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Mutations in the tyrosine kinase domain of the EGFR gene are only found in tumour cells and increase the dependency of these tumour cells to the intercellular signalling cascades that result in the promotion of tumour cell growth, blocking of apoptosis, increasing the production of angiogenic factors and facilitating the processes of metastasis.
In patients whose tumour contains an activating mutation of the EGFR-tyrosine kinase (TK), gefitinib binds to the EGFR TK domain with high specificity and affinity, resulting in potent inhibition of the over-active signalling pathways which can lead to tumour shrinkage.
Resistance: Most NSCLC tumors with sensitizing EGFR kinase mutations eventually develop resistance to IRESSA treatment with a median time to disease progression of 1 year. In about 60% of cases, resistance is associated with a secondary T790M mutation for which T790M targeted EGFR TKIs may be considered as a next line treatment option. Other potential mechanisms of resistance have been reported following treatment with EGFR signal blocking agents including bypass signaling such as HER2 and MET gene amplification and PIK3CA mutations. Phenotypic switch to small cell lung cancer has also been reported in 5 to 10% of cases.
Clinical Trials: A randomized, single dose, blinded, 2-way crossover comparative bioavailability study, conducted under fasting conditions, was performed on healthy male volunteers. The results obtained from 63 volunteers who completed the study are summarized in the following table. The rate and extent of absorption of gefitinib was measured and compared following a single oral dose (1 x 250 mg tablet) of Apo-Gefitinib (gefitinib) 250 mg tablet (Apotex Inc.) and IRESSA (gefitinib) 250 mg tablet (AstraZeneca Canada Inc.). (See Table 1.)
Click on icon to see table/diagram/imageFirst-line NSCLC Treatment: IPASS STUDY (D791AC00007): Study demographics and trial design: The efficacy and safety of gefitinib was demonstrated in a randomized, open-label, multicentre, Phase III trial versus carboplatin/paclitaxel doublet chemotherapy in the first-line setting (IPASS). This study was conducted in Asia in patients with locally advanced or metastatic (Stage IIIB or IV) NSCLC of adenocarcinoma histology who were ex-light smokers (ceased smoking ≥15 years ago and smoked ≤10 pack years) or never smokers. A total of 1217 patients from 87 centres in China, Hong Kong, Indonesia, Japan, Malaysia, Philippines, Singapore, Taiwan, and Thailand were studied. The primary efficacy endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective tumour response rate (ORR), safety, quality of life (QoL) and symptom improvement. Statistical adjustment for multiplicity was not performed for secondary and exploratory endpoints.
Demographic and baseline characteristics were well balanced between the two treatment groups (see Table 2).
Click on icon to see table/diagram/imageStudy results: In the primary analysis of PFS in the intent-to-treat (ITT) population (see Table 2), the hazard ratio was not constant over time, with the probability of being progression-free in favour of carboplatin/paclitaxel doublet chemotherapy in the first 6 months, and in favour of gefitinib in the following 16 months. This was likely to be because of the different effect of gefitinib in subgroups defined by EGFR mutation status. EGFR activating mutation status was a strong predictive biomarker for the effect of gefitinib compared to carboplatin/paclitaxel. Patients with activating mutations of the EGFR-TK are referred to as patients with EGFR mutation positive tumours as follows.
Pre-planned exploratory biomarker analyses of 437 patients (36%) with evaluable data for EGFR mutation analysis were conducted.
PFS was significantly longer for gefitinib than carboplatin/paclitaxel in patients with EGFR mutation positive tumours (n=261, HR 0.48, 95% CI 0.36 to 0.64, p<0.0001), and significantly longer for carboplatin/paclitaxel than gefitinib in patients with EGFR mutation negative tumours (n=176, HR 2.85, 95% CI 2.05 to 3.98, p<0.0001).
ORR in patients with EGFR mutation positive tumours treated with gefitinib was 71.2% vs. 47.3% for patients with EGFR mutation positive tumours treated with carboplatin/paclitaxel (OR 2.75, 95% CI 1.654 to 4.60, p=0.0001). ORR in patients with EGFR mutation negative tumours treated with gefitinib was 1.1% vs. 23.5% in patients with EGFR mutation negative tumours treated with carboplatin/paclitaxel (OR 0.04, 95% CI 0.01 to 0.27, p=0.0013).
