Originally published as JCO Early Release 10.1200/JCO.2005.04.057 on November 22 2004

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Practical Management of Patients With Non–Small-Cell Lung Cancer Treated With Gefitinib

From the Thoracic Oncology Service, Division of Solid Tumor Oncology, and Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center; and Departments of Biostatistics, Surgery, and Radiology, Weill Medical College of Cornell University, New York, NY

Address reprint requests to Mark G. Kris, MD, Memorial Hospital, 1275 York Avenue, New York, NY 10021; e-mail: krism{at}mskcc.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non–small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non–small-cell lung cancer.

METHODS: This article reviews gefitinib’s indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response.

RESULTS: We present our recommendations for the management of rash and diarrhea caused by this agent.

CONCLUSION: This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.

	INTRODUCTION

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The epidermal growth factor receptor (EGFR) is expressed or overexpressed in a number of tumors, including non–small-cell lung cancer (NSCLC). Activation of EGFR by ligand binding, mutation, or autocrine signaling stimulates cellular growth, proliferation, invasion, metastasis, and inhibits apoptosis. Blocking any one of the EGFR-mediated effects could inhibit the growth of tumors driven by EGFR signaling. This observation provided the rationale for the development for specific inhibitors of EGFR to halt malignant progression in patients with NSCLC. This hypothesis has recently been validated by the identification of EGFR mutations^1-3 and/or EGFR amplification⁴ in individuals with lung cancer whose tumors shrunk following gefitinib.

Gefitinib is an anilinoquinazoline compound that inhibits the EGFR tyrosine kinase in vitro with a 50% inhibitory concentration of 0.27 to 33 µmol/L, more than 100 times less than the concentration required to block the kinases of HER-2, KDR, MEK-1, and MEK-2.⁵ In its initial clinical study, gefitinib caused radiographic regressions and symptom improvement in patients with non–small-cell lung cancers refractory or resistant to chemotherapy.^6-9 Based on this experience, gefitinib has become the most extensively studied and most widely used small molecule inhibitor of the EGFR tyrosine kinase. It has been approved for use by the regulatory authorities in the United States, Japan, and many other countries.

The unique mode of action of gefitinib and its potential for use in patients with a common tumor who frequently need second-, third-, or even fourth-line therapy require a thorough understanding of how to care for individuals receiving this agent. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with NSCLC. These recommendations are based on published data as well as our clinical experience.

	METHODS

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Indication
Gefitinib is indicated for the treatment of patients with locally advanced (IIIB) or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapy. The effectiveness is based on radiographic response rates in two phase II trials.^10,11

Radiographic Regression Rates in Unselected Patients
Three of the four phase I trials of gefitinib reported radiographic regressions in patients with NSCLC refractory to multiple chemotherapy regimens.^6,8,9 In phase I testing, 10% of patients with NSCLC experienced partial radiographic responses often accompanied by rapid symptomatic improvement. This experience prompted two phase II trials in which radiographic regression was seen in 14% and symptomatic improvement in 39% of patients.^10,11 Radiographic responses occurred in as little as 1 week. These response rates compared favorably with those of conventional cytotoxic agents used after disease progression with cisplatin or carboplatin. In this setting, docetaxel had a response rate of 8% and vinorelbine 0%.^12,13 For our series of 21 patients with partial radiographic regressions, the median duration of response was 12 months. The shortest response lasted 4 months and the longest continues 60+ months after the start of gefitinib.

Pretreatment Clinical Factors Predicting Sensitivity to Gefitinib
Since radiographic responses are seen in only a fraction of patients, investigators have attempted to identify pretreatment characteristics associated with sensitivity to gefitinib (Table 1). In the international study (IDEAL I) where half of the patients were enrolled in Japan, Fukuoka et al¹⁰ described a higher response rate in Japanese patients compared to non-Japanese patients (28% compared to 10%; P = .0023). In addition, a multivariable analysis showed that performance status (PS) 0 to 1, female sex, adenocarcinoma histology, and prior immuno-/hormonal therapy (including picibanil, investigational drugs, minomycin, marimastat, and tamoxifen citrate) were prognostic factors associated with objective response to the agent. In the United States study (IDEAL2), higher rates of radiographic response were observed in women (19% compared to 3%) and patients with adenocarcinoma (13% compared to 4%).¹¹ Symptom benefit was also more likely in the same two groups.¹¹ A separate analysis performed by the US Food and Drug Administration on the US trial data detected higher rates of radiographic response in never smokers (29%) compared to previous or current smokers (5%).¹⁴

