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© 2002 American Society for Clinical Oncology Selective Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 Is Generally Well-Tolerated and Has Activity in Non–Small-Cell Lung Cancer and Other Solid Tumors: Results of a Phase I TrialByFrom the Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX; Arkansas Cancer Research Center, Little Rock, AR; Vanderbilt-Ingram Cancer Center, Nashville, TN; University of California San Francisco Comprehensive Cancer Center, San Francisco, CA; Cancer Institute of New Jersey, New Brunswick, NJ; Vall d’Hebron General Hospital, Barcelona, Spain; AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; AstraZeneca Pharmaceuticals, Wilmington, DE; and Karmanos Cancer Institute, Wayne State University, Detroit, MI. Address reprint requests to Patricia Mucci LoRusso, DO, Karmanos Cancer Institute, Wayne State University, Harper Hospital, 3990 John R, Rm 520, Hudson Wing, Detroit, MI 48201; email: lorussop{at}karmanos.org
PURPOSE: To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS: This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity.
RESULTS: Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non–small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses
CONCLUSION: Rash and diarrhea, generally mild and tolerable at doses
THE EPIDERMAL growth factor receptor (EGFR [HER1/erbB-1]) is a transmembrane receptor protein found primarily on cells of epithelial origin.1 Expression or high expression of EGFR has been widely reported in human tumors, including non–small-cell lung, breast, head and neck, gastric, prostate, bladder, renal, pancreatic, and ovarian cancers.2-8 Enhanced EGFR drive seems to promote tumor growth by increasing cell proliferation, motility,9 adhesion, and invasive capacity,10 and by blocking apoptosis.11 EGFR expression is associated with metastasis, late-stage disease, resistance to chemotherapy, hormonal therapy, and radiotherapy, and poor prognosis.3,4,12-17 EGFR signaling, via phosphorylation of the intracellular tyrosine kinase (TK) domain of the protein, can be blocked by small-molecule EGFR tyrosine kinase inhibitors (TKIs). ZD1839 (gefinitib, Iressa; AstraZeneca Pharmaceuticals, Wilmington, DE)18 is an orally active, selective EGFR-TKI. Initial pharmacokinetic studies support the use of ZD1839 as a daily oral treatment.19,20 In addition, ZD1839 has been administered in a phase I dose escalation study (14 days on, 14 days off) in patients with a range of tumors, and showed good tolerability. Dose-limiting toxicity (DLT) of grade 3 reversible diarrhea was observed at 700 mg once daily, a dose well above that at which antitumor activity was seen. In this study, pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation.21 The present study was undertaken to establish the safety and tolerability of ZD1839, given orally for 28 consecutive days, to patients with defined, advanced tumors, and to further explore the dose-related biologic effects on tumor growth and markers of pharmacodynamic effect in skin biopsies. An additional aim of the study was to determine the pharmacokinetic profile of a daily, chronic, oral dose of ZD1839.
Trial Design The primary end points in this multi-institutional, open, phase I, dose escalation, sequential block trial were safety, tolerability, and investigation of dose-related biologic effects on tumor growth and surrogate markers of pharmacodynamic effect. Secondary end points were pharmacokinetic profiling and assessment of quality of life.
Patients
Eligible patients had an absolute neutrophil count
Prior chemotherapy and radiation were permitted only if the last dose had been administered
Treatment Schedule and Dose Escalation
ZD1839 dose levels investigated were as follows: 150, 225, 300, 400, 600, 800, and 1,000 mg/d. To allow collection of sufficient pharmacokinetic and pharmacodynamic data in addition to safety and tolerability data, 6 to 14 patients were allowed at each dose level, although this was reduced to six or fewer patients at doses Dose escalation proceeded to 1,000 mg/d or until DLT was observed. DLT was defined as more than 30% of patients at a particular dose level with grade 3 or higher toxicity (National Cancer Institute common toxicity criteria version 2.0); or grade 2 or higher hematuria, serum creatinine, and proteinuria; or significant ocular toxicity (corneal punctate staining with symptoms, > one quadrant of conjunctival hyperemia or other objective findings considered more severe) in two or more patients in the first 28-day treatment period. If DLT was observed at a given dose level, at least six patients were studied at that level before dose escalation was considered. In the absence of DLT, treatment was continued until disease progression or withdrawal of patient consent. In the event of reversible DLT, or grade 2 or higher toxicity in hematuria, serum creatinine, and proteinuria, treatment was stopped immediately and supportive care given. If the toxicity resolved or reversed to grade 1 within 14 days of onset and the patient was showing clinical benefit, treatment could be restarted at one dose level lower (or at 100 mg/d in the case of dose reduction from 150 mg/d). Patients could be withdrawn from treatment after the following: toxicity not resolving or reversing to grade 1 within 14 days of onset; DLT or serious adverse event; withdrawal of consent; radiographic or symptomatic evidence of tumor progression; protocol violation; pregnancy; investigators’ concerns; or loss to follow-up. Toxicity-related prophylaxis (eg, antidiarrheals) was not allowed.
