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Originally published as JCO Early Release 10.1200/JCO.2004.08.110 on November 24 2003 © 2004 American Society of Clinical Oncology. Phase II Trial of Gefitinib in Recurrent GlioblastomaFrom the Departments of Medicine, Surgery, Pathology, and Cancer Center Biostatistics, Duke University Medical Center, Durham, NC; and the National Cancer Institute, Bethesda, MD Address reprint requests to Jeremy N. Rich, MD, Duke University Medical Center, Box 2900, Durham, NC 27710; e-mail: rich0001{at}mc.duke.edu
PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.
Despite advances in therapy, malignant gliomas remain essentially fatal, with a median survival of 10 to 12 months with maximal therapy [1]. Recurrent grade 4 gliomas (glioblastomas) have a strikingly low rate of clinical response and frequent treatment failure. Current therapies target tumors in a nonspecific fashion, usually through DNA damage. Novel targeted therapies currently under development include small-molecule inhibitors of receptor tyrosine kinases to block pathways mediating critical tumor phenotypes. The epidermal growth factor receptor (EGFR) pathway represents a particularly attractive therapeutic target in glioblastomas because EGFR is dysregulated in the majority of human malignant gliomas through overexpression, amplification, and activating mutations [2–4]. Activity of the EGF pathway in a variety of cancer types has been linked to an increase in motility, adhesion, invasion, and proliferation of tumor cells as well as an inhibition of apoptosis and induction of angiogenesis [5]. Several classes of EGFR inhibitors have been developed, including small-molecule tyrosine kinase inhibitors (TKIs), antibodies, immunotoxin conjugates, and antisense oligonucleotides. Because intracranial delivery of many agents is limited, the use of small-molecule TKIs offers a theoretical advantage over other modalities [6]. Gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE) is a novel, oral low-molecular weight, adenosine triphosphate mimetic of the anilinoquinazoline family that reversibly inhibits the tyrosine kinase activity associated with EGFR [7,8]. Gefitinib has shown an acceptable side-effect profile in phase I studies [9–11] and therapeutic activity in several phase II studies of several systemic cancers [12,13], leading to recent United States Food and Drug Administration approval for monotherapy for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. We undertook this trial to determine the activity and tolerability of gefitinib in the treatment of patients with glioblastoma at first recurrence. After trial initiation, gefitinib was found to be significantly metabolized by the CYP3A4 cytochrome P450 hepatic enzymes [14]. Because of the high utilization rate of CYP3A4 enzyme-inducing antiepileptic drugs (EIAEDs) and dexamethasone in the brain tumor patient population, we sought to also define the effect of enzyme-inducing drugs on the tolerated dose through an intrapatient dose escalation. In addition, we evaluated the expression of both wild-type EGFR and a constitutively active EGFR mutant (EGFRvIII) [15–19] in patient samples with therapeutic response.
Eligibility Patients were required to have histologically confirmed glioblastoma in first relapse. Fresh frozen tumor sample for analysis was obtained at the time of relapse to confirm recurrent disease. Histology was reviewed by one of the authors (R.E.M.) and graded according to the WHO's four-tiered system [20]. Patients were not required to have residual measurable disease, were not allowed any prior EGFR-based therapy, and were allowed no chemotherapy or radiotherapy within 4 weeks of study entry (6 weeks for a nitrosourea).
Patients had to be at least 18 years of age, nonpregnant, and not breastfeeding, have a life expectancy of greater than 12 weeks, have a Karnofsky performance status All patients were required to understand and to be willing to sign a written informed consent document approved by the Duke Institutional Review Board. This study was executed and completed before Health Insurance Portability and Accountability Act regulations took effect.