While immunohistochemical studies have not revealed any protein levels that correlate with gefitinib response, three groups have recently shown that mutations in the tyrosine kinase domain of EGFR are associated with sensitivity of NSCLC to gefitinib.^1-3 In total, deletions or amino acid substitutions in exons 18, 19, and 21 of EGFR were found in 20 of 24 tumors sensitive to the drug, but in none of 19 tumors with no response. In primary untreated NSCLCs, such mutations have been found in 29 (12%) of 240 specimens examined, with high frequencies observed in Japanese patients (15 of 58 patients; 28%)¹ and in never smokers with adenocarcinoma (seven of 15 patients; 47%).³ Mutations in the EGFR tyrosine kinase domain also appear to associate with sensitivity to erlotinib.³

EGFR mutations were not detected in four of 24 tumors examined from patients who experienced partial responses or marked clinical improvement while on therapy with gefitinib. Possible explanations for these results include: (1) tumor specimens analyzed did not represent the tumors assessed while patients were on drug studies; (2) mutations were present but were below the detection rate of sequencing assays; (3) other kinases crucial for lung tumor survival are affected by gefitinib; or (4) other mechanisms involving wild-type EGFR confer drug sensitivity. In regard to the last point, Hirsch et al²³ recently reported that EGFR copy number per cell, as assessed by fluorescent in situ hybridization, may also be used to predict sensitivity to gefitinib, even in EGFR wild-type tumors.

Pharmacology
Gefitinib peak plasma levels occur 3 to 7 hours after oral dosing. The mean oral bioavailability is 60%. The plasma half-life is 48 hours. Steady-state concentrations are achieved within 10 days. The elimination of gefitinib occurs through hepatic metabolism primarily through CYP3A4 and excretion in feces. Renal excretion accounts for less than 4% of the given dose. When tested in patients with moderately and severely elevated liver function tests, pharmacokinetics were found to be the same as in individuals with normal liver function.¹⁴

Potential Drug Interactions
Drugs which induce CYP3A4 activity increase the metabolism of gefitinib. Therefore, in patients taking drugs such as rifampin or phenytoin, a gefitinib dose increase to 500 mg daily can be considered in the absence of severe adverse effects. Patients should be closely monitored if the 500-mg dose is used, since the phase II trials showed this dose to cause significantly more rash and diarrhea. Patients taking warfarin should have their International Normalized Ratio (INR) monitored, since INR elevations, as well as bleeding events, have been reported in patients taking both gefitinib and warfarin. The specific reason for this interaction is unknown. Drugs that inhibit CYP3A4 activity (ketoconazole, itraconazole, and others) can lead to higher gefitinib plasma concentrations. Drugs that cause sustained elevations in gastric pH (such as the H2-receptor antagonists ranitidine or cimetidine) may reduce plasma concentrations of gefitinib.²⁴

Dosing
Four phase I trials assessed tolerability by dose and schedule and pharmacokinetics in pretreated patients with solid tumors testing daily oral doses up to 1,000 mg.^6-9 These trials identified diarrhea as dose-limiting at daily oral doses of gefitinib at 700 and 1,000 mg. Skin toxicities including a pustular rash, erythema, dryness, or pruritus were also commonly seen. Ten partial radiographic responses were observed in 100 patients with NSCLC treated on these four trials. Responses were seen at doses from 150 mg to 800 mg per day. The majority of adverse events causing dose adjustments were seen in patients receiving more than 600 mg per day. Based on these data, the two doses selected for phase II study were 250 mg and 500 mg, as 250 mg was higher than the lowest dose at which objective tumor regressions were seen, and 500 mg was the highest dose that was well tolerated when administered chronically.

