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Keywords:

  • epidermal growth factor receptor tyrosine kinase inhibitor;
  • gefitinib;
  • Iressa;
  • metabolism;
  • non-small-cell lung cancer;
  • pharmacokinetics

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Traditional cytotoxic anticancer therapies do not differentiate between tumour and host cells, and research efforts have been focused on finding new agents that target tumour tissue. Gefitinib (‘Iressa’, ZD1839) is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal pathways implicated in solid tumour growth and metastasis. In phase II trials, gefitinib 250 mg/day demonstrated efficacy in the control of advanced non-small-cell lung cancer (NSCLC) in patients who had undergone prior chemotherapy. Response rates were 18·4 and 11·8%, and disease control rates were 54·4 and 42·2%, at 250 mg/day in two multicentre trials – IDEAL 1 and 2. Gefitinib also caused rapid relief from the symptoms of NSCLC in approximately 40% of patients, while displaying a generally good tolerability profile that most commonly included mild, reversible gastrointestinal and skin adverse events. Gefitinib 250 mg/day has been approved for use in advanced, previously treated NSCLC in several countries including the USA, Japan and Australia. As a monotherapy and combination therapy, it is being investigated for the treatment of several common tumour types in addition to NSCLC. The pharmacokinetics of gefitinib have shown it to be suitable for once daily dosing, with a terminal half-life of approximately 48 h in patients with cancer. Steady-state exposure is achieved after 10 days dosing, and exposure is dose proportional up to 250 mg/day. Gefitinib is cleared principally by the biliary route and in part by metabolism. This review summarizes relevant data from studies of gefitinib that inform its clinical administration.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Current chemotherapy regimens are hampered by limited efficacy, high relapse rates, significant toxicity and the development of resistance, highlighting a need for new schedules and alternative therapeutic approaches. Novel, targeted therapies that combine antitumour activity with better tolerability are beginning to enter clinical practice, and in certain clinical settings are being deployed in place of chemotherapy. The epidermal growth factor receptor (EGFR) is an attractive target for cancer therapy, as EGFR signalling is a pathway that plays an important role in the growth, proliferation and survival of many solid tumours (1).

Gefitinib (‘Iressa’, ZD1839), a small-molecule EGFR tyrosine kinase inhibitor (EGFR-TKI), has been shown to inhibit a range of EGFR-mediated effects that promote tumour growth in preclinical models (2). Clinical development of gefitinib is ongoing in a range of solid tumour types and is farthest advanced in non-small-cell lung cancer (NSCLC). Oral gefitinib recently gained approval in several countries including Australia, Japan and the USA for the treatment of patients with NSCLC who have failed prior chemotherapy, or who are unsuitable for chemotherapy. Gefitinib's mode of action, efficacy and tolerability differ markedly from conventional chemotherapy, and this review discusses features of gefitinib treatment that are likely to affect the approach taken by clinicians, pharmacists and pharmacologists to patients in their care.

Mode of action of gefitinib

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

The EGFR belongs to the erbB family of four closely related cell membrane receptors: EGFR (HER1 or erbB1), erbB2 (HER2), erbB3 (HER3) and erbB4 (HER4) (2). These receptors comprise an extracellular ligand-binding domain, a transmembrane domain and an intracellular domain with tyrosine kinase activity mediating signal transduction. EGFR (HER 1, erbB1) activation occurs in response to ligand binding via dimerization of the receptor.

Activation of the EGFR signalling pathway in cancer cells has been linked to increased cell proliferation, angiogenesis, metastasis and decreased apoptosis (1). In addition, aberrant EGFR signalling in tumours has been associated with poor prognosis and drug resistance (2). Gefitinib, a small molecule capable of entering the cell, competes with adenosine triphosphate at the kinase ATP binding sites of EGFR, preventing its tyrosine kinase activity, thus blocking EGFR signal transduction.

Data from in vitro studies have shown that, in addition to reducing proliferation in transformed cells, gefitinib induces cell cycle arrest, increases apoptosis and has antiangiogenic activity (3, 4). In addition, in preclinical models, gefitinib has been shown to have antimetastatic properties in the following human tumour types: head and neck, prostate, breast, ovarian, colon, small-cell lung and NSCL (3, 5–7). Although these tumour types often express EGFR, sometimes at high levels, the level of expression of EGFR in tumour xenografts does not correlate closely with the efficacy of gefitinib, indicating that the level of expression of EGFR alone is not the predominant factor to influence gefitinib sensitivity. Factors such as the level of activated or phosphorylated EGFR and the level of ligand expression may also be important (1, 8).

