Biologically Targeted Treatment of Non–Small-Cell Lung Cancer: Focus on Epidermal Growth Factor Receptor

Biologically Targeted Treatment of Non–Small-Cell Lung Cancer: Focus on Epidermal Growth Factor Receptor Ronald B. Natale

Abstract The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. The postembryonic role of EGFR is normally limited. In cancer, however, abnormal EGFR–tyrosine kinase (TK) activity plays a central role in many of the processes involved in tumor progression, such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Several different approaches have been taken to inhibit EGFR-mediated activity in tumor cells, including monoclonal antibodies directed at the ligand-binding portion of the EGFR and small-molecule agents that directly inhibit the intracellular TK domain of EGFR. Two of these TK inhibitors, gefitinib and erlotinib (OSI-774, Tarceva™), have shown antitumor activity and good tolerability across several tumor types in early dose-finding clinical trials, particularly for non–small-cell lung cancer (NSCLC). In heavily pretreated patients with advanced NSCLC, gefitinib showed clinically significant tumor responses and symptom relief with good tolerability. Based on these results, gefitinib has now been approved for the third-line treatment of advanced NSCLC. The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors. Clinical Lung Cancer, Vol. 5, Suppl. 1, S11-S17, 2003

Introduction The fundamental concepts underlying cancer biology and treatment have changed a great deal during the past decade. In the past, tumors were seen to be composed simply of “cancer cells” and cancer treatment consisted of attacking the tumor from the outside using radiation, chemotherapy, or surgery. The more recent, and more sophisticated, view of cancer is that a tumor represents a microenvironment consisting of genetically heterogeneous tumor cells, stroma cells, immune cells, and blood vessels. This new understanding has changed therapeutic strategies. New therapies are now being designed either to destroy the microenvironment that supports tumor cell growth, or to destroy the way that tumor cells respond to the microenvironment. With respect to the latter, it is now known that tumor response to the microenvironment is mediated by cell-surface receptors and receptor-activated kinases, many of which are abnormally active in cancer. Cedars-Sinai Comprehensive Cancer Center, Los Angeles, CA Submitted: May 1, 2003; Revised: Aug 26, 2003; Accepted: Aug 27, 2003 Address for correspondence: Ronald B. Natale, MD, Cedars-Sinai Comprehensive Cancer Center, 8700 Beverly Blvd, Ste C2000, Los Angeles, CA 90048-1804 Fax: 310-652-8759; e-mail: [email protected]

Key words: Gefitinib, Targeted therapy, Tyrosine kinase inhibitor

Figure 1

Signal Transduction Pathways Activated by EGFR-TK Ligands = EGF, TGF-α EGFR

P

SOS

P

Ras

Raf

MEK/ERK PI3K

Nucleus MAPK

c-Jun c-Fos Akt

Proliferation Survival Angiogenesis (VEGF, FGF)

Effect on Cell Cycle: S phase (most radiation resistant) G2/M (most radiation sensitive)

Abbreviations: EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; ERK = extracellular signal–regulated kinase; FGF = fibroblast growth factor; MAPK = mitogenactivated protein kinase; MEK = mitogen-activated protein kinase kinase; PI3K = phosphatidylinositol-3 kinase; SOS = son of sevenless; TGF-α = transforming growth factor–α; TK = tyrosine kinase; VEGF = vascular endothelial growth factor

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Targeted Treatment of NSCLC: Focus on EGFR Table 1

Expression of EGFR and Its Ligands in NSCLC Rusch,9 1993

Rusch,10 1997

Fontanini,11 1998

EGFR Expression

93%

NA

81%

TGF-α Expression

86%

NA

99%

0

NA

NA

All patients

45%

70%

49%

SCC

68%

92%

57%

Non-SCC

36%

58%

38%

EGF Expression EGFR Overexpression

Abbreviations: EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; NA = not applicable; NSCLC = non–small-cell lung cancer; SCC = squamous cell carcinoma; TGF-α = transforming growth factor−α

