ScienceDirect - The Lancet Oncology : Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer

Srikala S Sridhar^a, Lesley Seymour^b and Frances A Shepherd ^,^,^a

^a SSS is a Clinical Research Fellow in Medical Oncology and FAS is a Professor of Medicine; both are at the Division of Medical Oncology, Department of Medicine of the University Health Network, Princess Margaret Hospital and the University of Toronto., Canada
^b LS is the co-ordinator of the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group and Queen's University, Ontario, Canada

Available online 1 July 2003.

Lung cancer is now the leading cause of cancer death in men and women in Europe and North America.[1] Although cytotoxic chemotherapy can relieve symptoms, improve survival, and occasionally contribute to cure in patients with localised disease, most individuals with lung cancer eventually relapse and die from either progressive local or metastatic disease. [2] During the past decade, our knowledge of the physiological role of growth factors and their receptors and their potential relevance to the pathogenesis of human cancer has greatly increased, leading to the development of novel targeted biological therapies.

One potential therapeutic target is the epidermal growth-factor receptor (EGFR) superfamily. These receptors are widely expressed cell-surface molecules implicated in the development and progression of cancer through effects on cell-cycle progression, apoptosis, angiogenesis, tumour-cell motility, and metastasis.[3, 4, 5 and 6] Overexpression of EGFRs correlates with a worse clinical outcome in several cancers including non-small-cell lung cancer (NSCLC), and tumours of the prostate, breast, stomach, colon, ovary, and head and neck, further supporting their role in tumorigenesis. [3, 4, 5 and 6] Many different strategies to interfere with EGFR-mediated signalling are being investigated and will hopefully translate into safe and effective treatments, especially in NSCLC where current therapies rarely offer a cure.

EGFRs and their ligands

The EGFR family is made up of four distinct, but structurally similar, tyrosine kinase receptors encoded by the proto-oncogenes c-ERBB1/EGFR/EGFR1 (commonly referred to as EGFR), c-ERBB2/HER2 (commonly referred to as HER2), c-ERBB3/HER3, and c-ERBB4/HER4. In general, the receptors possess extracellular ligand binding domains, transmembrane domains, and intracellular tyrosine kinase domains (figure 1). HER3 has little or no tyrosine kinase activity compared with the other receptors,[5] and HER2 has strong tyrosine kinase activity, but no known cognate ligand. HER2 therefore serves as a co-receptor, forming heterodimers with other types of EGFRs resulting in augmented signal transduction on ligand binding. [3]

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Figure 1. The EGFR superfamily of receptors.

Several endogenous ligands for EGFRs are known, but the most important stimulatory ligands are epidermal growth factor (EGF) and transforming growth factor small alpha, Greek (TGF). After ligand binding, the receptor undergoes dimerisation, forming either homodimers or heterodimers, followed by internalisation of the receptor–ligand complex and tyrosine autophosphorylation.[5] These events ultimately trigger a cascade of physiological responses affecting cell proliferation and survival, angiogenesis, and potentially metastasis ( figure 2).

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Figure 2. EGF binds to the receptor resulting in dimerisation and autophosphorylation. Dimerisation occurs between identical receptors (homodimers) or between two different members of the EGFR superfamily (heterodimers).

Several aspects of the EGFR family signalling system are abnormal in malignant cells. For example, in NSCLC and breast cancer the EGFR and HER2 genes are frequently amplified and the receptor gene products are overexpressed.[5 and 7] It is estimated that between 40% and 80% of NSCLCs overexpress EGFR, and 20–30% overexpress HER2. [8, 9, 10 and 11] This overexpression has been linked to poor overall outcome ( figure 3).[12 and 13]

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Figure 3. Estimated probability of survival of patients with non-small-cell lung cancer who underwent resection versus combined patterns of EGFR and HER2-neu co-expression. The median survival was 45·47 months in the high EGFR-expression group, 31·10 months (95% CI, 14·77–47·43) in the high HER2-neu-expression group, and 22·03 months (95% CI, 2·30; 41·76; P=0·003) in the high HER2-neu and EGFR-expression group.