In both phase II trials, improvement in disease-related symptoms and radiographic regression were nearly identical comparing the 250-mg and 500-mg dosages. However, the incidence of adverse events was significantly lower for the 250-mg/d dose.^10,11 Based on this data and additional information from the randomized trials comparing the 250-mg and 500-mg doses combined with chemotherapy, the 250-mg daily dosage was recommended. The gefitinib 250-mg daily oral tablet is also the dose and schedule approved by health authorities worldwide. Based on our clinical experience, the incidences of nausea and vomiting appeared to be even lower when patients were instructed to ingest gefitinib at bedtime. Therefore, we recommend gefitinib be routinely taken in this way.

	RESULTS

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Is Rash or Diarrhea a Prerequisite for Benefit?
The presence of skin toxicity and diarrhea has been associated with a higher likelihood of radiographic response and symptom benefit with gefitinib¹¹ and improved response and survival with the EGFR inhibitors erlotinib²⁵ and cetuximab.²⁶ Based on these observations, some studies have suggested that the dosages of EGFR inhibitors be escalated in all patients to a dosage that causes skin toxicity and diarrhea.²⁵ There is no evidence that pursuing this strategy will improve response rates or survival. Recent research has shown that EGFR tyrosine kinases in cell lines with mutated EGFR are completely inhibited by lower concentrations of gefitinib than those with wild-type EGFR.³ Clinically, there is conclusive evidence that doubling the dose of gefitinib results in more diarrhea, more skin toxicity, more grade 3 and 4 toxicity, more dose reductions, and more treatment discontinuations.¹¹ In addition, durable radiographic regressions and symptom improvement have been observed in the absence of rash and diarrhea. In all trials, the majority of patients with these toxicities fail to benefit from gefitinib. For these reasons, gefitinib dose escalation above 250 mg is not recommended.

That being said, how can we explain the higher likelihood of benefit among individuals with rash and diarrhea? The presence of rash identifies individuals with tumors containing signaling pathways more susceptible to inhibition by gefitinib. Whether this difference lies in the EGFR itself or in downstream effectors is not known. We, and others, are using clinical leads like this to guide preclinical investigations to uncover the molecular mechanisms that underlie sensitivity and toxicity to gefitinib. For example, EGFR contains a pleomorphic region in intron 1 that consists of a variable number of cytosine-adenine (CA) repeats that regulate gene transcription. Perea et al²⁷ have argued that variations of this region of EGFR influence both response and toxicity following gefitinib. They demonstrated greater sensitivity to gefitinib in cell lines with a shorter number of CA repeats as well as a higher frequency of rash in patients whose skin biopsies demonstrate short CA segments in EGFR exon 1. Their theory is further supported by that fact that Asian individuals who have shorter CA repeat segments^28,29 also have higher sensitivity to EGFR inhibitors^10,30 and a greater likelihood of toxicity with gefitinib.¹⁰

Ghosting, a Distinct Type of Radiographic Response With Gefitinib
In our recently reported analysis, 21 patients had partial radiographic regressions.¹⁵ In addition to demonstrating the usual decreases in the size and/or number of pulmonary lesions, we have observed a unique pattern of regression on computed tomography (CT) of the chest. Three (14%) of the 21 patients exhibited a decrease in density and virtual complete disappearance of tumor without the decrease in tumor diameter normally seen following conventional cytotoxic chemotherapy. An example of this phenomenon is presented in Figure 1. We have termed this diminution in tumor density seen on helical chest CT, "ghosting." Ghosting appears to be a form of durable objective regression associated with clinical benefit in persons treated with gefitinib. Based on our experience, it appears to be the equivalent of a partial response and should be counted a major objective response in practice and when reporting the results of clinical studies.

View larger version (110K): [in this window] [in a new window]   Fig 1. "Ghosting," a unique pattern of durable and clinically beneficial radiographic response following gefitinib. (A) Lesion (arrow) before gefitinib treatment; (B) lesion (arrow) after gefitinib treatment.

Effect on CNS Metastases
The degree to which gefitinib crosses the blood-brain barrier remains unclear. Among five sensitive patients in our series with evidence of cerebral metastases when they started gefitinib, two demonstrated objective regressions in their brain lesions. Other investigators have also documented responses in cerebral metastases.^22,31-33 However, several of our patients with radiographic regressions developed new or worsening cerebral metastases and leptomeningeal spread, while regressions in their primary tumors and metastatic sites were maintained. This observation is discussed further in the section on relapse below.

