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The FDA approved gefitinib based on results from the Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL-2), a phase II trial that included 216 patients, of whom 142 had not responded to both platinum-based and docetaxel chemotherapies. Approximately 10% of patients in this trial achieved a response rate defined as a decrease in tumor size by 50% after treatment with gefitinib.The results of published phase I/III clinical trials with gefitinib are summarized in Table 2.

Phase I Trials

Escalating oral doses of gefitinib were given to patients with NSCLC or other solid tumors for 14 days, followed by 14 days of observation or by 28 days of continuous observation. Patients were enrolled only if their solid malignant tumors were known to express or overexpress EGFR.

Table 2   Summary of Gefitinib Results in Clinical Trials

Study Endpoint No. Dose Conclusion
Phase I
Baselga et al.13 Safety


150-1,000 mg/day Gefitinib was well tolerated, and side effects were
Tolerability dose escalation reversible when the medication was discontinued.
Pharmacokinetics Disease progression was stabilized across a range of
Pharmacodynamics tumor types and doses. Inhibition of EGRF signaling
was indicated by pharmacodynamic changes in skin.
Ranson et al.10 Tolerability


50-925 mg/day Gefitinib was well tolerated. Dose-limiting toxicity
Pharmacokinetics dose escalation occurred at doses above that at which antitumor
Antitumor activity activity was seen. Once-daily dosing of gefitinib
tablets was confirmed by pharmacokinetic analysis.
Uejima et al.3,14 Tolerability


50-700 mg/day Gefitinib was generally well tolerated at all doses
Pharmacokinetics intermittent dosing with no dose-limiting toxicities occurring up to 525
Efficacy of intermittent mg/day. A confirmed partial response was demon-
daily oral dosing strated in 22% of patients.
Phase II
IDEAL-11517 Tumor response rate


250 or 500 mg/day There was no difference in response rate, disease
Safety control rate, progression-free survival, overall safety,
Disease control rate or safety between groups. The 250-mg dose of gefi-
Progression-free survival tinib is as efficacious as the 500-mg dose with a more
Overall survival favorable side-effect profile. Gefitinib 250 mg showed
clinically significant antitumor activity in patients who
had previously received platinum-based therapy.
IDEAL-216,18 Tumor response rate


250 or 500 mg/day Tumor response rate, symptom response, and safety
Disease-related were similar among the two treatment groups. Clini-
symptom response cally significant antitumor activity was demonstrated
Safety in both groups.
Phase III
INTACT-119 Overall survival


CT* + placebo Between the three groups, there were no statisti-
Progression-free survival or cally significant differences in overall survival, pro-
Time to worsening CT + gefitinib gression-free survival, or time to worsening of symp-
of symptoms 250 mg/day toms. Side effects were similar among all three
Symptom improvement or treatment groups. CT plus gefitinib did not improve
Objective tumor CT + gefitinib treatment outcomes.
response 500 mg/day
Disease control rate
Quality of life
INTACT-220 Overall survival


CT + placebo There were no statistically significant differences in
Progression-free survival or overall survival, progression-free survival, or time to
Time to worsening CT + gefitinib worsening of symptoms between the three treat-
of symptoms 250 mg/day ment groups. CT plus gefitinib failed to improve sur-
Symptom improvement or vival in this trial. Adverse events were similar in all
Objective response rate CT + gefitinib treatment groups.
Disease control rate 500 mg/day
Quality of life
Adverse-event profiling

The Baselga Study

Baselga et al. examined the safety, tol-erability, and pharmacokinetic and phar-macodynamic effects of gefitinib in patients with solid tumors. Gefitinib was to be administered once a day as a single oral dose for at least 28 consecutive days at 150, 225, 300, 400, 600, 800, and 1,000 mg/day. If one patient experienced a dose-limiting toxicity (DLT) before completing a 28-day cycle at a specific dose, six or more patients had to finish one 28-day cycle at the same dose before other patients were allowed to begin the next dose level. The DLT was defined as:
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  • a drug-related toxicity of National Cancer Institute Common Toxicity Criteria (NCI-CTC), grade 3 or higher
  • hematuria, proteinuria, or serum creatinine of NCI-CTC, grade 2 or higher
  • significant ocular toxicity (corneal punctate staining with symptoms, conjunctival hyperemia in more than one quadrant, or more severe objectively measured ocular events)
  • cardiac toxicity, such as heart conduction defects or prolongation of the PR interval (the time in seconds from the beginning of the P-wave to the beginning of the QRS complex) longer than 217 milliseconds or longer than 32 milliseconds over baseline

Clinical and laboratory assessments were performed at the baseline evaluation and at two-week intervals. The investigators analyzed the pharmaco-kinetic parameters by taking venous blood (4 ml) before administering the dose on days one, eight, 15, 22, and 29; at 28-day intervals subsequently; at withdrawal from the trial; and two weeks after withdrawal from the trial. Skin biopsy specimens were collected for pharmaco-dynamic assessment before the first dose and after about 28 days of gefitinib therapy. Tumors were measured according to the revised World Health Organization criteria within two weeks before the start of therapy, at approximately 29 days, at 28 days thereafter, and at withdrawal.

Eighty-eight patients received dose-escalating (150 to 1,000 mg/day), continuous regimens of gefitinib. At 1,000 mg/day, five of the 12 patients experienced a DLT; four patients experienced grade 3 diarrhea, and one had grade 3 somnolence. Grade 1 or 2 acne-like rash (64%) and diarrhea (47%) occurred frequently and were reversible once treatment ceased. Most patients had achieved steady-state concentrations by day seven. Inhibition of the EGFR signaling pathway was evident in the 28-day skin biopsy evaluation.

Of the 88 patients receiving gefitinib, 22 patients had NSCLC. In the NSCLC group, three patients had stable disease and received gefitinib for six months or more. Of the three patients, one was taking 150 mg/day and had had earlier radiotherapy and chemotherapy with carboplatin (Paraplatin®, Bristol-Myers Squibb) and fluorouracil and with doce­taxel and gemcitabine (Gemzar®, Eli Lilly); one was taking 225 mg/day and had received radiotherapy and carbo-platin; and the other was taking 300 mg/day and had previously undergone surgery and chemotherapy with gem-citabine and paclitaxcel (e.g., Taxol®, Bristol-Myers Squibb). viagra soft

The authors concluded that gefitinib was generally well tolerated. Most adverse drug events (ADEs) were controllable and reversible at doses up to 600 mg/day. Most DLTs occurred in patients receiving 800 to 1,000 mg/day. Stabilization of tumors was clinically meaningful, with multiple tumor types at various treatment doses.

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