Administration, pharmacokinetics and metabolism of gefitinib

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Pharmacokinetic studies following oral administration have been conducted in healthy volunteers (9, 10) in phase I studies (11–14) and in patients with hepatic impairment (15).

Results of a study that investigated the pharmacokinetics and tolerability of ascending single oral doses of gefitinib (1–75 mg) in healthy male volunteers (aged 18–62 years) have been reported (9). It was found that peak plasma drug concentrations (Cmax) of gefitinib occurred 3–7 h after administration and Cmax and area under the concentration–time curve (AUC) were increased with increasing dose. The terminal elimination half-life (t1/2β) was about 30 h (range 12–51 h). In another study, the dose proportionality of gefitinib pharmacokinetics was evaluated in 15 patients in whom single oral doses of 50, 100, 250 or 500 mg /day gefitinib were administered (9). Mean AUC and Cmax values for doses ≥250 mg/day increased in a dose-proportional manner, although this was not seen for 500 mg/day.

The absolute bioavailability of 250 mg gefitinib in healthy male volunteers has been found to be approximately 60% (range 49–68%), with a similar value determined in patients (AstraZeneca, data on file).

The pharmacokinetics of once-daily gefitinib were also evaluated in four phase I studies in patients with advanced solid tumours (11–14) summarized in Table 1. Following a single oral 50 mg gefitinib dose, the exposures achieved in cancer patients were between two and four times more than the exposures achieved in healthy volunteers dosed at 50 mg (14). The t1/2β data obtained from cancer patients over the dose range 50–700 mg/day had a mean of about 48 h (range 24–48 h) in Western patients (14) and a mean of about 50 h (range 29–80 h) in Japanese patients (13). Following administration of doses greater than 50 mg/day, exposure to gefitinib was seen to be dose proportional (Table 1; Figs 1 and 2). Steady-state exposure to gefitinib was usually achieved by days 7–10. Estimates of interpatient variability in exposure to gefitinib ranged from about 6 to 10-fold (Figs 1 and 2) (11–14).

Table 1.  Derived pharmacokinetic parameters following multiple dosing of gefitinib in phase I trials
Phase I trialEvaluable patientsDose range evaluated (mg/day)Mean t1/2, h (range) Geometric mean maximum plasma concentration (ng/mL)Geometric mean steady state trough plasma concentration (ng/mL)AUC0−24 (ng h/mL)
Lowest doseHighest doseLowest doseHighest dose
  1. SD, standard deviation.

  2. *14 days followed by 14 days without drug, in a 28-day treatment regimen.

5 (14)5650–700*48 (24–85)10621461670–36 077
11 (12)58150–600172 774
12 (11)69150–10001221099
V15–11 (13)3050–700*50·1 (27·8–79·7) 6011561021–21 580
image

Figure 1. Exposure to gefitinib (AUC0−24) increases with dose (mg/day): results of a phase I dose escalation trial (14).

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image

Figure 2. Mean predose plasma concentrations of gefitinib at doses during the multiple dosing phase in a phase I dose escalation trial (14).

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Evidence of antitumour activity in advanced NSCLC was seen in phase I trials across a wide dose range. Oral doses of 250 and 500 mg/day were chosen for phase II clinical trials of gefitinib monotherapy in patients with NSCLC who had received prior chemotherapy (16, 17). The two multicentre randomized trials demonstrated that there was no difference in efficacy between the two doses. However, adverse events were observed to be less frequent and less severe at 250 mg/day, and therefore this was chosen as the recommended dose in advanced NSCLC.