Pharmacokinetic Evaluation
Pharmacodynamic Evaluation
Antitumor Activity
Patient Assessments
Patients Of 71 patients enrolled onto the trial, 69 received at least one dose of ZD1839 and were assessable for safety, and 58 patients were assessable for efficacy. Non–small-cell lung cancer (NSCLC) (n = 39) (Table 1) and head and neck (n = 18) tumors were the most common, and most patients (80%) had a performance status of 1. The patient population was heavily pretreated: 68 patients (99%) had received prior cancer therapy, including 66 (96%) who had received chemotherapy (most of whom had received  two regimens), and 45 (65%) who had undergone prior radiotherapy (Table 2).
Patients were recruited at seven dose levels, ranging from 150 mg/d to 1,000 mg/d (Table 2). A total of 250 months of treatment were completed (median, 2 months; range, 1 to 18 months) and 59 (71%) of 69 patients completed more than one treatment period. Patient withdrawals. Ten patients did not complete the 28-day treatment period: four because of disease progression and three because of adverse events (including one patient with prostate cancer with a treatment-related event: grade 3 dehydration at 1,000 mg/d); one was lost to follow-up; one withdrew consent; and one deviated from the protocol by missing more than four consecutive doses of trial medication. Six patients withdrew because of adverse events that occurred after one or more treatment period, two of which were drug-related (diarrhea in one patient during the third cycle at the 600 mg dose, and corneal epithelial damage [caused by an ingrown eyelash] in one patient during the fourth cycle at the 800-mg dose; both patients had prostate cancer) and reversed on withdrawal from treatment followed by supportive care measures. There were no treatment-related deaths. Dose reductions. Of the seven patients requiring dose reductions because of drug-related adverse events, six experienced treatment interruption or dose delays. Dose reductions or interruptions were limited to doses between 600 and 1,000 mg: two patients at 600 mg (prostate and ovarian cancer), four patients at 800 mg (NSCLC [two patients], colorectal cancer [one patient], prostate cancer [one patient]), and one patient at 1,000 mg (NSCLC). Dose escalation. At the highest planned dose level of 1,000 mg, three patients had DLT: grade 3 diarrhea (NSCLC [one patient]), grade 3 diarrhea and grade 3 dehydration (prostate cancer [one patient]), and grade 3 diarrhea and grade 3 acne-like rash (NSCLC [one patient]). Three patients also had DLT at the 800-mg dose level: grade 3 diarrhea (NSCLC [one patient]), grade 3 diarrhea and grade 3 pruritus (colorectal cancer [one patient]), and grade 3 acne-like rash and grade 2 conjunctivitis (NSCLC [one patient]). Administration of ZD1839 was escalated to 1,000 mg as the DLTs experienced by patients at the 800-mg dose level were reported after five patients had been enrolled onto the 1,000-mg dose level. One patient at the 150-mg dose level experienced a DLT of grade 3 elevated gamma-glutamyl transpeptidases.
Safety and Tolerability
Grade 3 adverse events occurring in two or more patients consisted of acne-like rash (six of 69 patients [9%]), diarrhea (seven patients [10%]), anorexia, asthenia, elevated glutamyl transpeptidases, dehydration, and dyspnea (two patients each [3%]). Grade 4 events consisted of apnea (three patients [4%]); anorexia, asthenia, dysphagia, hemorrhage, pneumonia, and respiratory distress syndrome (two patients each [3%]); and abdominal pain, deep thrombophlebitis, dyspnea, epistaxis, hemolysis, heart failure, myasthenia, nausea, pulmonary embolism, stridor, and vomiting (one patient each [1.5%]). All episodes of grade 3 and grade 4 dyspnea or respiratory distress syndrome were judged to be disease related, and none of the grade 4 adverse events were clearly drug related. There was no evidence of recall of radiation injury.
