Gefitinib in Previously Treated Non-Small-Cell Lung Cancer
Gefitinib in Previously Treated Non-Small-Cell Lung Cancer
Background: We conducted an analysis of gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) to assess the antitumor efficacy of this epidermal growth factor receptor tyrosine kinase inhibitor.
Methods: Our single-center, prospective landmark analysis included 183 patients with advanced NSCLC who received 250 mg of gefitinib orally once daily in an expanded-use program at our institution. Thirty-three of the 183 patients were previously untreated. The patients included in this analysis had all received at least 12 weeks of gefitinib.
Results: The objective tumor response rate was 3.8%, but an additional 53.5% of patients experienced clinically meaningful disease stabilization. Median progression-free survival time was 3.6 months, and median overall survival time was 8.8 months. The 1-year survival rate for the entire cohort was 35%. Predictors of longer survival included female gender, adenocarcinoma or bronchoalveolar carcinoma histology, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea.
Conclusions: In this single-center experience, gefitinib demonstrated clinically significant antitumor activity and provided good palliation in a predominantly pretreated group of patients. Our results, which are likely to be reproducible in a community setting, demonstrated a 1-year survival rate of 35% in a cohort of patients who were able to take the drug for at least 12 weeks.
The epidermal growth factor receptor (EGFR) belongs to a subfamily of four closely related receptors: EGFR (ErbB-1), HER2/neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). The EGFR is a 170-kd plasma membrane glycoprotein composed of an extracellular ligand-binding domain, a transmembrane lipophilic segment, and an intracellular protein (tyrosine) kinase (TK) domain with a regulatory carboxyl terminal segment. The receptors exist as inactive monomers that homo-or hetero-dimerize (between EGFR and another member of the Erb receptor family) after ligand activation. The EGFR can also be activated by ligand-independent mechanisms. Activation of the EGFR TK has been identified as a key initiating event that generates a cascade of intracellular signaling events regulating cell proliferation, differentiation, survival, angiogenesis, and metastasis, all processes that are crucial to cancer progression.
EGFR is expressed, overexpressed, or dysregulated in many human solid tumors, including breast, ovarian, non-small-cell lung cancer (NSCLC), colorectal, and head and neck cancers. Its activation in these tumors seems to promote tumor growth by increasing cell proliferation, motility, adhesion, and invasive capacity and by blocking apoptosis. In support of its important role in tumor biology, EGFR overexpression and dysregulation have been reported to be associated with indices of poorer prognosis in patients and are associated with metastasis, late-stage disease, and resistance to chemotherapy, hormonal therapy, and radiotherapy.
Given the importance of EGFR in epithelial tumor biology, several EGFR-targeted cancer therapies are currently under development. Gefitinib (ZD1839) is an orally active, selective EGFR-tyrosine kinase inhibitor (TKI) that inhibits EGF-stimulated EGFR autophosphorylation in cell lines at submicromolar concentrations (50% inhibitory concentration range, 0.02 to 0.08 µmol/L). In preclinical studies, gefitinib demonstrated antitumor activity against EGFR, expressing NSCLC, ovarian, breast, and colon cancer cell lines and xenograft models.
Preclinical toxicology studies showed that gefitinib had a favorable toxicity profile over 6 months of oral dosing in animals, with mechanism-based, dose-dependent reversible effects on the skin, cornea, kidney, liver, and ovaries. This toxicity profile is predictable since EGFR signal transduction is involved in the normal physiology of these organs. Gefitinib pharmacokinetics in preclinical models demonstrated its good oral bioavailability and predicted its use as a daily oral treatment in humans. Two placebo-controlled studies investigated the pharmacokinetics and tolerability of single oral doses of gefitinib (1 to 75 mg) and multiple doses of gefitinib (100 mg once daily for 3 days). Gefitinib was well tolerated at doses up to 100 mg/day, with a low incidence of mild, transient adverse events. These studies also demonstrated that gefitinib is orally bioavailable in humans -- after a single oral dose of 250 mg, the mean absolute bioavailability of ZD1839 was 57% (90% confidence interval, 49% to 68%) -- and is absorbed moderately slowly, with the maximal plasma concentration (Cmax) attained between 3 and 7 hours after administration. The elimination half-life of 28 hours suggests that once-daily oral administration is appropriate. Binding of gefitinib to plasma proteins was approximately 90% and was independent of the gefitinib plasma concentration. Furthermore, absorption of gefitinib was not significantly affected by concomitant food intake.