Pharmacokinetic interactions between gefitinib and other agents

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Swaisland et al. (10) reported that, in vitro, gefitinib is metabolized by the cytochrome P450 isoenzyme CYP3A4 and that it may inhibit activity of CYP2D6. The pharmacokinetic interaction between gefitinib and inducers and inhibitors of CYP3A4 was assessed in two studies conducted in healthy volunteers, and the potential for steady-state levels of gefitinib to inhibit CYP2D6 was assessed in patients with cancer. During coadministration of the CYP3A4 inducer, rifampicin and gefitinib, geometric mean (gmean) AUC for gefitinib was reduced by approximately 85% (Fig. 3a), and the geometric mean Cmax by approximately 65%. In the second study, in which the CYP3A4 inhibitor itraconazole and gefitinib were coadministered, gmean AUC for gefitinib 250 mg was increased by 78% (Fig. 3b). In both these studies, systemic levels of rifampicin and itraconozole were consistent with therapeutic levels for these drugs. Coadministration of gefitinib and the CYP2D6 substrate metoprolol (at steady-state for gefitinib) resulted in a small increase of approximately 30% in the gmean metoprolol AUC(0−8) (Fig. 3c).

image

Figure 3. Geometric mean (SD) plasma concentrations of (a) gefitinib in the presence and absence of rifampicin; (b)gefitinib in the presence and absence of itraconazole; (c) metoprolol in the presence and absence of gefitinib (10).

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In summary, administration of these drugs in combination caused alterations in exposure, but the magnitude of these effects, in the context of the safety and pharmacokinetic data from patients in phase I studies, was judged unlikely to significantly alter the safety profile of the 250 mg daily dose of gefitinib, and showed that gefitinib is unlikely to have clinically significant effects if coadministered with other drugs that are substrates for CYP2D6 (10). However, caution should be exercised when administering gefitinib with potent inhibitors of CYP3A4, and clinical response and adverse events should be carefully monitored.

Hepatic impairment and metabolism

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Following a single dose of 50 mg 14C-labelled gefitinib given orally to six volunteers, approximately 60% of the radioactivity was recovered in faeces within 48 h, followed by a further 30% in the subsequent 8 days. High-performance liquid chromatography analysis of faecal extracts showed that about half the faecal radioactivity appeared as metabolites with only about 10% as unchanged gefitinib (18). Thus gefitinib is cleared in part by hepatic metabolism, mainly by the biliary route.

The effects of hepatic impairment in patients with a range of tumours have been investigated. Twelves et al. (15) evaluated the pharmacokinetics and tolerability of once-daily oral gefitinib in patients with a variety of malignancies who had developed hepatic impairment because of liver metastases. Hepatic impairment was scored by summing the baseline National Cancer Institute Common Toxicity Criteria grade (0–4) for aspartate aminotransferase, alkaline phosphatase and total bilirubin, to give a score from 0 to 12 (0–2 normal; 3–5 moderate impairment; 6–12 severe impairment). Gefitinib was administered for 28 days. Thirteen patients with moderate hepatic impairment were compared with a control group of 14 patients, and the two groups showed no significant difference in exposure as measured (a) by gmean steady-state AUC24 (moderate impairment 9553 ng h/mL; normal liver function 8896 ng h/mL) (Fig. 4), or (b) by gmean maximum plasma concentration at steady-state (Cmaxss) (moderate impairment 517 ng/mL; normal liver function 466 ng/mL). There were no apparent increases in the frequency or severity of adverse events in the patients with moderate hepatic impairment, some of whom took gefitinib for more than 5 months. However, current experience is limited, and studies have not been carried out in patients with severely compromised renal function.

image

Figure 4. Day-28 AUC24ss of gefitinib in hepatically impaired patients and patients with normal liver function, taking gefitinib 250 mg/day (15).

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An alternative second- and third-line treatment option: gefitinib for NSCLC

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

NSCLC is a common condition, and the large majority of patients are diagnosed with advanced, incurable and unresectable tumours. Despite improvements in the management of NSCLC, efficacy outcomes have improved only slightly with current conventional chemotherapy regimens. Currently, patients with advanced stage disease and relatively good performance status are offered first-line platinum-based chemotherapy, which produces major tumour responses in approximately 40% of such patients. However, it has become clear that the efficacy of cytotoxic treatment of NSCLC is reaching a plateau. Recent randomized trials have reported very similar response rates and survival outcomes between treatment arms. For example, similar response rates and survival were seen in a large randomized trial comparing cisplatin and paclitaxel; cisplatin and gemcitabine; cisplatin and docetaxel; and carboplatin and paclitaxel. In this large trial the median survival of patients with advanced stage NSCLC was 7·9 months (95% CI 7·3, 8·5) (19).