Treatment Plan and Dose Modifications Therapy was continued until disease progression, significant clinical decline, unacceptable toxicity, or patient decision. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria, version 2.0 [21]. For grade 2 skin rashes and diarrhea that were unacceptable to the patient for symptomatic reasons, gefitinib was temporarily held until resolution and subsequently restarted at the same dose. If symptomatic grade 2 diarrhea and skin rash recurred after reinstituting gefitinib at the same dose, treatment was held until resolution to grade 1 or less, and gefitinib was reinstituted at a dose lowered by 250 mg daily. For other significant grade 2 nonhematologic toxicity, treatment was held until resolution and reinstituted at a dose lowered by 250 mg daily. For grade 3 or 4 toxicity, treatment was discontinued, and the patient was re-evaluated at least weekly until toxicity resolution to grade 1 or less. Treatment was then reinstituted at a dose lowered by 250 mg daily. Patients with unresolved toxicity after 2 weeks were taken off study. If a patient dose was lowered, no increase was undertaken.
Measurement of Effect
EGFR Immunohistochemistry
EGFR DNA Quantification
Statistical Considerations The primary end point of the study was 6-month PFS, with secondary end point measurements of tumor response rate, event-free survival (EFS), overall survival (OS), and drug toxicity. All patients who met eligibility criteria and were assessable for PFS were included in efficacy analyses. PFS, EFS, and OS were measured as the time between registration and disease progression; disease progression, toxicity, or death; or death, respectively. The product-limit estimator developed by Kaplan and Meier was used to graphically summarize these end points. Relative to PFS, EFS, and OS, the log-rank test was used to compare subgroups defined by the following patient characteristics: age, sex, Karnofsky performance status, extent of resection, systemic toxicity, immunohistochemistry (wild-type EGFR and EGFRvIII), and EGFR DNA amplification. Patient follow-up was updated through June 5, 2003. All statistical analyses were conducted at the 0.05 level of significance. All patients who received the drug were included in toxicity analysis. The toxicity of gefitinib experienced by patients was tabulated by type and most severe grade.
Patients and Eligibility Fifty-seven patients were enrolled from May 2001, to November 2002 (Table 1). Four patients were enrolled but were deemed nonassessable for efficacy as follows: one patient died before receiving any drug; one patient developed a CSF infection after surgery and never received drug; one patient developed a pulmonary embolism after 15 days of therapy then developed an intracerebral hemorrhage after anticoagulation; and one patient had stable disease on MRI at 6 weeks of therapy but was diagnosed with a second malignancy (breast carcinoma), requiring protocol discontinuation. The last two patients were included in the toxicity analysis.
Prior therapy administered to the 53 assessable patients is listed in Table 1. Every patient had undergone prior surgical resection and external-beam radiotherapy. One patient received I125 radioactive seeds. Prior chemotherapy was administered as adjunctive therapy to surgery as carmustine-impregnated wafers (n = 9, 17%) or radiation (n = 5, 9%) and/or adjuvant therapy (n = 35, 66%). Patients were treated with either no chemotherapy or up to 12 prior cycles of chemotherapy (median, four cycles) with a median of two chemotherapy agents (range, zero to five agents), including nitrosoureas, temozolomide, irinotecan, etoposide, and retinoic acid. Many patients were treated with combinations of chemotherapeutic agents or rotated on different chemotherapeutic agents, as a standard practice, without evidence of progression. Nine patients (17%) had no prior chemotherapy. Every patient underwent an open biopsy (one patient, 2%) or resection (gross total resection: no residual enhancement, n = 11, 21%; near total resection: < 0.2 cm of enhancement, n = 16, 30%; subtotal resection: between 0.2 and 1 cm of residual contrast enhancement, n = 14, 26%; and partial resection: > 1 cm of residual contrast enhancement, n = 11, 21%) for confirmation of tumor recurrence. Follow-up continued for the majority of patients after disease progression. Sixteen patients entered hospice without further therapy. Thirty-seven patients received additional therapy, generally chemotherapy.
Measurement of Therapeutic Effect, Time to Progression, and Survival
Median survival has been 39.4 weeks (95% CI, 24.3 to 59.4 weeks), with a 1-year survival probability of 35.6% (Fig 1B). Of the 53 assessable patients, 19 patients remain alive.
