Phase II Trial of Gefitinib in Recurrent Glioblastoma
Open accessAbstract
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.
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The EGFR inhibitors gefitinib and erlotinib have failed to demonstrate efficacy in GBM, largely as a consequence of persistent PI3K signaling due to PTEN loss and/or coactivation of other receptor tyrosine kinases.
“Despite the compelling nature of EGFR as a drug target in GBM, the EGFR inhibitors gefitinib and erlotinib have failed to demonstrate efficacy (9–11), in large part as a consequence of persistent PI3K signaling due to PTEN loss and/or coactivation of other receptor tyrosine kinases (9, 10, 12).”
From An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway (2011) · cites this paper as [11]
In “Measurement of Therapeutic Effect, Time to Progression, and Survival” (page unavailable), the gefitinib trial reports no complete or partial responses and frequent progression, supporting limited demonstrated efficacy in recurrent GBM. But “Factors Related to Response, Progression, and Survival” (page unavailable) says erlotinib seemed to show activity; it does not establish persistent PI3K signaling, PTEN loss, or coactivation of other receptor tyrosine kinases as the reason for limited efficacy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe average historical PFS6 based on the above studies is 15.3 ± 3.8%.
“The average historical PFS6 based on the above studies is 15.3 ± 3.8%”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [28]
The average historical TTP is 9.5 ± 1.6 weeks.
“and the average historical TTP is 9.5 ± 1.6 weeks.”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [28]
Efficacy analysis was performed for 10 recurrent GBM patients by comparing TTP, PFS6, and OS in recurrent GBM patients treated with the NovoTTF-100A device with the TTP, PFS6, and OS of recurrent GBM patients in a literature based historical control group.
“Efficacy analysis was performed for 10 recurrent GBM patients by comparing TTP, PFS6, and OS in recurrent GBM patients treated with the NovoTTF-100A device with the TTP, PFS6, and OS of recurrent GBM patients in a literature based historical control group (10, 25–28).”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [28]
The average historical OS is 29.3 ± 6 weeks.
“OS averaged 29.3 ± 6 weeks (see SI Table 2).”
From Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors (2007) · cites this paper as [28]
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- Authors
- Rich, J. N., Reardon, D. A., Peery, T., Dowell, J. M., Quinn, J. A., Penne, K. L., Wikstrand, C. J., Van Duyn, L. B., Dancey, J. E., McLendon, R. E., Kao, J. C., Stenzel, T. T., Ahmed Rasheed, B. K., Tourt-Uhlig, S. E., Herndon, J. E., Vredenburgh, J. J., Sampson, J. H., Friedman, A. H., Bigner, D. D., & Friedman, H. S.
- Affiliations
- Duke University (US)
- From the Departments of Medicine, Surgery, Pathology, and Cancer Center Biostatistics, Duke University Medical Center, Durham, NC; and the National Cancer Institute, Bethesda, MD
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2004-01-01
- Volume
- 22
- Issue
- 1
- Pages
- 133-142
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2117941094
- Cited by
- 734
- References
- 32
- Citations by year
- 2026: 9 · 2025: 5 · 2024: 12 · 2023: 25 · 2022: 14 · 2021: 11 · 2020: 18 · 2019: 18 · 2018: 14 · 2017: 20 · 2016: 29 · 2015: 26 · 2014: 34 · 2013: 32 · 2012: 48
- FWCI
- 24.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Accelerate Brain Cancer Cure
- National Institutes of Health (1r21ca091548-01)
- National Cancer Institute (R21 CA 91548)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
- Keywords
- gefitinib, recurrent glioblastoma, epidermal growth factor receptor tyrosine kinase inhibitors, event-free survival, overall survival, drug toxicity, diarrhea, EGF receptor expression, dose escalation, enzyme-inducing antiepileptic drugs, dexamethasone
- MeSH terms
- Gefitinib, Adult, Aged, Brain Neoplasms, Dose-Response Relationship, Drug, Enzyme Inhibitors, Epidermal Growth Factor, Female, Glioblastoma, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Protein-Tyrosine Kinases, Quinazolines, Treatment Outcome, Disease-Free Survival
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