The prospect for response and clinical benefit from treatment following first-line chemotherapy is low. Further major response to cytotoxic drug treatment is rare with response rates decreasing with each successive treatment regimen (20). Indeed, most agents tested in second- and third-line settings have been deemed inactive. The most active cytotoxic agent so far tested in relapsed patients in multicentre randomized trials is docetaxel, which has produced response rates ranging from 6·7 to 10·8% (21, 22).

Antitumour activity  Data on the efficacy of gefitinib in patients with advanced, previously treated NSCLC are available from over 400 patients enrolled in two large multicentre, randomized, phase II trials (IDEAL 1 and 2) of gefitinib monotherapy (17, 23, 24). In both trials, patients were randomized to either 250 or 500 mg/day gefitinib. In IDEAL 1, patients had received one or two prior chemotherapy regimens, while those in IDEAL 2 had received two or more prior regimens and were required to be symptomatic from lung cancer at baseline. The majority of patients in IDEAL 2 were receiving gefitinib as at least fourth-line therapy, whereas most of the patients in IDEAL 1 were receiving gefitinib as second-line therapy.

In IDEAL 1, the objective tumour response rate at 250 mg/day was 18·4%. In IDEAL 2, with the more heavily pretreated patient population, the objective response rate was 11·8% for the 250 mg/day dose. Objective responses were seen irrespective of the number of prior chemotherapy regimens. The results showed that 250 mg/day gefitinib was as effective as 500 mg/day, and the superior tolerability of 250 mg/day makes this the recommended dose. Efficacy results for the 250 mg/day dose in both trials are shown in Table 2.

Table 2.  Tumour response, disease control and symptom improvement rates for gefitinib 250 mg/day in IDEAL 1 and 2
 IDEAL 1IDEAL 2
  1. CR, complete response; PR, partial response; SD, stable disease confirmed and sustained for at least 4 weeks.

  2. *Time of first post-baseline assessment.

Response rate (%) (CR + PR)18·411·8
Disease control rate (%) (CR + PR + SD)54·442·2
Median overall survival (months) 7·6 6·5
Overall symptom improvement rate (%)40·343·1
Time to symptom improvement (days)8–10*8–10*

Symptom improvement  Patients with late-stage NSCLC are often symptomatic, with specific pulmonary problems (e.g. cough, breathlessness, haemoptysis) and general symptoms (e.g. fatigue, weight loss) that impact on quality of life (QoL). The validated Functional Assessment of Cancer Therapy – Lung (FACT-L) questionnaire was used to assess QoL, and the disease-specific seven-item Lung Cancer Subscale (LCS) of FACT-L was used to evaluate tumour-related symptoms. The LCS, which measures lung cancer symptom severity on a scale of 0 (most symptomatic) to 28 (least symptomatic), has been validated as a tool that reflects the clinical severity of NSCLC, and can be used to evaluate clinically meaningful symptom change during treatment (25).

Overall symptom improvement rates were comparable in the two trials (40·3 and 43·1% in IDEAL 1 and 2, respectively) (26, 27). Symptom improvement occurred rapidly, within a median 8–10 days (the time of first assessment), and improvements in symptoms correlated with objective tumour response and overall survival (Fig. 5). In IDEAL 2, in which all recruited patients were symptomatic, 100% of patients with complete or partial response and 81% of patients with stable disease had improvements in lung cancer symptoms (26–28).

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Figure 5. Kaplan–Meier plots showing overall survival by symptom improvement in patients taking gefitinib 250 mg/day in phase II monotherapy trials (IDEAL 1 and 2) (39).

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Tolerability  In phase II trials of gefitinib monotherapy, adverse events with 250 mg/day were generally mild and reversible grade 1/2 diarrhoea and skin reactions (rash, pruritus, dry skin and acne; National Cancer Institute Common Toxicity Criteria, CTC; version 2.0), with a low incidence of dose reductions or withdrawals because of drug-related adverse events (17, 23, 24). Photographs of typical acne-like rash in patients receiving gefitinib are shown in Fig. 6.

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Figure 6. Adverse effects associated with gefitinib treatment: (a) grade 1 acne-like rash in the breast area of a 52-year-old patient treated with gefitinib 225 mg/day; (b) grade 2 acne-like rash on the face of a man treated with 1000 mg/day for 8 months (12).