In patients with EGFR mutation positive tumours, significantly more gefitinib-treated patients experienced an improvement in QoL and lung cancer symptoms vs. carboplatin/paclitaxel (FACT-L total score; 70.2% vs. 44.5%, p<0.0001) (TOI 70.2% vs. 38.3%, p<0.0001) (LCS 75.6% vs. 53.9%, p=0.0003). In patients with EGFR mutation negative tumours, significantly more carboplatin/paclitaxel-treated patients experienced an improvement in QoL and lung cancer symptoms vs. gefitinib (FACT-L total score; 36.3% vs. 14.6%, p=0.0021) (TOI 28.8% vs. 12.4%, p=0.0111) (LCS 47.5% vs. 20.2%, p=0.0002).
An analysis of overall survival (OS) was performed after 954 deaths (78% maturity) in the overall study population, as well as in subgroups by EGFR mutation status (e.g. patients with EGFR mutation positive tumours and EGFR mutation negative tumours). Results of these analyses are shown in Table 3 as well as Figures 1 and 2. (See Table 3 and Figures 1 and 2.)
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Click on icon to see table/diagram/imageWhen considering the OS data in the IPASS study, it is important to note that the majority of patients had received further systemic therapy following discontinuation of randomized first-line treatment, which is likely to confound assessment of the gefitinib treatment effect. Of the patients with EGFR mutation positive tumours randomized to gefitinib treatment, 68% received platinum-based chemotherapy at some point post-discontinuation of randomized gefitinib, and 64% randomized to carboplatin/paclitaxel received EGFR TKI at some point post discontinuation of carboplatin/paclitaxel.
In the IPASS study, a number of exploratory analyses of PFS, ORR and OS for subgroups were performed, including post-hoc analyses by EGFR mutation subtypes (exon 19 deletions and exon 21 L858R mutations) within the subgroup of patients with EGFR mutation positive tumours. The PFS, ORR and OS data for the comparison of gefitinib vs. carboplatin/paclitaxel were in patients with exon 19 deletions (N=140 patients), PFS HR=0.38 (95% CI 0.26 to 0.56), ORR=84.8% vs. 43.2% [OR 7.23 (95% CI 3.19 to 16.37)] and OS HR=0.79 (95% CI 0.54 to 1.15) (median OS 27.2 months vs. 20.6 months); and in patients with exon 21 L858R mutations (N=111 patients), PFS HR=0.55 (95% CI 0.35 to 0.87), ORR=60.9% vs. 53.2% [OR 1.41 (95% CI 0.65 to 3.05)] and OS HR=1.44 (95% CI 0.90 to 2.30) (median OS 18.7 months vs. 24.6 months). The study was not designed and powered to evaluate the differential PFS, ORR and OS by mutation subtypes, therefore the data should be interpreted in such context with caution.
Pre-treated NSCLC: INTEREST STUDY (D791GC00001): INTEREST was a Phase III, randomized, open-label, parallel-group, international, multicentre trial comparing gefitinib to docetaxel in 1466 patients with locally advanced or metastatic NSCLC who had previously received platinum-based chemotherapy and were eligible for further chemotherapy. Pre-planned exploratory subgroup analysis of 44 EGFR mutation positive patients provides supportive evidence for the approved indication. For patients with EGFR mutations, gefitinib was superior to docetaxel in terms of PFS (HR 0.16, 95% CI 0.05 to 0.49, p=0.0012) and ORR (42.1% vs 21.1%, p=0.00361).
NSCLC - Studies of Gefitinib in Combination with Chemotherapy: Controlled trials (INTACT I and II) with first-line treatment of NSCLC indicated no benefit from the addition of gefitinib to platinum-based combined chemotherapies.
Detailed Pharmacology: Pharmacodynamics: In vitro: ZD1839 was tested using a cloned potassium channel assay (hERG assay) to evaluate its effect upon the Ikr potassium current and was shown to be active in this hERG assay, with an IC50 of 1 mM. Dog Purkinje fibre studies were undertaken to investigate the potential for ZD1839 to affect the cardiac action potential. The results indicate a modest potential to affect re-polarisation at high plasma concentrations. There is some evidence for in vivo effects, in the conscious telemetered dog, however these were not clear even at the highest dose tested.
In vivo: ZD1839 has been administered orally at 5, 50 and 500 mg/kg to rats in studies designed to evaluate its effect on the major functional systems. These included the gastrointestinal (rat, GI transit), respiratory (rat, plethysmography), central nervous (rat, Functional Observation Battery and locomotor activity) and cardiovascular (dog, telemetry, only at 5 and 50 mg/kg) systems.
No effects were seen on intestinal transit. Minimal effects were noted at 50 and 500 mg/kg on the respiratory system (decreases in peak inspiratory and expiratory flows, tidal volume and minute volume); on the central nervous system (slight reduction in motor activity); and on the cardiovascular system (dog telemetry at doses of 50 mg/kg showed slight hypotension).