Toxicity
Several patients experienced adverse events that were felt to be secondary to their cancer rather than gefitinib treatment, including seizure, cerebral edema, CNS hemorrhage, lower extremity deep vein thrombosis, confusion, muscle weakness, and incontinence. Most of the neurologic events occurred within the context of a progressive tumor. No patient experienced pulmonary toxicity, cellulitis, nausea, vomiting, electrolyte changes, or renal dysfunction.
Wild-Type EGFR and EGFRvIII Expression: Protein and DNA Amplification
Factors Related to Response, Progression, and Survival We analyzed the relationship between several patient factors and either EFS (Table 4) or OS from treatment initiation (Table 5). The presence of diarrhea during therapy was a positive predictor for OS (Fig 2) but not EFS. The development of skin toxicity during therapy and extent of resection (ie, absence of measurable disease) were borderline significant as predictors of EFS (Fig 3A and B). The relationship between surgical resection and EFS was significant with further subgroup analysis (Fig 3C). Patients who underwent gross total or near total resections at initiation of therapy had both a significantly improved EFS (total resection: n = 27; median EFS, 15.9 weeks; 95% CI, 8.0 to 23.7 weeks; subtotal resection: n = 26; median EFS, 7.9 weeks; 95% CI, 7.4 to 8.1 weeks; P < .0001) and OS from treatment initiation (total resection: n = 27; median OS, 66.0 weeks; 95% CI, 31.6 weeks to not reached; subtotal resection: n = 26; median OS, 25.1 weeks; 95% CI, 17.9 to 40.4 weeks; P = .0058). Because all patients were diagnosed with glioblastoma and had prior surgical resection and external-beam radiation, these factors were not analyzed. Although only nine of 53 patients were not pretreated with chemotherapy, a trend was seen in improved duration of PFS, although it was not statistically significant. Sex, age, performance status, expression of either wild-type or mutant EGFR on immunohistochemistry, and DNA amplification did not predict either disease control or survival.
We report the first clinical trial with gefitinib, a small-molecule TKI of EGFR, in the treatment of glioblastoma. With 53 assessable patients, our study demonstrates tolerability and modest activity of this therapy in patients with this lethal cancer. The majority of patients (56.6%) experienced failure of therapy (ie, progressive radiographic or clinical disease or development of significant toxicity) by the first 8-week evaluation, but a subpopulation has done well, with six patients undergoing nine 4-week cycles of therapy and one patient remaining on treatment for 17 cycles. The 6-month PFS was the primary end point because all patients underwent surgical resection. We observed a 6-month PFS rate of 13.2%, which is worse than observed in patients with first relapse glioblastoma treated with temozolomide (21%) but better than procarbazine (8%) [25]. Of note, patients in the current protocol were enrolled after a longer period relative to diagnosis (median, 37 weeks; range, 12 to 164 weeks) and were more heavily pretreated with chemotherapy. The limited toxicity and modest efficacy seen in this trial suggests the potential utility of this agent. EGFR offers a particularly promising target in glioblastoma therapy because of the frequent increase in EGFR pathway activity in these tumors, the myriad pro-tumorigenic phenotypic effects of EGFR activation, and the lack of effective therapies. As in systemic cancers, the clinical trial design of anti-EGFR treatments like gefitinib poses significant challenges [27], including determining which patients respond best to these therapies and determining the optimal treatments regimen (dose, monotherapy v combination, and so on). We sought to determine the expression of both the wild-type and constitutively active mutant EGFR forms in our patients before treatment. As in other cancer types, the expression of either EGFR form was neither associated with an increased sensitivity to gefitinib nor did the absence of EGFR expression or amplification preclude tumor control by gefitinib [12,28]. We are currently investigating the activation states of EGFR and the downstream components to gefitinib response. Unfortunately, preclinical studies to date have failed to determine prognostic indicators of tumor response. The importance of treatment relative to the maximum-tolerated dose has been controversial in the use of targeted therapies. Rather, many have advocated a treatment at a dose where target inhibition is seen. Skin toxicity and diarrhea have been shown to be related to systemic EGFR antagonism and sometimes correlated with treatment response in some trials [12], but