. population. Docetaxel is approved for second-line therapy. Two large trials were conducted in chemotherapy- Third-line treatment is an unmet need. naive, stage III and IV NSCLC patients. Two thousand one Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 305 FDA Drug Approval: Gefitinib hundred thirty patients were randomized to receive gefi- Table 1. Demographics and disease characteristics, third-line treatment population tinib (250 mg or 500 mg daily) or placebo in combination Gefitinib dose with platinum-based chemotherapy regimens. The Characteristics chemotherapy regimens given in those first-line trials were 250 mg/day 500 mg/day gemcitabine plus cisplatin (n = 1,093) and carboplatin plus n* (%) n (%) Age group paclitaxel (n = 1,037). Results from those studies showed 18-64 years43(65) 43(57) no benefit (response rate, time to progression, or survival) 64-74 years19(29) 30(39) from adding gefitinib to chemotherapy. 75 years and older 4 (6) 3 (4) Sex SAFETY Male 38 (58) 41 (54) Drug-related adverse events occurring with incidences Female 28 (42) 35 (46) ≥5% in either the 250-mg or 500-mg dose group are sum- Race marized in Table 4. The most common adverse reactions Caucasian 61 (92) 68 (89) were diarrhea, rash, and acne. Treatment-related delays and African-American 1 (2) 2 (3) dose reductions occurred more often in the 500 mg/day Asian 1 (2) 2 (3) dose group than in the 250 mg/day group (dose delays: 26% Hispanic 0 (0) 3 (4) Other 3 (5) 1 (1) and 15%, respectively; dose reductions: 10% and 1%, respectively). Most toxicities were Common Toxicity Smoking history Criteria grade 1 or 2. There did not seem to be substantially Yes (previous or current smoker) 45 (68) 62 (82) different toxicities for different age groups. The small num- No (never smoked) 21 (32) 14 (18) bers of patients >75 years of age (11 in the 250 mg/day Baseline WHO performance status group and 10 in the 500 mg/day group) make it difficult to 0 14 (21) 9 (12) draw conclusions concerning this group. 1 36 (55) 53 (70) 2 15 (23) 14 (18) Not recorded 1 (2) 0 (0) PULMONARY TOXICITY Tumor histology Cases of interstitial lung disease (ILD) have been observed in patients receiving gefitinib. ILD is a complex Squamous9(14) 11(14) Adenocarcinoma 47(71) 50(66) disease, described by investigators using different terms. Undifferentiated 6(9) 4(5) (The sponsor captured cases by a collection of 24 MedDRA Large cell1(2) 2(3) [Medical Dictionary for Regulatory Affairs] terms.) The U.S. Squamous and adenocarcinoma 3 (5) 7 (9) Not recorded 0 (0) 2 (3) Food and Drug Administration (FDA) performed a detailed analysis of the sponsor’s drug safety database. This included Current disease status 50,005 patients (including 18,960 from marketed use in Locally advanced 11 (17) 5 (7) Metastatic 55 (83) 71 (93) Japan). Four hundred eight cases of ILD (324 from Japan and 84 from the U.S./rest of the world) were identified. The *total n of patients = 66 median time to onset of ILD was 24 days in the Japan group total n of patients = 76 and 42 days in the U.S. group. Worldwide, the incidence of Table 2. Response rates and duration in the third-line treatment of NSCLC Evaluable patients † ‡ 250 mg/day* (%) 500 mg/day (%) Combined (%) Objective response rate 13.6 7.9 10.6 95% CI 6.4-24.3 3.0-16.4 6.0-16.8 Median response duration (months) 8.9 4.5 7.0 Range 4.6-18.6+ 4.4-7.6 4.4-18.6+ *total n of patients = 66 total n of patients = 76 total n of patients = 142 +indicates data collection is ongoing; CI = confidence interval Downloaded from https://academic.oup.com/oncolo/article/8/4/303/6387136 by DeepDyve user on 31 January 2022 Cohen, Williams, Sridhara et al. 306 Table 3. Retrospective subgroup analysis of response rates in the third-line treatment of NSCLC Subgroup n of patients in subgroup Response rate 95% CI Females63 17.5% 9.1%-29.1% Males79 5.1% 1.4%-12.5% Nonsmokers 34 29.4% 14.6%-46.3% Smokers108 4.6% 1.5%-10.6% Male smokers 65 3.1% 0.4%-10.7% CI = confidence interval have a greater rate of mortality. In the randomized studies Table 4. Drug-related adverse events with an incidence of ≥5% of gefitinib combined with chemotherapy, the ILD rate was † ‡ Drug-related adverse event* 250 mg/day n (%) 500 mg/day n (%) about 1%, but the rate was similar in the gefitinib and con- Diarrhea 49 (48) 76 (67) trol (chemotherapy plus placebo) arms. In the event of pul- Rash 44 (43) 61 (54) monary symptoms (dyspnea, cough, fever), gefitinib Acne 25 (25) 37 (33) therapy should be interrupted, and a prompt investigation of Dry skin 13 (13) 30 (26) these symptoms should occur. If interstitial lung disease is Nausea 13 (13) 20 (18) confirmed, gefitinib should be discontinued and the patient Vomiting 12 (12) 10 (9) treated appropriately. Pruritus8(8) 10(9) Asymptomatic increases in liver transaminases have Anorexia 7(7) 11(10) been observed in gefitinib-treated patients; therefore, peri- Asthenia 6 (6) 5 (4) odic liver function testing (transaminases, bilirubin, and Weight loss 3 (3) 6 (5) alkaline phosphatase) should be considered. Discontinuation of gefitinib should be considered if changes are severe. *Each patient may have had more than one drug-related adverse event. total n of patients = 102 CONCLUSIONS total n of patients = 114 The accelerated approval regulations allow approval of cancer drugs based on a surrogate end point when the drug ILD associated with gefitinib treatment was about 1% (2% in provides a benefit over available therapy. Gefitinib the Japanese postmarketing experience and about 0.3% in received accelerated approval based on an objective approximately 23,000 patients treated with gefitinib in a U.S. response rate of 10.6%, with a median response duration of expanded-access program). Approximately one-third of the 7 months, in the third-line treatment of NSCLC, a setting cases were fatal. Patients often presented with the acute onset where no therapy has demonstrated efficacy. Under the of dyspnea, with or without cough or low-grade fever. accelerated approval regulations, the sponsor will be Symptoms often became severe within a short time and required to conduct further studies to verify that gefitinib required hospitalization. therapy is associated with clinical benefit in NSCLC. The ILD occurred in patients who received prior radiation recommended gefitinib dose is 250 mg/day because the 500 therapy (31% of reported cases), prior chemotherapy (57% mg/day dose was more toxic yet not more effective. of reported cases), and no previous therapy. Patients with The views expressed herein are the result of indepen- concurrent idiopathic pulmonary fibrosis whose condition dent work and do not necessarily represent the views and worsened while receiving gefitinib have been observed to findings of the U.S. FDA.

Journal

The OncologistOxford University Press

Published: Aug 1, 2003

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