Because the doses studied are higher than the clinically recommended dose, the effects seen in these studies are not likely to be clinically relevant, but caution is advised.
Pharmacokinetics: In vivo: ZD1839 is well absorbed in rat, dog and man based on measured bioavailabilities of >40% in all species. There is evidence of first pass metabolism and prolonged absorption at high doses in animals.
ZD1839 related radioactivity was well distributed into rat tissues and showed an association with melanin containing tissues; however, levels in the CNS were low. Plasma protein binding ranged from 86 to 94% across the species and is not concentration dependent. ZD1839 binds to both human serum albumin and α-1 acid glycoprotein.
ZD1839 was extensively metabolised with three sites of biotransformation. Circulating metabolite patterns in dog and man were similar and all metabolites measured in human plasma were present in the rat. ZD1839 showed no enzyme induction potential in animals and no appreciable inhibition of human P450 isozymes. In vitro, ZD1839 was predominantly metabolised by CYP3A4.
In all species, ZD1839 related material was primarily excreted in the faeces with <6.5% recovered in urine. Biliary elimination was demonstrated in the rat and enterohepatic recirculation of ZD1839 may occur.
In rat and dog, ZD1839 showed rapid clearance and a high volume of distribution. In man, the volume of distribution was greater than in animals and the half-life consequently longer leading to accumulation. When dose normalised, exposure in humans was greater than in rat and dog, but at chronically tolerated doses the exposures were comparable.
The pharmacokinetic parameters for ZD1839 in animals and man are summarised as follows: See Table 4.
Click on icon to see table/diagram/imagePharmacokinetics: The pharmacokinetics of gefitinib have been evaluated in healthy volunteers and in cancer patients following both single and multiple dosing.
Absorption: Following single oral administration to volunteers or to cancer patients, absorption was moderately slow and the mean terminal half-life was 30.5 and 41.0 hours, respectively. In volunteers, gefitinib AUC showed up to a 20-fold range at the same dose level and increased proportionally with dose over the dose range 50 to 250 mg. Between 250 and 500 mg, there was a slightly greater than dose proportional increase in exposure but the maximum degree of non-proportionality observed was only 2-fold. In cancer patients, gefitinib AUC increased with dose over the dose range 50 to 700 mg and showed up to an 8-fold range of values within a dose level.
Daily administration of gefitinib to patients resulted in a 2- to 8-fold accumulation with steady state plasma concentrations achieved within 7 to 10 days. At steady state, plasma concentrations were typically maintained within a 2- to 3-fold range across the 24-hour dosing interval. Population pharmacokinetic data from Trial 0016 showed a mean steady state trough concentration following a 250 mg oral dose of 264 ng/mL (95% CI: 92.2 to 755 ng/mL) with inter- and intra-patient variability of 54 and 21%, respectively.
Mean oral bioavailability of gefitinib was approximately 60% in both healthy volunteers and cancer patients, indicating that it was well absorbed. Cmax was typically achieved within 3 to 7 hours after dosing in both groups. Relative bioavailability of gefitinib in volunteers was not altered by food to an extent likely to be of clinical significance. In a trial in healthy volunteers where gastric pH was maintained above pH 5 by co-administration of high doses of ranitidine with sodium bicarbonate, relative bioavailability was reduced by 47%.
Distribution: Mean volume of distribution at steady state of gefitinib is 1600 L in volunteers and 1400 L in cancer patients indicating extensive distribution into tissue. At clinically relevant concentrations of gefitinib, binding (in vitro) to human plasma proteins is approximately 90% with the binding proteins involved being serum albumin and α1-acid glycoprotein.
Metabolism: In vitro data indicate that CYP3A4 is the major P450 isozyme involved in the oxidative metabolism of gefitinib. Three sites of biotransformation have been identified in the metabolism of gefitinib: metabolism of the N-propylmorpholino-group, demethylation of the methoxy substituent on the quinazoline, and oxidative defluorination of the halogenated phenyl group. Five metabolites have been fully identified in faecal extracts and the major component was O-desmethyl gefitinib, although this only accounted for 14% of the dose.
In human plasma, 8 metabolites were fully identified. The major metabolite identified was O-desmethyl gefitinib, which was 14-fold less potent than gefitinib at inhibiting EGFR-stimulated cell growth and had no inhibitory effect on tumour cell growth in mice. It is therefore considered unlikely that it contributes to the clinical activity of gefitinib.