Grade 3 diarrhea was recorded for a small proportion of patients (seven patients [10%]), and incidence seemed to be dose related (Fig 2). Grade 3 diarrhea, when occurring, had a mean time to first onset of 16 days (range, 3 to 41 days), with five cases occurring in the first 2 weeks and the remaining two cases occurring after 5 weeks (ie, > 1 week outside the period for maximum-tolerated dose [MTD] assessment) from the start of therapy. Two patients had grade 3 diarrhea on two occasions (days 3 and 82 of 85 days on study, and days 41 and 56 of 68 days on study, respectively) and received concomitant loperamide. In addition, 24 patients (35%) received antidiarrheal agents (eg, loperamide) after first occurrence of symptoms, a measure that was effective in controlling symptoms. On recovery from diarrhea, antidiarrheal agents were withdrawn. There was an apparent dose-relationship with all grades of diarrhea. Acne-like rash (folliculitis) (Fig 3), described variously as acne, rash, macropapular rash, pustular rash, vesiculobullous rash, or urticaria, occurred in 38 patients (55%) and was severe (grade 3) in six patients, but resolved in three of the six despite continuation of treatment. Although grade 1/2 acne-like rash was observed at all dose levels, grade 3 rash generally occurred at the higher dose levels (
Pharmacokinetics The steady-state concentrations of ZD1839 by dose, derived from predose plasma samples, are listed in Table 4 and Fig 4. Comparison of the predose concentration data demonstrated that steady-state concentrations of ZD1839 were achieved by day 7 of administration, when the first blood samples were collected (Fig 4). With the exception of two patients who had a two- to three-fold increase or decrease in plasma ZD1839 concentration in the first 3 weeks of therapy, fluctuations in the intrapatient coefficients of variation in steady-state plasma concentrations for patients with at least three evaluated concentrations were between 4% and 42%. Over the dose range 150 to 600 mg/d, despite variability between patients, the geometric mean steady-state plasma concentrations (mean of individual patient means at a given dose) seemed to increase with dose from 172 ng/mL to 774 ng/mL (Table 4), an exposure level well above the 90% inhibitory concentration for KB cells (Fig 4).4 Within these dose groups, exposure to ZD1839 showed a three-fold to 10-fold interpatient variability, with no apparent increase in variability with increasing dose.
Pharmacodynamics Skin biopsy data was collected for 22 patients, including at least one patient from each dose level (150 to 1,000 mg), before and after therapy (Fig 5). Total EGFR levels were not significantly changed after therapy (P = .2), as expected. There was a trend toward reduction in activated (phosph-orylated) EGFR, but this was not significant (P = .225). However, significant decreases in the proliferation markers mitogen-activated protein kinase (P = .028) and Ki-67 (P = .018) were seen, along with a significant increase in the cyclin-dependent kinase inhibitor p27KIP-1 (P = .043). In addition, the apoptotic index (terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end labeling) was significantly increased in posttreatment samples (P < .001), as was the thinness of the stratum corneum (Fig 5e) (P < .001). There was no evidence that the degree of the observed effects correlated with ZD1839 dose, steady-state ZD1839 plasma concentration (day 28), or adverse skin reactions; however, effects were seen at all dose levels. A wider and more detailed analysis that takes data from two phase I studies has found similar effects, often with increased significance because of the larger patient numbers.20
Antitumor Activity Fifty-eight patients were assessable for antitumor activity. Of these, 26 (45%) completed 3 months of therapy: nine of 39 patients with NSCLC, 12 of 18 patients with head and neck cancer, three of seven patients with colorectal cancer, and two of four patients with ovarian cancer. Furthermore, 13 (22%) of 58 patients completed 6 months of treatment.
