Combination therapy with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, gemcitabine and cisplatin in patients with advanced solid tumors

G. Giaccone1,*, J. L. González-Larriba2, A. T. van Oosterom3, R. Alfonso2, E. F. Smit1, M. Martens3, G. J. Peters1, W. J. F. van der Vijgh1, R. Smith4, S. Averbuch5 and A. Fandi4

1 VU University Medical Center, Amsterdam, The Netherlands; 2 Hospital Clinico San Carlos, Madrid, Spain; 3 University Hospital Gasthuisberg, Leuven, Belgium; 4 AstraZeneca, Macclesfield, UK; 5 AstraZeneca, Wilmington, DE, USA

Received 24 September 2003; revised 12 January 2004; accepted 22 January 2004


    ABSTRACT
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Background:

The aim of this study was to investigate the tolerability, pharmacokinetic interaction and antitumor activity of gefitinib (‘Iressa’, ZD1839), an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor, combined with gemcitabine and cisplatin in chemotherapy-naïve patients with advanced solid tumors.

Patients and methods:

This was an open-label feasibility trial evaluating two doses of gefitinib (250 and 500 mg/day) in combination with gemcitabine and cisplatin. Gefitinib was administered daily from day 2 onwards. Gemcitabine 1250 mg/m2 was given on days 1 and 8 and cisplatin 80 mg/m2 on day 1 for up to six 3-week cycles. Patients could then continue to receive gefitinib monotherapy.

Results:

Eighteen patients were entered, nine at each gefitinib dose level. Two patients developed dose-limiting toxicity: one grade 3 convulsion (250 mg/day dose group) and one grade 3 rash (500 mg/day dose group). The most frequently occurring adverse events in the combination phase were vomiting (17 patients), asthenia (16), nausea (14), diarrhea (14) and skin rash (13). The most common grade 3/4 adverse events were vomiting (seven patients), asthenia (six), thrombocytopenia (six), diarrhea (five) and anorexia (five). Pharmacokinetic analyses showed no apparent pharmacokinetic interaction between gefitinib and cisplatin or gemcitabine, with the exception of a possible small increase in the geometric mean exposure to gemcitabine seen on day 8 of therapy when given alone with the higher dose of gefitinib. Of 17 evaluable patients, nine had confirmed partial responses, seven had stable disease and one had progressive disease.

Conclusions:

Combination therapy of gefitinib with cisplatin and gemcitabine had a manageable and predictable safety profile, no major effect on exposure to any of the three drugs and antitumor activity.

Key words: combination therapy, efficacy, gefitinib, Iressa, NSCLC, tolerability


    Introduction
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
The epidermal growth factor receptor (EGFR) plays an important role in the growth and survival of many solid tumors. It is frequently expressed in a variety of tumors including colorectal and head and neck cancers, and non-small-cell lung cancer (NSCLC) [15]. The tyrosine kinase within the intracellular domain of the EGFR is activated upon ligand binding; this initiates a cascade of signaling events, leading to cell proliferation, cell survival, angiogenesis and metastasis [6, 7]. High EGFR expression, demonstrated immunohistochemically in cases of metastatic breast cancer [8] and NSCLC [910], appears to correlate with poor patient prognosis.

The importance of the EGFR in tumor biology provides the rationale for the development of EGFR-targeted cancer therapies. Gefitinib (‘Iressa’, ZD1839) is an orally active, selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in proliferation and survival of cancer cells and other host-dependent processes promoting cancer cell growth [5].

Phase I monotherapy trials in >250 patients have shown that gefitinib is generally well tolerated, the most frequent adverse events (AEs) being mild diarrhea and skin rash, and has promising antitumor activity in a variety of solid tumors [1113] (K. Nakagawa, T. Tamura, S. Negoro et al., unpublished data). Furthermore, this acceptable tolerability profile has been confirmed in two large, phase II, randomized studies of gefitinib in >400 patients with advanced NSCLC that had been pretreated with chemotherapy. In these trials, response rates of 18.4% (second- and third-line therapy) and 11.8% (at least third-line therapy) were obtained with the recommended gefitinib dose of 250 mg/day [1417]. Significant symptom relief was also demonstrated in these studies [1417].