The production of O-desmethyl gefitinib has also been shown, in vitro, to be via CYP2D6. The role of CYP2D6 in the metabolic clearance of gefitinib has been evaluated in a clinical trial in healthy volunteers genotyped for CYP2D6 status. In poor metabolisers (devoid of CYP2D6) no measurable levels of O-desmethyl gefitinib were produced. The range of gefitinib exposures achieved in both the extensive and the poor metaboliser groups were wide and overlapping but the mean exposure to gefitinib was 2-fold higher in the poor metaboliser group. The higher average exposures that could be achieved by individuals with no active CYP2D6 may be clinically relevant since adverse experiences are related to dose and exposure.
Excretion: Gefitinib total plasma clearance is approximately 500 mL/min. Excretion is predominantly via the faeces with renal elimination of drug and metabolites accounting for less than 4% of the administered dose.
Special Populations and Conditions: Paediatrics: There are no pharmacokinetic data in paediatric patients.
Hepatic Impairment: In a phase I open-label study of single dose gefitinib 250 mg in patients with mild, moderate or severe hepatic impairment due to cirrhosis (according to Child-Pugh classification), there was an increase in exposure in all groups compared with healthy controls. An average 3.1-fold increase in exposure to gefitinib in patients with moderate and severe hepatic impairment was observed. None of the patients had cancer, all had cirrhosis and some had hepatitis. This increase in exposure may be of clinical relevance since adverse experiences are related to dose and exposure to gefitinib (see Hepatic Impairment under Precautions).
Gefitinib has been evaluated in a clinical trial conducted in 41 patients with solid tumours and normal hepatic function or, moderate or severe hepatic dysfunction due to liver metastases. It was shown that following daily dosing of gefitinib tablets 250 mg, time to steady state, total plasma clearance and steady state exposure (Cmaxss, AUC24ss) were similar for the groups with normal and moderately impaired hepatic function. Data from 4 patients with severe hepatic dysfunction due to liver metastases suggested that steady state exposures in these patients are also similar to those in patients with normal hepatic function.
Renal Insufficiency: No clinical studies were conducted with gefitinib in patients with severely compromised renal function. Gefitinib and its metabolites are not significantly excreted via the kidney (<4%). A limited number of patients with moderate renal insufficiency (calculated creatinine clearance of 30 to 50 mL/min) participated in the clinical trials. Based on the data from these studies, no safety concerns were raised regarding the use of gefitinib in patients with mild or moderate renal impairment in comparison to patients with normal renal function at baseline. Due to the small number of patients, there is insufficient data to evaluate the safety profile of gefitinib in patients with severe renal impairment.
Toxicology: A standard programme of non-clinical safety evaluation studies of up to 6 months in duration has formed the basis of the support for the clinical development of once daily oral therapy to patients.
The no-effect dose level, after administration of ZD1839 for up to 1 month, is 2 mg/kg/day and over a 6-month period is 1 mg/kg/day. In the 1-month studies, a dose of 40 mg/kg/day produced pathological changes in the ovaries of rats and in the eyes, kidneys and skin of both rats and dogs. Loose faeces were recorded in dogs, with no associated histopathological correlate. Similar changes were detected in the 6-month studies and, in addition in rats, minimal/mild hepatocellular necrosis was also detected, together with increased levels of circulating plasma liver enzymes. These effects showed signs of partial or full reversibility after drug withdrawal. There was evidence of reduced fertility in the female rat at 20 mg/kg/day, as well as slight maternal and fetotoxicity in the rabbit. These changes were all attributed to the pharmacological effects of ZD1839 on EGF-dependent tissues. Reversible abnormalities of atrio-ventricular conduction were also seen in the dog, at 40 mg/kg/day in the 1-month study and at 15 mg/kg/day in the 6-month study.
Preclinical work in guinea pigs indicates that gefitinib may be a potential skin (contact) sensitiser. Results of an in vitro phototoxicity study demonstrated that gefitinib may have phototoxicity potential.
Acute Toxicity: Following a single oral dose of ZD1839 at 2000 mg/kg to rats, there was a 5-day interval prior to the onset of abnormal signs. All animals showed adverse signs, leading to 4 premature deaths in females. The cause of death of 1 of these 4 decedents was a perforated duodenal ulcer. Other compound-related findings were present in tissues of these animals, including the kidneys, liver, skin and upper gastro-intestinal tract. No abnormalities were seen in mice given the same oral dose nor in rats and mice at the maximum achievable dose of 20 mg/kg by the intravenous route. Single oral doses of up to 1000 mg/kg to dogs produced no deaths, but caused adverse effects that had a rapid onset, but were reversible. These effects comprised emesis, diarrhoea, loss of skin tone, reduced blood pressure, reduced appetite, loss of body weight and increased plasma ALT, AST and ALP activities.