Among the most important molecules that drive tumor cell growth are the cell-surface receptors. These signal-transduction molecules have in common a membrane-spanning segment and an intracellular tyrosine kinase (TK) domain, whereas their extracellular domains vary with respect to their ligand-binding specificities. The ErbB family of receptors consists of 4 members: epidermal growth factor receptor (EGFR, ie, ErbB-1), ErbB-2 (ie, HER2/neu), ErbB-3, and ErbB-4.1-3 Of these, EGFR has the greatest number of known ligands: epidermal growth factor (EGF), transforming growth factor–α (TGF-α), amphiregulin, betacellulin, heparin-binding EGF, and epiregulin. ErbB-3 and ErbB-4 bind the heregulins, whereas ErbB-4 also binds neuregulin (NRG) 2, NRG3, and betacellulin. Although ErbB-2 has no known ligand, it is a primary partner for the activation of ErbB-1 and ErbB-3.2,3 Signal transduction through the EGFR is initiated when ligand binds to the extracellular domain (Figure 1). The receptor then dimerizes with various ErbB family members (ErbB-2 primarily), leading to activation of the TK catalytic domain and autophosphorylation of tyrosine residues in the intracellular domain. These phosphorylated tyrosine residues provide docking sites for signal transduction molecules with Src homology or

protein tyrosine binding domains.4 Such signal-transduction molecules include phosphatidylinositol-3 kinases, phospholipase Cγ, the adaptor molecules Shc and growth factor receptor–bound protein 2, and components of the p21 ras signaling cascade. The results of EGFR-TK signaling are pleiotropic, including stimulation of proliferation, suppression of apoptosis, inhibition of hormone secretion, and influences on differentiation and angiogenesis.5 In normal cells, EGFR-TK activity is tightly regulated. In cancer cells, a variety of mechanisms can lead to increased EGFR-TK activity, which results in inappropriate activation of many of these cellular processes.6,7 Increased expression or activation of EGFR is a hallmark of many types of solid human tumors and has been associated with late-stage disease, invasion, metastasis, resistance to chemotherapy and hormone therapy, and poor outcome. In non–small-cell lung cancer (NSCLC), as in other common solid tumors, EGFR and TGF-α are thought to form an autocrine loop that plays an important role in tumor progression.8 In studies of NSCLC, EGFR expression was detected in 81%-93% of tumors and TGF-α expression was seen in 86%-99% (Table 1).9-11 These and other studies found increased levels of EGFR in 45%-70% of resected tumors from patients with NSCLC. Expression levels were variously defined by the intensity of staining or the percentage of cells labeled in tumor samples in comparison to surrounding tissue. Normal, uninvolved tissue was generally found to express little or no EGFR. Thus, any expression in cancerous tissue was considered overexpression.

Novel Approaches to Inhibiting Epidermal Growth Factor Receptor-Tyrosine Kinase

The properties of EGFR described herein have made it an attractive therapeutic target for a broad range of common solid tumors, including NSCLC. The main approaches tested thus far for inhibition of EGFR include monoclonal antibodies (MoAbs) that interact with the EGFR extracellular domain and small-molecule TK inhibitors (TKIs) that are directed at the intracellular catalytic domain of the kinase enzyme. Proof of the concept of EGFR inhibition for cancer therapy will include tumor responses, clinical benefits, and good tolerability in randomized clinical trials.7 The idea of targeting tumor cells with antibodies to HER family of receptors is not new. Humanized MoAbs, such as trastuzumab, with specificity Table 2 Clinical Trials of Epidermal Growth Factor Receptor−Targeted Agents14-21 for HER2 (ErbB-2) have already been developed for advanced breast cancer.12 Chimeric Monotherapy Drug-Related MoAbs, such as the EGFR-specific cetuximab, Maximum EGFRPhase II/III Agent Tolerated Adverse Events* Positive are in advanced clinical trials in combination Trial Dose Dose Screening with cytotoxic therapies.13 The rationale for Rash Diarrhea these studies comes from xenograft tumor 700-1000 mg/day 250-500 mg/day No 37%-50% ≈50% Gefitinib models in which combination treatment with anti-EGFR MoAbs and cytotoxic drugs result150 mg/day 150 mg/day Erlotinib Yes and no 73%-79% 54% ed in enhanced antitumor activity.12 400 mg/m2 A second approach to targeting EGFR was > 400 mg/m2 then Yes 5% 9% Cetuximab 200 mg/m2/week based on the observation that mutations in the adenosine triphosphate (ATP)–binding *Mainly grade 1/2. Abbreviation: EGFR = epidermal growth factor receptor pocket of the receptor block its TK activity.