There is preclinical evidence to suggest that gefitinib may enhance the antitumor activity of a variety of cytotoxic drugs [18]. In human cancer cell lines, such as colon, breast and ovarian, and in tumor xenografts including vulval, lung, colon and prostate, gefitinib significantly potentiated the efficacy of various cytotoxic drugs, including platinum compounds [19, 20]. Pretreatment with gefitinib has also been shown to enhance the sensitivity of head and neck cancer cell lines to 5-fluorouracil and cisplatin [21]. These studies, together with the activity demonstrated for the combination of gemcitabine and cisplatin in the treatment of several advanced solid tumor types [2224], provide the rationale for combining gefitinib with these agents in clinical studies.

This feasibility study was designed to assess the tolerability and antitumor activity of the combination of gefitinib, gemcitabine and cisplatin in chemotherapy-naïve patients with advanced and/or metastatic solid tumors, and to assess whether there was a pharmacokinetic interaction between these drugs when administered concurrently.


    Patients and methods
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Trial design
This was an open-label feasibility study of two doses of gefitinib in combination with gemcitabine and cisplatin in chemotherapy-naïve patients with advanced and/or metastatic solid tumors, conducted at three centers—one each in The Netherlands, Spain and Belgium. The primary end point was assessment of the safety profile and the secondary end points were assessment of any pharmacokinetic interaction and antitumor activity.

Patients
Eligible patients were chemotherapy-naïve, aged ≥18 years with a World Health Organization (WHO) performance status of 0–2. Patients had advanced and/or metastatic solid tumors not curable with surgery or radiotherapy for which the investigator believed the combination of gemcitabine and cisplatin may be beneficial.

Patients were ineligible if they had mixed small-cell lung cancer and NSCLC (as they were treated as small-cell lung cancers); pure adenocarcinoma or squamous-cell carcinoma of the urothelial tract; brain metastasis or spinal cord compression, either newly diagnosed or not definitively treated with surgery and/or radiation; unresolved toxicity from previous radiation therapy or incomplete healing from previous surgery; common toxicity criteria (CTC) grade ≥2 pre-existing motor or sensor neurotoxicity; evidence of severe or uncontrolled systemic disease or uncontrolled significant active infections; an abnormal hematological profile; serum bilirubin >1.25x the upper limit of reference range (ULRR); aminotransferases >2.5x ULRR, or >5x ULRR in the presence of liver metastases; serum creatinine >1.5x ULRR; creatinine clearance ≤60 ml/min; radiotherapy <2 weeks prior to enrollment, or prior curative radiotherapy to the chest.

Patients underwent a physical examination, hematology, biochemistry and creatinine clearance tests, and urinalysis within 7 days of trial entry and at regular intervals thereafter.

Demography, past medical history, ophthalmologic assessments, ECG and baseline objective tumor assessments were performed no more than 3 weeks before entry into the trial. Ophthalmologic assessments and ECG were also evaluated if clinically indicated thereafter.

All patients gave written, informed consent, and approval for the trial was obtained from the ethics committee at each trial center. The study was conducted in accordance with the Declaration of Helsinki [25] and International Conference on Harmonisation Good Clinical Practice guidelines.

Treatment
Two dose levels of gefitinib were investigated, 250 and 500 mg/day, continuously administered orally from day 2 onwards and given with 3-week cycles of chemotherapy: gemcitabine 1250 mg/m2 (30 min infusion), administered on days 1 and 8, and cisplatin 80 mg/m2 (2 h infusion), administered 30 min after gemcitabine on day 1 of each cycle (Figure 1). To ensure rapid achievement of steady-state levels of gefitinib, patients took an evening dose 12 h after the morning dose on day 2 only. Thereafter, gefitinib trial treatment was taken once daily at approximately the same time each morning.



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Figure 1. Treatment schedule. iv, intravenous; po, by mouth.

 
Unless chemotherapy was stopped due to toxicity or disease progression, combination treatment was continued for up to a total of six cycles; patients could then receive gefitinib monotherapy until disease progression, if felt to be in the patient’s best interest.