Multiple Dose Toxicity Studies: The no effect dose level after administration of ZD1839 to rats and dogs for up to 1 month was 2 mg/kg/day. A dose of 10 mg/kg/day showed only minor changes in red blood cell parameters, plasma protein, and albumin in the 1-month dog study and no adverse effects in the 1-month rat study. A dose of 40 mg/kg/day in the rat for a month produced reversible increases in plasma ALT and AST levels, but with no pathological correlate. There were histopathological changes in the ovaries of rats (reduced corpora lutea) and in the eyes (corneal epithelial atrophy), kidneys (papillary necrosis), and skin of both rats and dogs, all of which showed signs of partial or full reversibility, 4 weeks after drug withdrawal. Loose faeces were recorded in dogs, with no associated histopathological correlate. These changes were attributed to the pharmacological effects of ZD1839. Reversible prolonged PR intervals, with large variations between individual measurements were recorded for 2 out of 12 dogs at 40 mg/kg/day. In addition, one of these two dogs also showed second-degree heart block.
The findings in the 6-month studies were consistent with those detected in the 1-month studies and were similarly attributed to the pharmacological effects of ZD1839. These studies commenced with a high dose of 25 mg/kg/day, however this was not tolerated and the dose level was reduced to 15 mg/kg/day from day 11 in dogs and from week 9 in rats. The no adverse effect dose level, after administration of ZD1839 to rats and dogs for up to 6 months was 1 mg/kg/day. At 5 mg/kg/day, rats and dogs showed skin lesions and the rats had reversible corneal atrophy of the eyes. These eye effects were more evident in both species at 15 mg/kg/day, but still showed signs of recovery. However, at this dose level in dogs, some areas of opacity developed that did not fully recover during the 12-week withdrawal period. Evidence of an effect on liver function was detected in the rat at 5 mg/kg/day; this was more pronounced in both species at 15 mg/kg/day. In addition, in the rat at this dose, there was hepatocellular necrosis, associated with the increases in plasma liver enzyme levels. A single female dog showed evidence of a reversible effect on P-R interval, similar to that seen in the 1-month study, at the 15 mg/kg/day dose level.
Carcinogenicity & Mutagenicity: ZD1839 has been tested for genotoxic activity (mutagenicity) in a series of in vitro (bacterial mutation, mouse lymphoma, and human lymphocyte) assays and an in vivo rat micronucleus test. Under the experimental conditions adopted, there was no evidence demonstrated of genotoxic activity for ZD1839.
A 2-year oral (gavage) carcinogenicity study in rats resulted in a small but statistically significant increased incidence of hepatocellular adenomas in both male and female rats and mesenteric lymph node haemangiosarcomas in female rats at the high dose (10 mg/kg/day) only. The clinical relevance of these findings is unknown. The hepatocellular adenomas were also seen in a 2-year oral (gavage) carcinogenicity study in mice, which demonstrated a small increased incidence of this finding in male mice dosed at 50 mg/kg/day, and in both male and female mice at the highest dose of 90 mg/kg/day (reduced from 125 mg/kg/day from week 22). The effects reached statistical significance for the female mice, but not for the males. The clinical relevance of these findings is unknown.
Reproduction & Teratology: There was, as expected from the pharmacological activity of ZD1839, a reduction in female fertility in the rat at a dose of 20 mg/kg/day. Gefitinib has been found to cross the placenta following oral administration at 5 mg/kg in rats. When administered during organogenesis, there were no effects on rat embryofetal development at the highest dose (30 mg/kg/day); however in the rabbit, there were reduced fetal weights at 20 mg/kg/day and above. There were no compound induced malformations in either species. When pregnant rats that were treated with 5 mg/kg/day from the beginning of organogenesis to the end of weaning gave birth, there was a reduction in the number of offspring born alive. In pregnant rats treated with 20 mg/kg/day, the effects were more severe and included high neonatal mortality. The no observed adverse effect dose level in this study was 1 mg/kg/day. There was evidence that ZD1839 was present in the milk of lactating rats. Following oral administration of carbon-14 labelled gefitinib to rats 14 days postpartum, concentrations of radioactivity in milk were higher than in blood. Levels of gefitinib and its metabolites were 11- to 19-fold higher in milk than in blood, after oral exposure of lactating rats to a dose of 5 mg/kg. These data suggest that there is the potential for adverse effects if ZD1839 was administered to patients who are pregnant or are breast-feeding.