Symptom Improvement
In addition to assessing radiographic responses, the phase II trials of gefitinib also measured symptom improvement. Both utilized the Lung Cancer Subscale of the Functional Assessment of Cancer Therapy—Lung.³⁴ At baseline and throughout the studies, patients rated the severity of seven symptoms including shortness of breath, weight loss, clarity of thinking, cough, appetite, chest tightness, and difficulty breathing using a 0 to 4 point scale. A score of zero denotes worst symptoms and 28, no symptoms. Symptom improvement was defined as a two-point increase in Lung Cancer Subscale score sustained for 4 or more weeks. This two-point change in the summed Lung Cancer Subscale score correlates with both survival and performance status.^34,35

In the international phase II trial, documented symptom improvement occurred in 40% of individuals receiving gefitinib 250 mg.¹⁰ More than 50% of patients who had stable disease also demonstrated symptom improvement. The US trial reported similar results.¹¹ Confirming phase I observations, over half of the symptom improvements were apparent after only 1 week of treatment. For patients with symptom benefit, improvement was evident in 85% of patients 4 weeks after starting gefitinib. The greatest improvement in Lung Cancer Subscale symptom scores occurred in those patients demonstrating radiographic response, and the least improvement was seen in those with disease progression.³⁶

Side Effects and Their Management
In the phase I trials, diarrhea was dose-limiting and skin toxicity of some type was seen in the majority of patients.^6-9 Unlike conventional cytotoxic agents, gefitinib did not cause myelosuppression, neuropathy, significant nausea, vomiting, or alopecia.

Adverse effects reported in the phase II trials using the 250-mg recommended daily dosage were generally mild, manageable, noncumulative, and reversible with discontinuation of drug or sometimes even continued use. The most common adverse events were diarrhea, skin toxicity (variably recorded as rash, acne, dry skin, or pruritus), nausea, and vomiting. As a measure of overall tolerability in the international double-blind trial, only 16% of patients had an adverse event requiring a short treatment interruption, and none required a dose reduction.¹⁰ The main events resulting in dose interruptions were skin toxicity, gastrointestinal disturbances, and elevated serum hepatic transaminases. These events necessitated drug withdrawal in 1.9% of patients. Overall, grade 3 or 4 toxicities were seen in 1.5% of patients receiving 250 mg of gefitinib.

The US trial reported similar low frequency and severity of adverse events with gefitinib 250 mg daily. Only one person experienced an adverse event leading to study withdrawal, and one patient required dose reduction for toxicity. Grade 3 or 4 toxicities were reported in seven patients. Our institutional experience with gefitinib has been comparable to the phase II studies.

Skin Toxicity
A characteristic rash has been documented to be a "class adverse effect" of agents that target the EGFR and includes erlotinib²⁰ and cetuximab³⁷ as well as gefitinib. The eruption is characterized by inflammatory papules and pustules most often seen on the face, chest, and back and may resemble folliculitis or an acneiform drug eruption (Fig 2). The distribution of the eruption has been termed acneiform, as lesions are predominantly present at sites where there are large numbers of pilosebaceous units such as the scalp, face, neck, and upper trunk. This eruption is distinguished from classic acne vulgaris in its lack of comedones. Busam et al³⁷ studied histologic sections from patients who developed rashes while receiving cetuximab, and described suppurative folliculitis and superficial perifolliculitis as the most common histologic changes. Microcomedones were notably absent.

View larger version (93K): [in this window] [in a new window]   Fig 2. A typical pustular/papular eruption on the neck and trunk following gefitinib.

View larger version (102K): [in this window] [in a new window]   Fig 3. Skin cracking and desquamation on the palm after treatment with gefitinib.

View larger version (101K): [in this window] [in a new window]   Fig 4. Fingernail and cuticle cracking following gefitinib.

Dry skin responds well to bland emollients such as Eucerin cream (Beiersdorf, Jobst, Germany), Cetaphil cream (Galderma, Lausanne, Switzerland), and Aquaphor (Beiersdorf) healing ointment. Many patients have told us that Bag Balm (Dairy Association Co, Rock Island, Quebec, Canada) has been helpful in soothing fissures on the palms and soles. Liquid cyanoacrylate (BAND AID Brand Liquid Bandage; Johnson & Johnson, Skilman, NJ) applied into the cracks and fissures may also relieve pain and promote healing. Water-based make-ups and gentle cleansers such as Cetaphil cleanser are well tolerated with the above-mentioned topical and systemic therapies. We recommend that patients with extensive or persistent skin involvement be referred to a dermatologist.