Five patients received ZD1839 for
This phase I trial of ZD1839 was principally designed and conducted to assess the safety and tolerability of increasing doses of ZD1839 in patients with refractory solid tumors in cancer types associated with EGFR pathway activation. EGFR is widely reported to be highly expressed in NSCLC.5-8 However, study patients were not recruited on the basis of EGFR status, as any predictive relationship to tumor progression is unclear.8,23-28 Pharmacokinetic data (mean steady-state plasma concentrations) indicate that exposure seemed to increase with dose over the dose range 150 to 600 mg/d, and that steady-state concentrations of ZD1839 were achieved by day 7 of administration. Diarrhea (occurring in 65% of patients), acne-like rash (55%), and asthenia (49%) were the most common adverse events, were reversible on treatment discontinuation, predominantly began within the first treatment period, and showed no relationship to therapy duration. There was an apparent dose relationship with all grades of diarrhea and with grade 3/4 acne-like rash. Diarrhea (five patients) was the most common DLT. Three patients had DLT at the 800-mg dose level, suggesting that the MTD of ZD1839 is 800 mg/d on this trial. However, antitumor activity was seen at all dose levels, and the doses chosen for phase II investigations were 250 and 500 mg/d, doses at which both antitumor activity and pharmacokinetics consistent with preclinical activity were routinely seen. Unlike other phase I studies, the design of this study did not allow prophylactic or expectant management of toxicities, even if these could be severe enough to cause DLT events. This study has shown that the daily dosing schedule is generally well tolerated, has a wide safety margin, and has antitumor activity over a wide range of doses. Previously, two placebo-controlled studies in human volunteers investigated the pharmacokinetics and tolerability of single oral doses of ZD1839,19 and pharmacokinetic analysis from another phase I trial has confirmed that ZD1839 is suitable for administration as a once-daily oral tablet formulation.21 In this trial of ZD1839, 26 patients (38%; 12 with head and neck cancer and eight with NSCLC) benefited from treatment and remained on study for 3 to 18+ months. Stable disease or partial response was seen in patients who had undergone a range (zero to five) of prior chemotherapy regimens, with or without prior radiotherapy. Antitumor activity (response or prolonged stable disease) was observed at all dose levels: at the lowest dose level (150 mg), one patient with NSCLC responded rapidly and had a partial response that lasted for 15 months (in other phase I trials of ZD1839 monotherapy, a total of 61 patients with NSCLC were treated, nine of whom had responses).18,21,29 The high rate of disease stabilization may be expected on the basis of the mode of action of ZD1839 as an inhibitor of cell growth and proliferation and preclinical observations that ZD1839 caused higher rates of disease stabilization or slowing of disease progression than tumor regression.30-32 Ideally, modified measures of clinical efficacy (eg, stable disease duration, time on study, and symptom improvement) are needed to fully evaluate novel therapies targeting specific biologic pathways important in tumor biology.33 In this trial, Functional Assessment of Cancer Therapy questionnaires34-37 seemed to provide sensitive measures of disease-related symptoms, reflecting the length of time on study. Symptom improvement and quality of life data will be reported separately (LoRusso et al, manuscript in preparation). The acne-like rash associated with ZD1839 treatment probably reflects the positive EGFR status of epidermal keratinocytes and other cells residing in the skin (a tissue that is dependent on epidermal growth factor for growth and development). In a wider pharmacodynamic study, Albanell et al20 found that the stratum corneum of the epidermis was thinner during ZD1839 therapy, and that keratin plugs and microorganisms were found in hair follicles. Skin reactions in ZD1839 treatment may therefore be consistent with pharmacologic expectations, and suggest that the antitumor activity of ZD1839 is occurring by the expected EGFR-inhibitory mechanism. In addition, pharmacodynamic effects occurred at doses well below those producing unacceptable toxicity.20 Based on skin effects, methods are in development for monitoring the biologic activity of EGFR-TKIs such as ZD1839 without recourse to tumor biopsy. However, no posttreatment tumor biopsy samples were collected in this trial, and further studies are needed to allow comparison of intrapatient pharmacodynamic data for skin and tumor. Several EGFR-targeted agents are in clinical trials, including the antibody IMC-C225 that targets the extracellular ligand-binding domain,38 and other EGFR-TKIs including PKI-16639 and OSI-774.40,41 Phase I studies of IMC-C225 combined with chemotherapy or radiation for patients with squamous-cell carcinoma of the head and neck have shown encouraging response rates in patients with recurrent or refractory disease, and good tolerability, with skin rashes and allergic