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Ronald B. Natale Pharmacophore modeling was used to design selective EGFRTKIs such as gefitinib and erlotinib (OSI-774, Tarceva™), which competitively inhibit the binding of ATP to the catalytic TK domain.8 In contrast to the extracellular EGFR MoAbs, EGFRTKIs act intracellularly to directly inhibit autophosphorylation of EGFR, thus blocking downstream signaling. Other TKIs in development include EKB-569, which is irreversible; GW572016, which targets both EGFR and HER2; and the irreversible inhibitor CI1033, which can inhibit all 4 ErbB family members.7 The different TKIs are in various stages of clinical testing as monotherapy and in combination with cytotoxic chemotherapy or radiation. EGFR-TKIs are being tested in clinical trials of various solid tumors, with initial development focusing on NSCLC and cancers of the head and neck.8,13 The status of clinical trials for the 3 anti-EGFR agents that are furthest along in development is shown in Table 2.14-21 Gefitinib, erlotinib, and cetuximab have all undergone phase I trials in which the maximum tolerated dose (MTD) was determined. The specificity that these and other molecular agents exhibit for their respective targets means that the clinically effective dose may be considerably lower than the MTD. On the basis of the phase I trials, doses were selected for phase II/III studies that were at the MTD (erlotinib) or below the MTD (gefitinib, cetuximab) for these agents. Randomized phase II clinical trials of gefitinib and erlotinib as monotherapy have resulted in tumor response and clinical benefit. Exploratory trials have shown that gefitinib, erlotinib, and cetuximab can be combined safely with several standard chemotherapy regimens.18,22-28 Gefitinib has recently been approved for the treatment of patients with advanced NSCLC after previous chemotherapy. Despite the different mechanisms of EGFR inhibition by these agents, all 3 had similar tolerability profiles in clinical trials. With respect to the most commonly seen adverse events, skin changes (especially rash) and diarrhea, the profiles suggest that these adverse events represent a class effect of EGFR-TK inhibition (Table 2). The skin rash is a maculopapular or acneiform rash on an erythematous base that is likely caused by the role of EGFR in skin biology.29-32 The rash frequency, and to some extent the severity, are dose-related and generally manageable. Differences in frequency and severity may reflect the pharmacology of the specific agent and the treatment dose. Gefitinib has been associated with a low incidence of rash, which is likely a result of treatment with doses well below the MTD. In trials of gefitinib, the rash rarely led to discontinuation of treatment.

Erlotinib (OSI-774, Tarceva™) in the Treatment of Advanced Non–Small-Cell Lung Cancer In phase I trials of erlotinib alone or in combination with chemotherapy, tumor response or stable disease was observed in patients with a variety of solid tumors.14,24-26 The most common adverse events were diarrhea and skin toxicities. The majority of adverse events were mild and reversible. As monotherapy, the MTD was 150 mg/day. Dose-limiting toxicities were observed with erlotinib at 100 mg/day in combination with cisplatin/gemcitabine and carboplatin/paclitaxel (neutropenia and diarrhea), and at 75 mg/day in combination with docetaxel (neutropenia).24-26

Figure 2 Schematic of Trial Design for IDEAL 1 and IDEAL 251-54 IDEAL 1 Patients (N = 210) ≥ 1 previous platinum chemotherapy regimens IDEAL 2 Patients (N = 216) ≥ 2 prior chemotherapy regimens including platinum and docetaxel

R A N D O M I Z E

250 mg Gefitinib once daily

500 mg Gefitinib once daily

Primary endpoints: • Objective tumor response • Safety profile (IDEAL 1 only) • Symptom improvement (IDEAL 2 only)

Continue gefitinib until disease progression or intolerable toxicity Abbreviation: IDEAL = Iressa Dose Evaluation in Advanced Lung Cancer

In a small phase II trial (N = 56) in patients with advanced, chemotherapy-refractory NSCLC, the objective response rate was 12% and median survival was 37 weeks.33 Stable disease was observed in 26% of patients. Rash was the most common adverse event, occurring in 78% of patients. Although both the phase I and II trials of erlotinib included an evaluation of EGFR expression, tumor response was not correlated with EGFR expression levels.14,33 Erlotinib is currently undergoing phase III evaluation in NSCLC as second- and third-line monotherapy and as firstline therapy in combination with carboplatin/paclitaxel or cisplatin/gemcitabine. In addition, erlotinib is being investigated in a phase III trial as first-line therapy for pancreatic cancer.