In an open-label, phase I, dose-escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/day) administered once daily for 28-continuous-day cycles until disease progression or undue toxicity, rash and diarrhea were found to be the dose-limiting toxicities at an 800 mg/day dose level but were generally mild at 600 mg/day or less. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). Pharmacokinetic analysis showed that steady state occurred by day 7 and confirmed the suitability of once-daily oral dosing. Two other phase I studies confirmed these findings. Responses were seen across the dose range from 150 to 800 mg/day. However, the majority of dose interruptions and reductions due to toxicity occurred in patients receiving more than 600 mg/day. Hence for phase II and phase III studies, two doses levels were selected. The dose level of 250 mg was selected because it was higher than the lowest dose level at which objective responses were seen, while 500 mg/day was the highest dose level that was well tolerated over an extended period of time. A recently reported randomized phase II trial comparing the efficacy of the 250 mg/day dose level vs. the 500 mg/day dose level confirmed that the efficacy was similar for the two dose levels, with toxicities seen more frequently at the higher dose level.
We report here a prospective, landmark analysis of a single, tertiary cancer center experience of patients with advanced NSCLC treated with gefitinib on an expanded use program given orally daily at a dose of 250 mg. Since patients were enrolled on an expandeduse program, no patient was refused drug and a significant proportion of patients died before an adequate trial of the drug was possible. Hence, we chose to report a landmark analysis, thus restricting the evaluation to patients who had received the drug for at least 3 months. This selection process ensured that the patients had received an adequate trial of the drug.
Background: We conducted an analysis of gefitinib in patients with advanced non-small-cell lung cancer (NSCLC) to assess the antitumor efficacy of this epidermal growth factor receptor tyrosine kinase inhibitor.
Methods: Our single-center, prospective landmark analysis included 183 patients with advanced NSCLC who received 250 mg of gefitinib orally once daily in an expanded-use program at our institution. Thirty-three of the 183 patients were previously untreated. The patients included in this analysis had all received at least 12 weeks of gefitinib.
Results: The objective tumor response rate was 3.8%, but an additional 53.5% of patients experienced clinically meaningful disease stabilization. Median progression-free survival time was 3.6 months, and median overall survival time was 8.8 months. The 1-year survival rate for the entire cohort was 35%. Predictors of longer survival included female gender, adenocarcinoma or bronchoalveolar carcinoma histology, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea.
Conclusions: In this single-center experience, gefitinib demonstrated clinically significant antitumor activity and provided good palliation in a predominantly pretreated group of patients. Our results, which are likely to be reproducible in a community setting, demonstrated a 1-year survival rate of 35% in a cohort of patients who were able to take the drug for at least 12 weeks.
The epidermal growth factor receptor (EGFR) belongs to a subfamily of four closely related receptors: EGFR (ErbB-1), HER2/neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). The EGFR is a 170-kd plasma membrane glycoprotein composed of an extracellular ligand-binding domain, a transmembrane lipophilic segment, and an intracellular protein (tyrosine) kinase (TK) domain with a regulatory carboxyl terminal segment. The receptors exist as inactive monomers that homo-or hetero-dimerize (between EGFR and another member of the Erb receptor family) after ligand activation. The EGFR can also be activated by ligand-independent mechanisms. Activation of the EGFR TK has been identified as a key initiating event that generates a cascade of intracellular signaling events regulating cell proliferation, differentiation, survival, angiogenesis, and metastasis, all processes that are crucial to cancer progression.