Diarrhea
Diarrhea, as described in the National Cancer Institute Common Toxicity Criteria (version 2.0), occurred in 40% of patients on the 250-mg dose in the international trial.¹⁰ Twenty-four percent of patients took antidiarrheals. Diarrhea resolved in 84% of patients. The US study reported diarrhea in 57% of patients on the 250-mg dose (grade 1 to 48 (83%); grade 2 to 9 (15%); grade 3, one patient; grade 4, no patients).¹¹ Approximately one-third of patients took antidiarrheal medications. Diarrhea was observed in the first treatment cycle in 76%.

In most cases, loperamide controls diarrhea caused by gefitinib. We advise our patients to purchase loperamide before starting treatment and to keep it with them at all times. If any diarrhea is experienced, we recommend taking two 2-mg loperamide tablets immediately, followed by one 2-mg tablet after every loose bowel movement, up to a maximum daily dose of 10 tablets (20 mg). If the diarrhea does not resolve with this regimen, we advise the patient to stop taking gefitinib and to call a physician promptly. Other causes of diarrhea should also be entertained in this setting.

Ophthalmologic Toxicity
An unusual consequence of treatment with gefitinib, seen in some individuals taking the drug for many months, is excessive eyelash growth. Rarely, misdirectional growth of eyelashes toward the globe, termed trichiasis, can cause corneal irritation. This can be prevented by regular eyelash trimming and treated by removal of the aberrant eyelash. We suggest checking for excessive eyelash growth at routine physical examinations. Patients with symptoms of corneal irritation should be referred to an ophthalmologist.

Although eye symptoms were noted in all gefitinib trials, none have been dose-limiting or led to treatment withdrawal. Because the study participants have many comorbid conditions and are taking concomitant medications that could also affect the eye, with the exceptions of excessive eyelash growth and trichiasis discussed above, the relationship of the eye symptoms to gefitinib is unclear. The US phase II trial is especially difficult to evaluate because all participants had received docetaxel, a drug that causes conjunctivitis and hyperlacrimation, which can persist after the drug is discontinued.³⁸ Future trials involving gefitinib will provide more information about the possible ophthalmologic effects of gefitinib.

The International phase II trial reported eye toxicity in 21% of patients described as conjunctivitis, blepharitis, keratitis, eye pain, dry eyes, and corneal erosion.¹⁰ Grade 1 or 2 eye irritation was reported in 19% of patients in the United States including redness, itchiness, dry eyes, and trichiasis.³⁶ Nonprescription eye drops such as Refresh (Allergen Inc, Irvine, CA) or saline relieve symptoms of dryness and hyperlacrimation.

Interstitial Lung Disease
Interstitial lung disease is a recognized but uncommon adverse effect of cytotoxic drugs³⁹ and has also been described following treatment with the tyrosine kinase inhibitor imatinib as well.⁴⁰ The overall incidence of interstitial lung disease in patients receiving gefitinib has been reported at approximately 1%. Approximately one third of the affected individuals died. The postmarketing experience in Japan reported an incidence of 2%. The rate was 0.3% in approximately 23,000 patients treated on the US-expanded access program.¹⁴ In the trials of NSCLC patients receiving chemotherapy who were randomly assigned to receive concomitant gefitinib or placebo, the observed incidence of interstitial lung disease was less than 1% and slightly higher in the placebo arm. Overall, this incidence of pulmonary toxicity is lower than that reported with the cytotoxic chemotherapy agents now in use for the treatment of NSCLC.

Interstitial lung disease associated with gefitinib has been described as interstitial pneumonia, pneumonitis, and alveolitis. Patients present with the acute onset of dyspnea, sometimes associated with cough or low-grade fever. It occurred in patients receiving prior radiation therapy (31% of reported cases), prior chemotherapy (57% of reported patients), and no prior therapy (12% of reported cases). Most cases occurred in the first month of therapy. Typical chest CT findings include bilateral diffuse ground glass opacities. Patients with concurrent idiopathic pulmonary fibrosis who experience worsening conditions while receiving gefitinib were observed to have a higher mortality compared to those without pulmonary fibrosis.