Dose escalation
The initial cohort of six patients was assigned to the 250 mg/day dose level of gefitinib. The first full safety evaluation was performed after the first six evaluable patients completed 28 days of the combination of gefitinib and chemotherapy. An individual dose-limiting toxicity (DLT) based on the anticipated toxicities of the gemcitabine and cisplatin combination alone and of gefitinib monotherapy was defined as any of the following National Cancer Institute Common Toxicity Criteria (NCI CTC), version 2.0, drug-related adverse events (AEs): grade 3/4 thrombocytopenia with severe bleeding; grade 3/4 neutropenia for >7 days, or neutropenia of any duration associated with fever; grade 3/4 skin toxicity; grade 3/4 gastrointestinal toxicity (diarrhea, nausea or vomiting persisting at the same or higher grade for >4 days despite aggressive antiemetic and/or antidiarrheal therapy); deterioration of visual acuity or other significant ocular toxicity consistent with preclinical corneal changes; grade 3/4 CNS, cardiac, lung, renal toxicity or an increase over the expected incidence of hepatic toxicity.

The expected DLT rate with the chemotherapy regimen alone is ~10%. On this basis, the DLT rate in combination with gefitinib would be considered acceptable, and the gefitinib dose level increased to 500 mg/day if no more than one patient experienced DLT in cycle one. If two or three patients experienced DLT, the dose level would be expanded to include 12 evaluable patients, and if no more than three of these patients had DLT, the gefitinib dose would be increased to 500 mg/day. After the first cycle of the 250 mg/day dose level, if more than three of the first six evaluable patients experienced DLT, the dose was not to be considered safe. The same criteria applied to the 500 mg/day dose group, although there was no further increase in dose.

Dose interruptions/modifications
In the event of grade 3/4 non-hematological toxicity considered to be gefitinib-related, administration of gefitinib could be interrupted for up to 14 days to allow resolution of the AE or a decrease in severity to grade 1; if the AE recurred, a second interruption was allowed but the dose would subsequently be reduced from 500 to 250 mg/day or from 250 to 100 mg/day. One gefitinib dose reduction was permitted for each patient. Standard criteria based on the known toxicities of gemcitabine and cisplatin were applied to determine dose interruptions/modifications to chemotherapy.

Tolerability
Patients were monitored for AEs throughout the trial and, if withdrawn from the study, for 30 days after the last dose of the trial drug.

Treatment could be discontinued for any of the following reasons: disease progression; ocular toxicity consistent with corneal changes seen in preclinical studies; cardiac toxicity attributed to gefitinib or to the combination of gemcitabine–cisplatin and concurrent gefitinib; severe hypersensitivity to gemcitabine or cisplatin despite antihistamine and steroidal premedication; any NCI CTC grade 3/4 toxicity that lasted for >2 weeks and was found to be unmanageable (excluding alopecia, nausea and vomiting); or if patient consent was withdrawn.

Pharmacokinetics
The steady-state pharmacokinetic parameters minimum (trough) plasma concentration (Cminss) and area under the plasma concentration–time curve (AUC0–24ss) of gefitinib were determined from venous blood samples collected on days 21, 22 and 23 (Figure 1). In addition, pre-dose (trough) blood samples were collected from each patient on day 1 of cycle 3 and every cycle thereafter. Venous blood (3 ml) was sampled on day 21 pre-dose and 3 and 7 h post-dose, on day 22 pre-dose (24 h post-day 21 dose) and 3 and 7 h post-dose, and on day 23 pre-dose (24 h post-day 22 dose). Blood samples were centrifuged for 10 min at 1000 g within 30–60 min of collection to obtain plasma. Plasma concentrations of gefitinib were determined by high-performance liquid chromatography (HPLC) with mass spectrometric detection, based on an assay described by Jones et al. [26].

Maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from 0 to last measurable time point (AUC0–t) were determined for gemcitabine and its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU) from venous blood collected on days 1, 8 and 22, and for cisplatin (as free platinum) on days 1 and 22. To obtain gemcitabine plasma samples, venous blood (5 ml) was taken pre-dose and 15, 30, 45, 60 and 90 min after the start of infusion on days 1, 8 and 22 of the trial. Blood was collected into a heparin tube, to which was added 100 µl of 10 mg/ml tetrahydrouridine solution to inhibit ex vivo metabolism of gemcitabine. Samples were kept mobile and centrifuged for 10 min at 1000 g within 10–15 min of collection. Samples were analyzed for both gemcitabine and dFdU, following trichloroacetic acid precipitation of proteins in the supernatant, by ion-pair reversed-phase HPLC with ultraviolet detection at 254 nm. To obtain cisplatin samples, venous blood (5 ml) was collected into tubes containing lithium heparin anticoagulant on days 1 and 22 pre-dose and 2, 2.5, 3, 4 and 5 h after the start of infusion. Plasma ultrafiltrate material was prepared by immediately placing the samples in an ice bath before centrifugation for 10 min at 1000 g, 4°C. Part of the supernatant was frozen at –20°C for total platinum; the other part was incubated with ethanol for 2 h at –20°C followed by centrifugation for 30 min at 2000 g, 4°C. The supernatant contains free platinum. Concentrations of cisplatin were determined as free platinum by graphite furnace flameless atomic absorption spectrophotometry against matrix matched standard solutions.