The Role of Gefitinib in the Treatment of Advanced Non–Small-Cell Lung Cancer Preclinical Data The EGFR-TKI gefitinib is an orally bioavailable quinazoline that selectively inhibits EGFR-TK activity, with an IC50 (inhibitory concentration 50%) in preclinical studies that is approximately 50 times lower than that for the related ErbB-2 receptor (EGFR IC50 = 0.023-0.079 μmol/L, ErbB-2 IC50 = 1.2-3.7 μmol/L). In a xenograft tumor model, the growth of human A549 NSCLC cells was almost completely inhibited by gefitinib. When treatment was stopped, tumor growth continued. Gefitinib has also shown antitumor activity against xenograft models of prostate, breast, colorectal, gastric, and ovarian tumors.34 Furthermore, gefitinib has shown additive and synergistic antitumor activity in some preclinical studies when combined with cytotoxic chemotherapy or radiation.35-41 For example, combination treatment with gefitinib and the chemotherapy agent paclitaxel achieved an apparent complete tumor regression in an LX-1 lung cancer xenograft model.35 This combination inhibited tumor growth more potently than did either drug alone. Moreover, overexpression of EGFR did not seem to be required for the inhibitory effect, as LX-1 cells express only low levels of EGFR.35

Phase I Monotherapy Trials Four phase I monotherapy trials of gefitinib enrolled a total of 252 patients with a median age of 59 years.42-47 Patients had

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Targeted Treatment of NSCLC: Focus on EGFR Table 3

Patient Demographics in IDEAL 1 and IDEAL 251-54 IDEAL 1

IDEAL 2

Gefitinib Gefitinib Gefitinib Gefitinib 250 mg/day 500 mg/day 250 mg/day 500 mg/day Patients Randomized

104

106

102

114

Men/Women

75%/25%

66%/34%

59%/41%

55%/45%

61

60

61

62

0

17%

19%

18%

13%

1

70%

68%

63%

66%

2

13%

13%

19%

20%

3

0

0

0

1%

Median Age (Years) Performance Status

The pharmacodynamics of treatment with gefitinib were also studied in phase I trials. Paired skin biopsies were taken from 65 patients with cancer before therapy and 28 days after therapy with gefitinib was initiated.30 Immunohistochemistry was used to assess the activation (phosphorylation) state of EGFR-TK and its downstream effectors, including mitogen-activated protein kinase, signal transducer and activator of transcription–3, and the Cdk inhibitor p27KIP1 (the latter 2 molecules are linked to keratinocyte maturation). An oral once-daily dose of gefitinib was found to inhibit EGFR-TK activation and affect downstream receptor-dependent processes in patients. The effects of gefitinib were profound at doses well below the MTD.

Phase II Monotherapy Trials

Gefitinib as monotherapy (250 mg/day vs. 500 mg/day) for the treatment of advanced NSCLC was investigated in 2 large randomized phase II trials: 67% 64% 64% 69% Adenocarcinoma* Iressa Dose Evaluation in Advanced Lung Cancer 17% 16% 24% 14% Squamous (IDEAL) 1 and IDEAL 2 (Figure 2).51-54 Both trials enrolled patients with locally advanced or 9% 3% 9% 2% Large cell metastatic NSCLC. In the international trial 8% 17% 15% Other (IDEAL 1), patients had received 1 or 2 previous 3% chemotherapy regimens, of which ≥ 1 was platPrior inum-based.53 In the US trial (IDEAL 2), patients Chemotherapy Regimens had received ≥ 2 previous chemotherapy regimens containing platinum and docetaxel, given either 0 0 1 57% 56% concurrently or separately, and all patients had ≥ 1 42% 40% 2 43% 44% disease-related symptom.51,52 The patients in IDEAL 2, therefore, represented a more extensively 36% 30% 3 0 0 pretreated population with more advanced disease ≥4 compared with those in IDEAL 1. Patient demo22% 28% 0 0 graphics for both trials are shown in Table 3.51-54 Disease Stage The primary endpoints in IDEAL 1 were tumor response rate and safety profile associat† Locally advanced 19.5% 8% ed with gefitinib.53 In IDEAL 2, the primary 80.5%† 92% Metastatic endpoints were tumor response rate and disease-related symptom improvement rate.51 Pa*Includes patients with adenosquamous histology. †Data combined for both doses. tients were therefore required to be Abbreviation: IDEAL = Iressa Dose Evaluation in Advanced Lung Cancer symptomatic at baseline (score of ≤ 24 on the Lung Cancer Subscale [LCS]) in IDEAL 2.52 a variety of solid tumors, including NSCLC (n = 100), colorectal In IDEAL 1, the radiographic tumor response rates were simi(n = 40), ovarian (n = 33), head and neck (n = 30), prostate (n = lar in the 250-mg/day group and the 500-mg/day group, with 19), breast (n = 10), and other types of solid cancer (n = 20). Over overall response rates of 18.4% and 19.0%, respectively (Table the average time of 2.4 months of monotherapy with gefitinib, ad4).53,54 The disease control rates (tumor response plus stable disverse events included diarrhea (grade 3 diarrhea was a dose-limitease) were also comparable for the 2 dose groups. Median overall ing toxicity of gefitinib 700 mg/day),48 grade 1/2 gastrointestinal survival times for patients in these groups were 7.6 months and effects, and skin rash within the first 2 months. At doses of gefi8.0 months, respectively.53,55 In summary, the 250-mg/day and tinib > 600 mg/day, adverse events required an increasing percent500-mg/day dosages provided similar efficacy in this population. age of patients to either reduce their dose level or withdraw from In IDEAL 2, the radiographic tumor response rate was 11.8% the study. No cardiac, marrow, or renal toxicity was documented for patients receiving gefitinib at 250 mg/day. Similar response in this study, nor was toxicity cumulative.16,42-44,46,47,49,50 rates were achieved with gefitinib treatment at 500 mg/day Tumor Histology