Inoue et al⁴¹ reported four patients in Japan with NSCLC who developed severe acute interstitial pneumonia in association with gefitinib. Two patients recovered after treatment with steroids and two patients with advanced lung cancer died from progressive respiratory failure. Diffuse alveolar damage was noted on specimens taken at autopsy. More patients with interstitial pneumonia also had received prior thoracic irradiation and had poor performance status. These investigators recommended that physicians should be vigilant for lung damage induced by gefitinib, especially in patients with prior chest radiotherapy, a history of idiopathic pulmonary fibrosis, or poor performance status.

If a patient receiving gefitinib experiences the acute onset or worsening of pulmonary symptoms, particularly in the first 4 weeks of therapy, we recommend that gefitinib be interrupted and an investigation of these symptoms be performed promptly. If interstitial lung disease is suspected, the patient should receive appropriate treatment, including corticosteroids, antibiotics, bronchodilators, and supplemental oxygen. There is no information on the safety of restarting gefitinib after its discontinuation in suspected cases of interstitial lung disease. Based on current information, we would not recommend gefitinib in persons who have experienced interstitial lung disease following its use.

Elevation of Serum Hepatic Transaminases
Rarely, asymptomatic increases in ALT and AST have been reported during treatment with gefitinib. Grade 3 transaminase elevation was noted in two of 103 patients on the 250-mg dose in the international phase II trial, necessitating study withdrawal of one of these patients.¹⁰ None of the 102 patients on the US trial had grade 3 or 4 transaminase elevations.¹¹ Given the rarity and reversibility of this toxicity and the finding that pharmacokinetics in patients with liver metastasis and elevated blood tests of liver function are similar to those in patients with normal livers, we do not recommend any routine measurement of blood tests of liver function.

Patterns and Sites of Relapse
In the analysis reported by Miller et al,¹⁵ among the 21 patients with radiographic regressions, 14 experienced disease progression. Eight patients showed progression of disease in the lung, with one patient suffering both lung and liver progression. Unlike disease progression after conventional chemotherapy, where obvious new metastatic deposits and enlargements of existing lesions are clear cut, patients with initial response following gefitinib in pulmonary lesions who then develop disease progression based on objective criteria can have subtle, millimeter-sized enlargements. Often, reviewing any two consecutive scans does not confirm progression, which can be documented only by a direct comparison to the study that demonstrated the best response. Many patients report a worsening of symptoms and a decreased sense of well-being when gefitinib is discontinued because of objective evidence of disease progression, suggesting that some degree of tumor control persists even after the objective criteria for progression have been met. This situation may be analogous to that of patients with gastrointestinal stromal tumors sensitive to imatinib (another tyrosine kinase inhibitor) whose tumor masses subsequently grow to the point that objective criteria for disease progression are met. When imatinib is stopped, patients report feeling worse and their positron emission tomography scans show increased tumoral fluorodeoxyglucose avidity that can be reversed by the reinstitution of imatinib.^42,43 Other investigators studying imatinib-sensitive, then refractory, gastrointestinal stromal tumors have described a nodule within a mass that on biopsy contains a new activating kinase mutation.⁴⁴ Surrounding tumor tissue, that presumably does not harbor a new mutation, does not grow while imatinib is maintained. Physicians treating clinically well patients who have previously responded to gefitinib should be aware that unusual patterns of progression are possible (and even likely) when using a kinase inhibitor in individuals with tumors harboring activating mutations that underlie their sensitivity to these agents.

Of the 21 patients with partial responses following gefitinib reported by Miller et al,¹⁵ seven developed new or worsening metastases in the CNS, in either the brain or leptomeninges.⁴⁵ In several of these individuals, CNS metastases were the first and only site of relapse. Our experience suggests that the CNS may be a "sanctuary site" for resistant lung cancer cells in persons where the disease is otherwise well controlled. Metastases to the brain or leptomeninges should be high in the differential for patients with tumors sensitive to gefitinib who develop new complaints.