patients with other cancer types have also responded to gefitinib in the absence of toxicity [13,29]. Although we found a borderline significant relationship between the presence of rash and EFS but not OS from treatment initiation, significant rash was seen in a minority of patients, and development of diarrhea was linked to improved OS. Thus, we may be underestimating the importance of measures of systemic EGFR effects in relationship to potential drug activity in patients. A recent report of gefitinib in malignant gliomas and meningiomas suggests that patients treated with EIAEDs may tolerate a dose of 1,500 mg [30]. Similar drops in pharmacokinetic measures were seen with brain tumor patients taking EIAEDs and another EGFR TKI, erlotinib (OSI-774), which seems to also demonstrate activity in this patient population [31]. Drug levels may be of particular importance in the brain tumor population because patients who undergo surgical resection have substantial residual tumor protected by a blood-brain barrier. Another small-molecule TKI, imatinib (STI571), has been recently shown to have little brain penetration [32,33], suggesting that low-molecular weight inhibitors may not have free brain access. Another challenge in the brain tumor population is the frequent use of EIAEDs and corticosteroids as a potential source of drug interactions with gefitinib, a CYP3A4-metabolized agent. We have tried to address the potential for drug interactions through a two-step intrapatient dose escalation in the current trial. The low toxicity seen suggests that still greater doses may be tolerated by some patients on P450-inducing drugs. Our results suggest that targeting EGFR activity in glioblastoma by gefitinib may offer benefit. Gefitinib may offer improved therapeutic benefit with different approaches. First, future trials may be designed to escalate the dose of gefitinib until evidence of significant systemic activity is present either through real-time pharmacokinetics or surrogate markers of systemic anti-EGFR activity, as established by skin biopsy or the development of rash or diarrhea. Although systemic activity does not define activity in the tumor, it may represent a minimal level of activity. Ideally, the activity of gefitinib at the tumor site could be measured by the pretreatment activity of EGFR and downstream mediators with subsequent determination of drug delivery into the tumor as well as suppression of EGFR pathway components. Primary brain tumors pose a challenge in the acquisition of tumor tissue. Therefore, clinical trials incorporating short-term pretreatment with gefitinib before resection followed by chronic therapy may offer an important set of data to link doses, delivery, target suppression, and patient outcome. Finally, it is clear that a single targeted therapy is unlikely to control the complex biology of glioblastoma as monotherapy. Rather, the future use of gefitinib in combination with other complementary targeted therapies or cytotoxic therapies of radiation and chemotherapy may significantly improve clinical efficacy. We have seen preclinical evidence of synergistic therapeutic effects between an EGFR TKI and an inhibitor of mammalian target of rapamycin (J. Rich, manuscript in preparation) in the treatment of malignant glioma, suggesting that gefitinib and rapamycin analogs may offer a therapeutic advantage.
The authors indicated no potential conflicts of interest.
We thank the Duke Brain Tumor Center staff for the essential support they provided this study.
Supported by Federal funds from the National Cancer Institute, National Institutes of Health, Bethesda, MD (grant No. R21 CA91548), and foundation funds from Accelerate Brain Cancer Cure. Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31–June 3, 2003, Chicago, IL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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33. Wolff NC, Richardson JA, Egorin M, et al: The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia. Blood 101:5010–5013, 2003 Submitted August 14, 2003; accepted October 27, 2003. Related Correspondence
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ABSTRACT
INTRODUCTION
60%, and be on a nonincreasing dose of corticosteroids for at least 1 week. Normal laboratory measures of hepatic, renal, and bone marrow function were required as defined as a leukocyte count 
2.5x the upper limit of institutional normal. Patients were not allowed to receive any other investigational agents or have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to gefitinib. Exclusion criteria included uncontrolled severe intercurrent illness, and HIV-positive patients receiving combination antiretroviral therapy. 