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Ronald B. Natale Table 4

IDEAL 1 Efficacy Results53,54

Table 5

IDEAL 2 Efficacy Results51,52 Gefitinib 250 mg/day

Gefitinib 500 mg/day

102

114

Gefitinib 250 mg/day

Gefitinib 500 mg/day

103

105

Overall Response Rate (95% CI)

18.4% (11.5%-27.3%)

19.0% (12.1%-27.9%)

Stable Disease Rate

31%

27%

Disease Control Rate (95% CI)*

54.4% (44.3%-64.2%)

51.4% (41.5%-61.3%)

Symptom Response Rate

43%

35%

Median Progression-Free Survival (Months)

2.7

2.8

Median Overall Survival (Months; 95% CI)

6.1 (4.8-7.7)

6.0 (4.3-7.2)

Median Overall Survival (Months)

7.6

8.0

40.3% (28.5%-53.0%)

37.0% (26.0%-49.1%)

Symptom Improvement Rate (95% CI)

*Disease control rate = tumor response + stable disease. Abbreviations: CI = confidence interval; IDEAL = Iressa Dose Evaluation in Advanced Lung Cancer

(Table 5).51,52 Overall, the rate of symptom improvement (an increase of ≥ 2 points on the LCS) was 39%. Symptom improvement was positively correlated with tumor response: in the 250-mg/day group, 100% of patients with an objective tumor response improved by ≥ 2 points on the LCS, as did 90% of patients in the 500-mg/day group. In contrast, among patients with progressive disease in the 250-mg/day and 500-mg/day groups, only 12% and 20%, respectively, showed improvement of ≥ 2 points on the LCS (Figure 3).51,52 Among patients with stable disease, 81% in the 250-mg/day group and 61% of those in the 500-mg/day group showed symptom improvement, indicating that a tumor response is not required for relief of NSCLC-associated symptoms during treatment with gefitinib. Furthermore, symptom improvement was associated with longer progression-free and overall survival times. In the 250mg/day group, median overall survival for patients without symptom improvement was 3.7 months, whereas the median survival for patients with symptom improvement had not yet been reached after a median follow-up of 9.2 months (range, 2.7-13.6 months). In the 500-mg/day group, median overall survival was 3.8 months in patients without symptom improvement and 8.1 months for patients without or with symptom improvement. Similarly, patients with symptom improvement had longer progression-free survival times than did those who did not show symptom improvement: 4.8 months and 1.0 month, respectively, for those in the 250mg/day group, and 3.7 months and 1.1 months, respectively, for those in the 500-mg/day group.52 In both trials, the majority of adverse events were mild. The most common adverse events were grade 1/2 diarrhea and skin rash. Grade 3/4 adverse events were infrequent and occurred less often at the lower dose of 250 mg/day (Table 6).51,53 The percentage of patients who withdrew from treatment because of drugrelated adverse events was low (1.9% and 9.4%, in the 250-mg/day and 500-mg/day groups, respectively, in IDEAL 1, and 1.0% and 4.4%, respectively, in IDEAL 2).55 The results from

Evaluable Patients

Overall Response Rate (95% CI) 11.8% (6.2%-19.7%) 8.8% (4.3%-15.5%)

Abbreviations: CI = confidence interval; IDEAL = Iressa Dose Evaluation in Advanced Lung Cancer

these trials show that oral treatment with gefitinib at 250 mg/day and 500 mg/day in patients with NSCLC provided clinically significant tumor responses and stable disease with good tolerability. With comparable efficacy and better tolerability, a daily dose of 250 mg is recommended in this clinical setting.