	DISCUSSION

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Gefitinib represents the first new treatment modality for NSCLC to emerge from decades of research. In phase I trials, this agent, developed to specifically inhibit the tyrosine kinase of the EGFR, caused unexpected and dramatic regressions of NSCLCs that were refractory or resistant to conventional chemotherapy. These regressions were often evident in a matter of days, suggesting that the benefit was the result of tumor destruction by a unique mechanism. Equally impressive, patients receiving gefitinib reported prompt improvement in lung cancer–related symptoms like dyspnea, pain, and cough. In addition, these individuals, accustomed to chemotherapy-induced side effects of vomiting, anemia, neutropenia, neuropathy, and alopecia, found gefitinib’s unique adverse effects of rash and diarrhea easier to tolerate.

Phase II trials selected a single 250-mg daily oral dosage as equally effective and safer than a 500-mg dose. These studies confirmed observations from phase I studies documenting a 14% radiographic regression rate, a 40% symptom improvement rate, and manageable diarrhea and rash as the only common adverse effects. Based on these phase II data, regulatory authorities have approved gefitinib given as a single 250-mg daily oral dose as a treatment for patients with advanced NSCLC with tumors that have failed to respond to cisplatin or carboplatin, docetaxel, and other agents. In contrast, studies combining gefitinib with chemotherapy for the initial treatment of advanced NSCLC failed to improve response or survival over chemotherapy alone.^46,47 Until more data emerge, gefitinib should be used only after conventional chemotherapy (which has been proved to improve survival) has failed. Compared to other treatments for advanced NSCLC, gefitinib is generally better tolerated. The adverse effects it causes are nearly always manageable, reversible, and lessen even with continued use in most patients.

Gefitinib should always be administered at a dose of 250 mg orally daily, with follow-up initially after a month, then every 2 to 3 months. Dose escalation is not routinely recommended, as the randomized trials that led to its approval revealed similar efficacy but increased adverse events by doubling the dose. We suggest 1- to 2-week discontinuations for the rare individual who experiences severe skin toxicity or diarrhea despite the supportive measures we have outlined. Treatment-limiting toxicities such as interstitial lung disease are extremely rare. Even that adverse effect can usually be managed effectively by stopping gefitinib and administering corticosteroids, supplemental oxygen, and other supportive care measures.

Unfortunately, the majority of unselected patients with NSCLC derive no benefit from gefitinib. How this situation can best be addressed is now the focus of intense research. Already, several clinical characteristics and the presence of EGFR mutations or amplification can identify patients more likely to benefit, especially persons who have never smoked cigarettes and individuals whose tumors have any features of bronchioloalveolar carcinoma.^10,11,14,15 The presence of one or more of these characteristics can help the clinician choose between the conventional chemotherapy choices and gefitinib. By contrast, neither the presence nor the degree of EGFR expression, as measured by immunohistochemistry, predicts outcomes, and therefore they should not be used to select patients for treatment with this agent.¹⁸

In the near future, two molecular tests may possibly be used to predict tumor sensitivity to gefitinib: EGFR mutation status, as assessed by DNA sequencing, and EGFR gene copy number, as assessed by fluorescent in situ hybridization or chromogenic in situ hybridization. Although technically validated, widely available testing for the most common mutations will be available in the near future, prospective studies will need to be performed before these kinds of tests are used in routine practice. In the meantime, the clinical characteristics previously discussed can still be useful predictors of gefitinib response.

Gefitinib provides both benefit and hope for patients with NSCLC who have exhausted other options. For the researchers who postulated decades ago that blocking growth factor receptors like EGFR could lead to tumor regressions, gefitinib represents a promise fulfilled. This success has stimulated the search for new kinase inhibitors and other strategies to block signaling in lung cancer cells.

	Authors’ Disclosures of Potential Conflicts of Interest

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Neelam T. Shah, Britsol-Myers Squibb. Acted as a consultant within the last 2 years: Vincent A. Miller, AstraZeneca; Mark G. Kris, AstraZeneca, Bristol-Myers Squibb, Genentech, GlaxoSmithKline. Received more than $2,000 a year from a company for either of the last 2 years: Vincent A. Miller, AstraZeneca, OSI Pharmaceuticals; Mark G. Kris, Genentech.

	NOTES

 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted April 8, 2004; accepted October 2, 2004.

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