Antitumor activity
Tumor measurements were assessed at entry and objective tumor response was evaluated according to modified UICC/WHO criteria [27] every 6 weeks during the combination phase, and then every 8 weeks when being treated with daily gefitinib monotherapy, until disease progression.


    Results
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 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
Patients
Eighteen patients were enrolled in the trial between November 2000 and February 2001 (Table 1), nine at each dose level. Patients had a variety of primary solid tumors, the most common being NSCLC (n = 10), and most had a WHO performance status of 1 (n = 13). Half of the patients had received no prior treatment for cancer and all patients were chemotherapy-naïve for advanced and/or metastatic disease.


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Table 1. Patient demographics
 
Nine patients continued into the monotherapy phase of the trial: six on gefitinib 250 mg/day and three on 500 mg/day.

Tolerability
All patients were evaluable for tolerability and safety. Only two patients, one from each gefitinib dose group, experienced drug-related (gefitinib or chemotherapy) DLT. These events were as follows: grade 3 convulsion (250 mg/day group) in a patient with a history of epilepsy; and grade 3 rash (500 mg/day group) that resolved while the patient was on treatment.

Common AEs occurring throughout the trial are shown in Tables 2 and 3; they were consistent with the toxicity profiles of the chemotherapy agents and gefitinib or advanced cancer. These included vomiting, nausea, hematological toxicity, asthenia, diarrhea and skin rash; most AEs were mild (grade 1 or 2).


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Table 2. Number of patients with common adverse events that occurred during the combination phasea
 

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Table 3. Number of patients with common adverse events that occurred during the monotherapy phasea
 
The most frequently occurring grade 3/4 non-hematological AEs during the combination treatment phase of the trial were vomiting, asthenia, anorexia and diarrhea. Two patients had non-hematological grade 4 AEs; one had grade 4 asymptomatic serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) elevation that lasted for 2 days, and one had grade 4 pneumonia. The number of grade 3/4 AEs was higher in the 500 mg/day than the 250 mg/day gefitinib dose group, particularly for diarrhea and asthenia.

Hematological AEs throughout the trial included anemia, thrombocytopenia, leukopenia and non-febrile neutropenia with no proven sepsis. Grade 3/4 AEs at gefitinib 250 mg/day included neutropenia, anemia, leukopenia and thrombocytopenia, and at 500 mg/day included anemia and thrombocytopenia. All hematological AEs were considered to be related to chemotherapy.

There were no clinically significant cardiovascular or thromboembolic AEs during the combination phase of the trial. One patient with previously reported vomiting and diarrhea experienced renal failure as a result of Streptococcus pneumoniae septicemia, which resolved in 3 days, but there were no other clinically significant renal findings.

For gefitinib administered without chemotherapy, most AEs were grade 1/2. No individual grade 3/4 AE was seen in more than one patient. At the gefitinib 250 mg/day dose level, one patient had grade 3 neutropenia, and one patient had grade 3 thrombocytopenia. The non-hematological AE profile in this phase of the trial was consistent with that observed previously in gefitinib monotherapy studies.

Five patients had interruptions to their gefitinib therapy. Three patients had gefitinib interruptions during the combination phase. In one patient receiving gefitinib 250 mg/day, this was due to grade 4 elevated transaminases and vomiting. In the two patients in the 500 mg/day group, interruptions were due to diarrhea, sepsis, pneumonia (without neutropenia), dehydration (one patient) and vomiting (one patient). The dose of gefitinib was reduced to 250 mg/day in these two patients as a result of their gastrointestinal toxicity. Two patients, both at the gefitinib 250 mg/day dose, had dose interruptions during gefitinib monotherapy, one due to radiation pneumonitis (developed following radiotherapy after completion of the chemotherapy period), and the other due to grade 4 paralysis of the vocal cords (which subsequently resolved and was not considered to be drug related).

