1 Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan; 2 Division of Diagnostic Radiology, Istituto Clinico Humanitas, Rozzano, Milan; 3 University of Milan Medical School and Division of Pathology, Istituto Clinico Humanitas, Rozzano, Milan; 4 Division of Thoracic Surgery, Istituto Clinico Humanitas, Rozzano, Milan, Italy
Received 16 April 2003; revised 7 August 2003; accepted 13 August 2003
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ABSTRACT |
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Gefitinib (IressaTM, ZD1839) is an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. Phase I studies showed that it is well tolerated, with evidence of tumor regression in patients with advanced non-small-cell lung cancer (NSCLC). Therefore, we aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as a part of a compassionate use program.
Patients and methods:
To be eligible, all patients were required to have histologically or cytologically proven advanced or metastatic NSCLC, prior chemotherapy with at least one cisplatin-containing chemotherapy regimen or contraindication to cytotoxic drugs, Eastern Cooperative Oncology Group performance status 2, and adequate hematological, renal and hepatic parameters. All patients provided signed informed consent. Patient re-evaluation was performed every 46 weeks.
Results:
Seventy-three consecutive patients were enrolled. Response rate, including complete and partial response, was 9.6%; an additional 43.8% of patients achieved stable disease, for an overall disease control of 53.4%. EGFR1 status was evaluated by immunocytochemistry in 25 patients. According to EGFR1 immunoreactivity all responses were observed with medium/strong imunoreactivity while three out of four responses were observed in high expressive patients. Median survival for all patients was 4 months while it reached 6 months for patients with disease control. The 1-year survival rate was 13.1% for the entire series and 23.2% for patients with disease control. Non-hematological toxicity was generally mild.
Conclusion:
Gefitinib has promising activity with a good toxicity profile in patients with progressive NSCLC who have received one or two prior chemotherapy regimens. A possible relationship within response and EGFR1 expression is suggested.
Key words: epidermal growth factor receptor, gefitinib, non-small-cell lung cancer
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Introduction |
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The EGFR family comprises four distinct transmembrane receptors (EGFR/Erb B-1, HER 2/Erb B-2, HER 3/Erb B-3, and HER4/Erb B-4) composed of an extracellular ligand-binding domain and a cytoplasmic region with enzymatic activity. A number of different ligands, including EGF-like molecules, neuregulins and transforming growth-factor (TGF)-, activate the receptor permitting the release of activated effector and adaptor proteins into the cytoplasm where they stimulate many different signal transduction cascades, such as the mitogen-activated protein kinase pathway, the anti-apoptotic kinase Akt, phosphoinositol kinase and several transcriptional regulators [47].
It has been well demonstrated that the aberrant activity of EGFR signalling plays a key role in the development of tumor cell growth. In particular, growth factor receptors are overexpressed in a variety of common solid tumors, including non-small-cell lung, head and neck, colorectal, pancreatic, renal and ovarian cancer [810]. Increased EGFR expression is therefore likely to be a strong prognostic indicator in various tumor types [11] and its inhibition by agents designed to target these specific molecular processes seems to induce substantial therapeutic benefits [12, 13]. One of the most important milestones in the development of these novel antitumor agents was the concept of therapy based on the inhibition of the EGFR.
Gefitinib (IressaTM, ZD1839) is an orally active, selective EGFR tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer growth [4, 10]. Phase I studies showed gefitinib to be generally well tolerated with evidence of tumor regression and disease stabilization in patients with advanced non-small-cell lung cancer (NSCLC) [14, 15]. Two large phase II studies seem to indicate clinically meaningful antitumor activity and symptom relief in patients with advanced NSCLC who had received prior chemotherapy [16, 17]. We aimed to assess the antitumor activity and tolerability of gefitinib in a series of patients with previously treated, advanced NSCLC, as part of a compassionate use program.
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Patients and methods |
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Study design
Before starting gefitinib treatment, all patients underwent a complete medical history and physical examination. Additionally, in all patients complete hematological and biochemical testing was carried out as well as electocardiogram and baseline chest X-ray. Assessment of disease extent was performed with complete tomographic scans (CT) of thorax and upper abdomen. Brain CT scan was carried out in case of suspicious neurological symptoms of metastases. A radionuclide bone scan was performed when clinically required. Patients were re-evaluated every 6 weeks with regard to response as well as to toxicity. Both CT scan and assessment of other parameters of disease were repeated every 6 weeks and treatment was continued until disease progression and/or unacceptable toxicity.
Gefitinib was supplied by AstraZeneca on a named patient basis in tablets of 250 mg, which constitutes the daily treatment dose. Patients were not selected by tumor EGFR status.