EGFR is expressed, overexpressed, or dysregulated in many human solid tumors, including breast, ovarian, non-small-cell lung cancer (NSCLC), colorectal, and head and neck cancers. Its activation in these tumors seems to promote tumor growth by increasing cell proliferation, motility, adhesion, and invasive capacity and by blocking apoptosis. In support of its important role in tumor biology, EGFR overexpression and dysregulation have been reported to be associated with indices of poorer prognosis in patients and are associated with metastasis, late-stage disease, and resistance to chemotherapy, hormonal therapy, and radiotherapy.
Given the importance of EGFR in epithelial tumor biology, several EGFR-targeted cancer therapies are currently under development. Gefitinib (ZD1839) is an orally active, selective EGFR-tyrosine kinase inhibitor (TKI) that inhibits EGF-stimulated EGFR autophosphorylation in cell lines at submicromolar concentrations (50% inhibitory concentration range, 0.02 to 0.08 µmol/L). In preclinical studies, gefitinib demonstrated antitumor activity against EGFR, expressing NSCLC, ovarian, breast, and colon cancer cell lines and xenograft models.
Preclinical toxicology studies showed that gefitinib had a favorable toxicity profile over 6 months of oral dosing in animals, with mechanism-based, dose-dependent reversible effects on the skin, cornea, kidney, liver, and ovaries. This toxicity profile is predictable since EGFR signal transduction is involved in the normal physiology of these organs. Gefitinib pharmacokinetics in preclinical models demonstrated its good oral bioavailability and predicted its use as a daily oral treatment in humans. Two placebo-controlled studies investigated the pharmacokinetics and tolerability of single oral doses of gefitinib (1 to 75 mg) and multiple doses of gefitinib (100 mg once daily for 3 days). Gefitinib was well tolerated at doses up to 100 mg/day, with a low incidence of mild, transient adverse events. These studies also demonstrated that gefitinib is orally bioavailable in humans -- after a single oral dose of 250 mg, the mean absolute bioavailability of ZD1839 was 57% (90% confidence interval, 49% to 68%) -- and is absorbed moderately slowly, with the maximal plasma concentration (Cmax) attained between 3 and 7 hours after administration. The elimination half-life of 28 hours suggests that once-daily oral administration is appropriate. Binding of gefitinib to plasma proteins was approximately 90% and was independent of the gefitinib plasma concentration. Furthermore, absorption of gefitinib was not significantly affected by concomitant food intake.
In an open-label, phase I, dose-escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/day) administered once daily for 28-continuous-day cycles until disease progression or undue toxicity, rash and diarrhea were found to be the dose-limiting toxicities at an 800 mg/day dose level but were generally mild at 600 mg/day or less. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). Pharmacokinetic analysis showed that steady state occurred by day 7 and confirmed the suitability of once-daily oral dosing. Two other phase I studies confirmed these findings. Responses were seen across the dose range from 150 to 800 mg/day. However, the majority of dose interruptions and reductions due to toxicity occurred in patients receiving more than 600 mg/day. Hence for phase II and phase III studies, two doses levels were selected. The dose level of 250 mg was selected because it was higher than the lowest dose level at which objective responses were seen, while 500 mg/day was the highest dose level that was well tolerated over an extended period of time. A recently reported randomized phase II trial comparing the efficacy of the 250 mg/day dose level vs. the 500 mg/day dose level confirmed that the efficacy was similar for the two dose levels, with toxicities seen more frequently at the higher dose level.
We report here a prospective, landmark analysis of a single, tertiary cancer center experience of patients with advanced NSCLC treated with gefitinib on an expanded use program given orally daily at a dose of 250 mg. Since patients were enrolled on an expandeduse program, no patient was refused drug and a significant proportion of patients died before an adequate trial of the drug was possible. Hence, we chose to report a landmark analysis, thus restricting the evaluation to patients who had received the drug for at least 3 months. This selection process ensured that the patients had received an adequate trial of the drug.
Source...