Three patients were withdrawn from the study because of AEs: two patients receiving gefitinib 500 mg/day (during the combination phase) were withdrawn due to diarrhea, vomiting and dehydration (one patient) and asthenia (one patient), and one patient receiving gefitinib 250 mg/day as monotherapy was withdrawn due to dyspnea. Dyspnea leading to withdrawal of the patient receiving gefitinib 250 mg/day actually began during the combination phase, and was considered to be related to both gefitinib and chemotherapy. Notably, this patient had radiation pneumonitis in addition to NSCLC and a serious AE of pericarditis. No drug-related deaths were reported during this trial.

The mean gefitinib dose adherence was high for both dose groups, suggesting good compliance with treatment (Table 4). Nine patients received gefitinib for at least 6 months and continued into the monotherapy phase of the trial; of these patients, three received gefitinib for >12 months. The median number of cycles and dose intensity of chemotherapy were high in both dose groups (Table 4).


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Table 4. Gefitinib dose adherence and total exposure to gemcitabine and cisplatin
 
Pharmacokinetics
The pharmacokinetic results are summarized in Table 5 and Figure 2.


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Table 5. Plasma exposure to gefitinib, cisplatin and gemcitabine
 


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Figure 2. Geometric mean (SD) plasma concentration–time profiles. Plasma concentrations of gefitinib treated with a dose of 250 and 500 mg gefitinib/day (with or without chemotherapy) are shown in a and b, respectively. The plasma concentrations of unbound platinum in patients treated with 250 and 500 mg gefitinib/day are shown in c and d, respectively, and that of gemcitabine in e and f, respectively.

 
The geometric mean AUC0–24ss and steady-state Cminss values for gefitinib were similar in the presence and absence of chemotherapy in both dose groups (Table 5).

For both AUC0–t and Cmax of free platinum, the geometric mean values were similar when cisplatin was administered with gemcitabine in the presence or absence of gefitinib at either dose level (Table 5).

In terms of AUC0–t and Cmax of gemcitabine (and its metabolite dFdU), the geometric mean values demonstrated that gemcitabine exposure in the 250 mg/day dose group appeared to show little difference from day 1 (<10%) on day 8, but tended toward a small increase (20%) on day 22 (Table 5). However, in the 500 mg/day dose group, the combination of gefitinib with gemcitabine given with cisplatin (day 22) showed no apparent change from day 1 in exposure to gemcitabine, although a small increase (17%) was observed on day 8.

Antitumor activity
Seventeen patients were evaluable for antitumor activity (one patient with mesothelioma at the gefitinib 500 mg/day dose level withdrew consent and was therefore not evaluable for tumor response); nine had a partial response, seven had stable disease and one patient had progressive disease (Table 6). Of the nine patients with a partial response, six had a response duration of ≥3 months and three patients with NSCLC receiving gefitinib 250 mg/day had a response that was maintained for ≥6 months. Of the seven patients with stable disease, three had disease control for >4 months (one with NSCLC and two with esophageal cancer). Furthermore, of these seven patients, one had an unconfirmed partial response and a further three had a decrease in tumor size from baseline of ≥30%.


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Table 6. Best overall response of evaluable patients
 
Among the 10 patients with NSCLC, median progression-free survival (assessed from the date of first dose of trial treatment to the date objective tumor progression was observed) was 5.2 months (range 2.5–12.5).

As of February 2002, six patients were still alive. Four patients lived for ≥12 months after their first dose of trial treatment; of these four patients, three had NSCLC and one had adenocarcinoma of unknown primary.


    Discussion
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
This study demonstrates that daily oral gefitinib in combination with gemcitabine and cisplatin has a manageable and predictable tolerability profile and shows antitumor activity. Both doses of gefitinib in combination with chemotherapy were well tolerated, and this is reflected in the high dose intensities and median number of chemotherapy cycles.

The results of the current study indicate that gefitinib does not appear to increase the overall toxicity of chemotherapy; the hematological AEs are consistent with the safety profile of gemcitabine plus cisplatin [24].