reactions being the most clinically important adverse events reported.42 A phase I study of OSI-774 has shown diarrhea and cutaneous events to be the most common toxicities, and several patients with epidermoid malignancies demonstrated either antitumor activity or relatively long periods of stable disease.40 Phase II and III trials of ZD1839 in multiple tumors are underway. Two daily doses of ZD1839 (250 and 500 mg) were chosen for investigation because they were supported by pharmacokinetic data from this study and others,19,21,29 they were above the 90% inhibitory concentration identified in preclinical studies (AstraZeneca, data on file), and they combined efficacy with low toxicity, as the doses were lower than the MTD identified in this and other phase I trials.18,21 The toxicity profile of ZD1839 suggests that this agent will be well tolerated in combination therapy, a premise supported by preclinical studies.30,31,43 A pilot trial of ZD1839 with carboplatin/paclitaxel in previously untreated NSCLC has demonstrated this combination to be well tolerated.44 In advanced NSCLC, two phase III multinational placebo-controlled clinical trials are underway, combining ZD1839 with commonly used chemotherapy regimens for the treatment of chemotherapy-naive patients. In summary, the novel EGFR-TK–targeted agent ZD1839, given as oral once-daily administration, shows favorable tolerability and has a relatively mild and biologically predictable adverse-event profile as well as antitumor activity. The most common adverse events were diarrhea, acne-like rash, and asthenia, all of which were reversible on treatment discontinuation. Antitumor activity was seen at all doses, against all five tumor types included in the trial, and occurred in both chemotherapy-naive and heavily pretreated patients. Phase II monotherapy trials in NSCLC have confirmed the phase I observations of the activity and safety of ZD1839.45,46 Phase III combination trials in NSCLC are in progress to determine the efficacy, optimal daily oral dose, and safety and tolerability of ZD1839. Ongoing clinical studies in other cancers will allow wider appraisal of this promising therapeutic agent.
Supported by AstraZeneca, Wilmington, DE.
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20. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20: 110-124, 2002
21. Ranson M, Hammond LA, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor–tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20: 2240-2250, 2002 22. Response evaluation criteria in solid tumors (RECIST) quick reference. Http://www.nci.nih.gov/bip/RECIST.htm 23. Veale D, Kerr N, Gibson GJ, et al: The relationship of quantitative epidermal growth factor receptor expression in non-small cell lung cancer to long term survival. Br J Cancer 68: 162-165, 1993[Medline] 24. Ohsaki Y, Tanno S, Fujita Y, et al: Epidermal growth factor receptor expression correlates with poor prognosis in non-small cell lung cancer patients with p53 overexpression. Oncol Rep 7: 603-607, 2000[Medline]
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30. Ciardiello F, Caputo R, Bianco R, et al: Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 6: 2053-2063, 2000
31. Sirotnak FM, Zakowski MF, Miller VA, et al: Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 6: 4885-4892, 2000 32. Woodburn JR, Kendrew J, Fennell M, et al: ZD1839 (‘Iressa’) a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI): Inhibition of c-fos mRNA, an intermediate marker of EGFR activation, correlates with tumor growth inhibition. Proc Am Assoc Cancer Res 41: A2552, 2000 (abstr)
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40. Hidalgo M, Siu LL, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19: 3267-3279, 2001 41. Karp DD, Silberman SL, Csudae R, et al: Phase I dose escalation study of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) inhibitor CP-358,774 in patients with advanced solid tumors. Proc Am Soc Clin Oncol 18: 388a, 1999 (abstr 1499) 42. Herbst RS, Kim ES, Harari PM: IMC-C225, an anti-epidermal growth factor receptor monoclonal antibody, for treatment of head and neck cancer. Expert Opin Biol Ther 1: 719-732, 2001[CrossRef][Medline] 43. Woodburn JR, Barker AJ, Gibson KH, et al: ZD1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development. Proc Am Assoc Cancer Res 38: 633-634, 1997 44. Miller VA, Johnson D, Heelan RT, et al: A pilot trial demonstrates the safety of ZD1839 (‘Iressa’), an oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in combination with carboplatin (C) and paclitaxel (P) in previously untreated advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20: 326a, 2001 (abstr 1301) 45. Fukuoka M, Yano S, Giaccone G, et al: Final results from a phase II trial of ZD1839 (‘Iressa’) for patients with advanced non–small-cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol 21: 298a, 2002 (abstr 1188) 46. Kris MG, Natale RB, Herbst RS, et al: A phase II trial of ZD1839 (‘Iressa’) in advanced non–small-cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 21: 292a, 2002 (abstr 1166) Submitted March 7, 2002; accepted June 11, 2002. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing. 