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Overall grade 3/4 drug-related adverse events occurred in only 8·7% of patients in IDEAL 1 and 6·9% of patients in IDEAL 2. Gefitinib was not associated with haematological toxicity or stomatitis. The results from both these trials demonstrate that gefitinib is generally well tolerated in patients with advanced NSCLC who have relapsed following prior chemotherapy.

Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Given the promising activity of gefitinib monotherapy in phase I and II trials in advanced NSCLC, two trials were performed to evaluate whether gefitinib given concurrently with combination chemotherapy (paclitaxel/carboplatin or cisplatin/gemcitabine) gave improved efficacy as first-line treatment for patients with advanced NSCLC. Two phase III trials, INTACT 1 and 2, randomized patients to chemotherapy plus placebo, chemotherapy plus gefitinib 250 mg/day or to chemotherapy plus gefitinib 500 mg/day. The results of these large international trials showed that the addition of gefitinib to standard chemotherapy did not improve patient survival over that achievable with chemotherapy alone (29, 30).

Gefitinib for the treatment of other solid tumours

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

EGFR expression is often present in a range of tumour types, including breast, colorectal, head and neck and ovarian cancers (1). Phase I monotherapy studies demonstrated that gefitinib has some activity in patients with advanced head and neck, colorectal, prostate and breast cancer (11, 12, 14). The combination of gefitinib with many chemotherapeutic drugs has proved feasible and tolerable, and exploratory trials are in progress (31–35).

Cost of treatment

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Currently the major expenses in treating advanced lung cancer are hospitalization for disease and treatment-related events. One study estimated that 64–78% of total 2-year costs were for hospital-based facility services, either as an inpatient or an outpatient (36). A second study found that the management of grade 3/4 adverse events associated with cisplatin-containing chemotherapy regimens accounted for 66–79% of costs, whereas the cost of chemotherapy and concomitant medications accounted for only 7–12% of costs (37). Currently, docetaxel is the only agent that has been approved as second-line treatment for advanced NSCLC. In a retrospective cost-effectiveness analysis of docetaxel use during a phase III randomized trial of docetaxel vs. best supportive care, the largest cost (over one-third) for both treatment with docetaxel and best supportive care was hospitalization, followed by chemotherapy in the docetaxel arm (32%) and medication on best supportive care (28%) (38).

There has been no published assessment of treatment costs associated with gefitinib to date. However, with novel orally administered agents that are active as monotherapy such as gefitinib, fewer hospitalizations for treatment administration and for management of toxicity can be expected. In addition, the need for i.v. infusion and management of common cytotoxic adverse events such as neutropenia or other haematological toxicity, is obviated.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References

Gefitinib is a novel agent that has proven antitumour activity in advanced, relapsed NSCLC. Gefitinib use is being investigated in clinical trials for several other common solid tumour types in addition to NSCLC. In comparison with chemotherapy regimens, oral gefitinib is well tolerated, and the most common toxicities are mild reversible, skin rash and diarrhoea, which rarely require treatment cessation. There is no need for routine premedication, or for prophylactic management of side-effects (e.g. with antiemetics or antidiarrhoeals). Gefitinib has a good oral bioavailability. Its terminal half-life is about 48 h in patients with cancer, giving steady-state exposure within 10 days for once-daily dosing. The major route of excretion of gefitinib is via hepatic metabolism, and caution should be exercised when administering CYP3A4 inhibitors with gefitinib.

Gefitinib 250 mg is administered orally, once daily. The convenience of oral dosing contrasts with the requirement for significant levels of patient care and attention during and after i.v. infusion of most conventional cytotoxic agents. As novel agents such as gefitinib enter the clinic, new paradigms of patient care that affect pharmacists as well as physicians and nurses, look likely to come into effect.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Mode of action of gefitinib
  5. Administration, pharmacokinetics and metabolism of gefitinib
  6. Pharmacokinetic interactions between gefitinib and other agents
  7. Hepatic impairment and metabolism
  8. An alternative second- and third-line treatment option: gefitinib for NSCLC
  9. Phase II studies of gefitinib monotherapy in patients with NSCLC
  10. Gefitinib in combination with chemotherapy for the first-line treatment of NSCLC
  11. Gefitinib for the treatment of other solid tumours
  12. Cost of treatment
  13. Conclusion
  14. References
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