The safety data reported for the monotherapy phase of the present trial were consistent with the safety data from previous gefitinib monotherapy trials. The most frequently reported AEs in phase I trials of gefitinib monotherapy were mild grade 1/2 skin reactions, diarrhea, nausea and vomiting [1113] (K. Nakagawa, T. Tamura, S. Negoro et al., unpublished data). Grade 3/4 drug-related AEs were uncommon, even at the highest doses. The tolerability results of two phase II trials of gefitinib in pretreated patients with NSCLC provided further confirmation of the AE profile for the 250 and 500 mg/day doses [14, 15]. These two studies reported similar activities of the two doses and better tolerability of the lower dose.

In the present study, the overall tolerability profile was manageable and predictable with a lower incidence of CTC grade 3/4 AEs observed at the 250 mg/day dose level.

No pharmacokinetic interactions were expected that would affect the exposure to gefitinib, cisplatin or gemcitabine when given in combination, as gefitinib and the chemotherapy agents have different routes of metabolism and elimination. Interpatient variability and the small number of patients precluded a formal statistical evaluation of any potential pharmacokinetic interaction. However, the intrapatient comparison showed no evidence of any pharmacokinetic interaction between gefitinib and cisplatin, and only the possibility of a small increase in exposure to gemcitabine when given with gefitinib 500 mg/day in the absence of cisplatin. This possible increase did not appear to affect the tolerability profile.

Although the current study involved only a small number of patients, results were promising, as nine patients had a partial response and overall, only one of 17 evaluable patients had progressive disease. Antitumor activity was demonstrated at both gefitinib doses in a range of solid tumor types.

In summary, combination therapy of gefitinib 250 or 500 mg/day (‘Iressa’, ZD1839) with a standard 3-weekly regimen of cisplatin and gemcitabine has a manageable and predictable tolerability profile. There was no apparent effect on exposure to any of the three drugs, and antitumor activity was demonstrated in this study.

The combination of cisplatin, gemcitabine and gefitinib has been developed in order to be able to safely run large studies in patients for whom this combination chemotherapy is in common use. A large randomized study in advanced NSCLC has been performed. This study employed chemotherapy alone versus chemotherapy and the two doses of gefitinib, as in this feasibility study. Unfortunately, this study failed to show a survival advantage of gefitinib when added to chemotherapy [28]. The lack of patient selection might have influenced these results. Further studies are necessary to assess the optimal use of chemotherapy and gefitinib, in looking at sequencing versus concomitant treatments.


    Acknowledgements
 
We thank M. Kedde and K. van der Born for their excellent technical assistance. This research was supported by AstraZeneca.


    FOOTNOTES
 
* Correspondence to: Dr G. Giaccone, VU University Medical Center, Department of Oncology, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel: +31-20-4444-321; Fax: +31-20-4444-079; E-mail: g.giaccone{at}vumc.nl Back


    REFERENCES
 Top
 ABSTRACT
 Introduction
 Patients and methods
 Results
 Discussion
 REFERENCES
 
1. Rusch V, Baselga J, Cordon-Cardo C et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993; 53 (Suppl 10): 2379–2385.[Abstract]

2. Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183–232.[CrossRef][ISI][Medline]

3. Fox SB, Harris AL. The epidermal growth factor receptor in breast cancer. J Mammary Gland Biol Neoplasia 1997; 2: 131–141.[CrossRef][Medline]

4. Ke LD, Adler-Storthz K, Clayman GL et al. Differential expression of epidermal growth factor receptor in human head and neck cancers. Head Neck 1998; 20: 320–327.[CrossRef][ISI][Medline]

5. Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther 1999; 82: 241–250.[CrossRef][ISI][Medline]

6. Goustin AS, Leof EB, Shipley GD, Moses HL. Growth factors and cancer. Cancer Res 1986; 46: 1015–1029.[Abstract]

7. Aaronson SA. Growth factors and cancer. Science 1991; 254: 1146–1153.[ISI][Medline]

8. Niu Y, Fu X, Lv A et al. Potential markers predicting distant metastasis in axillary node-negative breast carcinoma. Int J Cancer 2002; 98: 754–760.[CrossRef][ISI][Medline]