Phase III Combination Trials Based on promising additive results in combination with chemotherapy in phase I trials, gefitinib has also been investigated in phase III trials in combination with chemotherapy for the treatment of NSCLC.56,57 These trials were known as the Iressa NSCLC Trials Assessing Combination Therapy (INTACT) 1 (cisplatin/gemcitabine) and INTACT 2 (carboplatin/paclitaxel). Each trial enrolled > 1000 patients with advanced NSCLC who were previously untreated. Patients were randomized to receive either chemotherapy (maximum, 6 cycles) or chemotherapy plus 250-mg/day or 500-mg/day gefitinib. In these trials, there were no significant differences in response rates, time to progression, or survival between the gefitinib and placebo groups. Treatment with gefitinib was not associated with a worsening of adverse events compared with chemotherapy, except for an increased incidence of gastrointestiFigure 3

Symptom Improvement Rate (%)

Evaluable Patients

100

Rates of Symptom Improvement ≥ 2 Points on the Lung Cancer Subscale in IDEAL 251,52 100% 90% 81%

80

Gefitinib 250 mg/day Gefitinib 500 mg/day

61%

60 40

20%

20 0

12% (n = 12) (n = 10) Partial Response

(n = 31) (n = 31) Stable Disease

(n = 59) (n = 59) Progressive Disease

Abbreviation: IDEAL = Iressa Dose Evaluation in Advanced Lung Cancer

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Targeted Treatment of NSCLC: Focus on EGFR Table 6

Serious AEs and AEs Leading to Withdrawal in IDEAL 1 and IDEAL 2 Trials51,53 IDEAL 1

IDEAL 2

Gefitinib Gefitinib Gefitinib Gefitinib 500 250 500 250 mg/day mg/day mg/day mg/day

ing of gefitinib with radiation and other novel agents is ongoing. Gefitinib is being evaluated in common solid tumors, including colorectal, head and neck, prostate, breast, gastric, ovarian, and endometrial cancers, as well as less-common tumors such as renal cell carcinoma, glioblastoma, mesothelioma, and transitional cell carcinoma of the urothelium.

References Evaluable Patients

103

106

102

114

Grade 3/4 Drug-Related AEs

3.9%*

27.3%

6.9%

17.5%

Withdrawals Due to DrugRelated AEs

1.9%

9.4%

1.0%

4.4%

*Grade 3 only. Abbreviations: AEs = adverse events; IDEAL = Iressa Dose Evaluation in Advanced Lung Cancer

nal and skin toxicities.56,57 The lack of benefit in these trials may have resulted from issues of timing or sequencing of anti-EGFR therapy in combination with chemotherapy. Alternately, it may be that responsiveness to gefitinib is restricted to an as-yetunidentified subgroup of patients. Some tumors, especially in advanced disease, may have redundancies in deregulated growth pathways that bypass a block of EGFR-TK.58,59 It is hoped that these issues will be resolved through further investigation.

Gefitinib Approved for Treatment of Non–Small-Cell Lung Cancer Based on the results of IDEAL 1 and IDEAL 2, gefitinib has now been approved in the United States, Australia, Japan, Singapore, Korea, and Argentina for second- or third-line treatment of advanced NSCLC after the use of a platinum agent and docetaxel.60 Gefitinib is the first agent to be approved in the class of EGFR-targeted agents, and offers patients with advanced lung cancer a therapeutic option where none existed before. In postmarketing use in Japan, treatment with gefitinib has been associated with a low incidence (1.7%) of interstitial lung disease (ILD).61 Worldwide, the incidence of ILD associated with the use of gefitinib is < 1%. The relationship of gefitinib to these occurrences of ILD is unclear. Interstitial lung disease is a known complication of lung cancer and occurs to varying degrees in association with different chemotherapies and with radiation therapy.62-65 Physicians prescribing gefitinib should be aware of the symptoms of ILD, which include nonproductive cough and shortness of breath, abnormal breath sounds, fever, weight loss, fatigue, muscle and joint pain, and clubbing of the fingernails.66,67 The skin toxicities that occur with the use of gefitinib and other EGFR-targeted agents are generally mild and typically subside with time. If necessary, these side effects can be managed with clindamycin, antibiotics, or corticosteroids.

Conclusion Gefitinib is also being investigated for treatment of early-stage NSCLC and for lung cancer prevention. In addition, clinical test-

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