The primary aim of this analysis was to evaluate the objective tumor response (complete plus partial response) rate, disease control (objective response plus stable disease) rate, and safety profile of gefitinib at 250 mg/day in patients with previously treated NSCLC. Secondary aims were to evaluate survival and to correlate EGFR1 tumor status with response to gefitinib.
Assessment of response and toxicity
Objective tumor response and its duration were assessed according to RECIST response criteria [18] and all responses had to be confirmed 30 days after the initial assessment of response. Time to disease progression was calculated from the date of start of therapy until the date of disease progression. Survival was assessed from the first dose of gefitinib until the date of death. All patients were evaluated in an intent-to-treat analysis. Toxicity was recorded according to the NCI Common Toxicity Criteria 2.0.
Assessment of EGFR immunoreactivity
EGFR1 status was evaluated by immunocytochemistry carried out using the MoAb EGFrAb-10 (clone 111.6), neomarkers (Union City, CA, USA) diluted 1:100 and revealed by the En Vision detection system (Dako, Glostrup, Denmark). Normal skin, placenta and liver were used as normal control. Only membrane immunoreactivity was considered. The percentage of neoplastic cells showing membranous immunoreactivity was semiquantitatively evaluated (range 0100%). Cases showing 019% immunoreactive cells were considered negative/low expressors while cases showing 20% immunoreactive cells were considered high expressors.
The staining intensity of immunoreactive cells was also scored as negative to faint (0/1+) or medium to strong (2+/3+).
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Results |
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EGFR immunoreactivity and response
EGFR1 analysis was performed in tumor specimens available from 25 patients included in this study (Table 5). According to staining intensity, 14 and 11 patients had, respectively, medium/strong and negative/faint immunoreactivity, while, according to percentage immunoreactive cells, nine and 16 patients had high and low/negative expressors, respectively. Four patients achieved partial remission, 11 stable disease and 10 progressive disease. All responses were observed in patients with medium/strong immunoreactivity while three out of four responses were observed in high expressor patients.
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Discussion |
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Following these trials, docetaxel at 75 mg/m2 every 3 weeks has been considered as the gold standard for patients with NSCLC who have previously been treated with a first-line platinum-based regimen. Nonetheless, from these results it appears clear that new approaches are required to further improve the outcome of patients with NSCLC [22].
Apart from prevention, screening and early detection, novel treatments based on a better understanding of the molecular mechanisms of this disease could change the long-term expectations for patients with NSCLC. From this viewpoint, the development of EGFR tyrosine kinase inhibitors currently represents the most appealing biological approach for NSCLC [6, 12, 23]. The preliminary results of randomized [16, 17] and non-randomized [2426] studies reported response rates ranging from 0 to 18.4%, disease control rates of 26.654.4% and median survival of 4.28.1 months. Some differences in the results could be explained by different patient selection; for example, in the two IDEAL studies gefitinib was administered to patients who had received at least one (IDEAL 1) or at least two (IDEAL 2) prior chemotherapy regimens [16, 17].
In our series we reported a response rate of 9.6% and a disease control rate of 53.4% with a median overall survival of 4 months. However, a major concern has been the observation that all responses were observed in patients with high expression of EGFR or medium/strong immunoreactivity (Table 5). This issue deserves further evaluation in larger series on both clinical and biological basis.
Our results are in agreement with the two major randomized phase II studies with gefitinib and strongly support the use of this drug as second- or third-line treatment of advanced NSCLC. Additionally, the good toxicity profile of this drug, mainly consisting of mild skin reactions, further supports an adequate clinical-benefit evaluation versus docetaxel as standard treatment for patients refractory to first-line therapy.
Recently, the results of two randomized trials comparing chemotherapy alone versus chemotherapy plus gefitinib [27, 28] failed to demonstrate any advantage in response rate, progression-free survival, time to worsening of symptoms or overall survival. Yet it is likely that only a subset of NSCLC patients should be sensitive to EGFR inhibitors. Obviously the level of EGFR expression in the tumor could be the mainstep in evaluating the EGFR inhibitors as well as the network of interactions at the ligand, receptor and downstream signaling levels [12, 29]. Another important unsolved issue could be represented by the definition of the best administration schedule, i.e. intermittent versus continuous, as well as the optimal combination with chemotherapy.
Thus, well-designed randomized trials are required to determine the role of gefitinib as first- as well as second-line treatment, alone or in combination with chemotherapy. Additionally, its role as adjuvant therapy as well as maintenance should be investigated. In the meantime, after decades of nonselective and nonspecific chemotherapy regimens, we can hope for a real improvement in NSCLC outcome with the introduction of specific, selective and non-toxic biological drugs.
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FOOTNOTES |
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