9. Piyathilake CJ, Frost AR, Manne U et al. Differential expression of growth factors in squamous cell carcinoma and precancerous lesions of the lung. Clin Cancer Res 2002; 8: 734–744.[Abstract/Free Full Text]

10. Wells A. The epidermal growth factor receptor (EGFR)—a new target in cancer therapy. Signal 2000; 1: 4–11.

11. Ranson M, Hammond LA, Ferry D et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002; 20: 2240–2250.[Abstract/Free Full Text]

12. Herbst RS, Maddox AM, Rothenberg ML et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol 2002; 20: 3815–3825.[Abstract/Free Full Text]

13. Baselga J, Rischin D, Ranson M et al. Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 2002; 20: 4292–4302.[Abstract/Free Full Text]

14. Fukuoka M, Yano S, Giaccone G et al. Final results from a phase II trial of ZD1839 (‘Iressa’) for patients with advanced non-small-cell lung cancer (IDEAL 1). Proc Am Soc Clin Oncol 2002; 21: 298a (Abstr 1188).

15. Kris MG, Natale RB, Herbst RS et al. A phase II trial of ZD1839 (‘Iressa’) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum- and docetaxel-based regimens (IDEAL 2). Proc Am Soc Clin Oncol 2002; 21: 292a (Abstr 1166).

16. Douillard J-Y, Giaccone G, Horai T et al. Improvement in disease-related symptoms and quality of life in patients with advanced non-small-cell lung cancer (NSCLC) treated with ZD1839 (‘Iressa’) (IDEAL 1). Proc Am Soc Clin Oncol 2002; 21: 299a (Abstr 1195).

17. Natale RB, Skarin AT, Maddox A-M et al. Improvement in symptoms and quality of life for advanced non-small-cell lung cancer patients receiving ZD1839 (‘Iressa’) in IDEAL 2. Proc Am Soc Clin Oncol 2002; 21: 292a (Abstr 1167).

18. Woodburn JR, Barker AJ, Wakeling A et al. 6-Amino-4-(3-methyiphenylamino)-quinazoline: an EGF receptor tyrosine kinase inhibitor with activity in a range of human tumour xenografts. Proc Am Soc Clin Oncol 1996; 37: 390 (Abstr 2665).

19. Sirotnak FM, Zakowski MF, Miller VA et al. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res 2000; 6: 4885–4892.[Abstract/Free Full Text]

20. Ciardiello F, Caputo R, Bianco R et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (Iressa), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin Cancer Res 2000; 6: 2053–2063.[Abstract/Free Full Text]

21. Magne N, Fischel JL, Dubreuil A et al. Sequence-dependent cytotoxic effects of binary and ternary combinations of ZD1839 (‘Iressa’) with 5-fluorouracil and/or cisplatin: application in head and neck cancer cell lines. Proc Am Assoc Cancer Res 2001; 42: 88 (Abstr 473).

22. Hitt R, Castellano D, Hidalgo M et al. Phase II trial of cisplatin and gemcitabine in advanced squamous-cell carcinoma of the head and neck. Ann Oncol 1998; 9: 1347–1349.[Abstract]

23. Kroep JR, Pinedo HM, Giaccone G et al. Phase II study of cisplatin preceding gemcitabine in patients with advanced esophageal cancer. Ann Oncol 2004; 15: 230–235.[Abstract/Free Full Text]

24. Sandler AB, Nemunaitis J, Denham C et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 2000; 18: 122–130.[Abstract/Free Full Text]

25. World Medical Association. The Declaration of Helsinki. [Online]. http://www.wma.net/e/policy/b3.htm, 2002 (date last accessed 6 October 2002).

26. Jones HK, Stafford LE, Swaisland HC, Payne R. A sensitive assay for ZD1839 (Iressa) in human plasma by liquid–liquid extraction and high performance liquid chromatography with mass spectrometric detection: validation and use in phase I clinical trials. J Pharm Biomed Anal 2002; 29: 221–228.[CrossRef][ISI][Medline]

27. Green S, Weiss GR. Southwest Oncology Group standard response criteria, end point definitions and toxicity criteria. Invest New Drugs 1992; 10: 239–253.[ISI][Medline]

28. Giaccone G, Herbst R, Manegold C et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: a phase III trial – INTACT I. J Clin Oncol 2004; 22: 777–784.[Abstract/Free Full Text]