EGFR also exists in a mutant form, EGFRvIII, which is the result of a 267-aminoacid inframe deletion and insertion of a glycine in the fusion junction of the extracellular domain. This mutation is detected in about 15% of NSCLCs and in other solid tumours, and leads to ligand-independent constitutive tyrosine kinase activity, altered subcellular localisation of the receptor, and may confer resistance to chemotherapy.[14]

Autocrine overproduction of EGF and TGF small alpha, Greek may also promote tumour formation and progression. Some tumours that overexpress EGFR may also overexpress TGF, although there is no absolute association between their simultaneous overexpression.[5] This evidence suggests that some tumours have the potential for multifactorial modulation of signalling through EGFR via control of both the receptor and its ligand.

Understanding the EGFR superfamily and their ligands has lead to the development of new therapeutic strategies including monoclonal antibodies, vaccines against EGF, ligand-toxin conjugates, and tyrosine kinase inhibitors. In this review we discuss the results of research to date with particular emphasis on studies in patients with NSCLC.

Monoclonal antibodies

Monoclonal antibodies have been developed that target different members of the EGFR superfamily. They are highly specific with few side-effects and may be synergistic with chemotherapy and radiation. The agents that fall into this category include antibodies to EGFR and monoclonal antibodies against HER2, truncated monoclonal antibody fragments (scFv), and fusion ligands conjugated with toxins and antisense oligonucleotides (tables 1 and 2).

Table 1. Monoclonal antibodies that target EGFRs
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Table 2. Other compounds that target the EGFRs
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Antibodies to EGFR

Cetuximab (IMC-C225) is a human–murine chimeric IgG monoclonal antibody that competitively binds to the extracellular domain of EGFR, preventing tyrosine kinase activation, inhibiting cell growth, and in some cases inducing apoptosis.[15] Preclinical studies show that cetuximab inhibits the proliferation of cell lines expressing EGFR, and increases the cytotoxic activity of chemotherapy and radiation. [15 and 16] Cetuximab alone and in combination with chemotherapy or radiotherapy was generally well tolerated in phase I trials; fever, asthenia, nausea, elevation of liver enzymes, and allergic and acneiform skin reactions were reported to be the major toxic effects. [16 and 17] The acneiform rash that is a characteristic side-effect of many EGFR-targeted therapies does not preclude continued cetuximab treatment, and its presence may even predict the subgroup of patients that respond to treatment. [16 and 18] Cetuximab in combination with chemotherapy has shown activity in head and neck and colorectal cancers with acceptable toxic effects. [18, 19 and 20] Phase II trials of cetuximab combined with gemcitibine and carboplatin, paclitaxel and carboplatin, and single-agent docetaxel in patients with NSCLC have all shown it is possible to combine cetuximab safely with chemotherapy. [21, 22 and 23] In the two first-line trials, the 28·6% response rate in the gemcitabine study [21] and the 29% response rate in the paclitaxel study [22] do not appear to be higher than would be expected with chemotherapy alone. Similarly, in the second-line setting, cetuximab and docetaxel resulted in a 22·3% overall response rate, but the median survival was only 7·5 months. [23] A small randomised phase II trial compared chemotherapy with vinorelbine and cisplatin to the same chemotherapy with cetuximab in the first line treatment of NSCLC. [24] Overall response rates favoured the cetuximab group (53·3% vs 32·2%), as did disease control rates (93·3% and 77·4%). Progression-free survival and overall survival have not been reported to date. A phase III trial testing use of cisplatin with or without cetuximab in patients with advanced head and neck cancer showed an increased response rate with the addition of cetuximab but this did not translate into an increase in progression-free survival ( table 3).[25]

Table 3. Results of trials of monoclonal antibodies directed against EGFRs
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ABX-EGF is a fully humanised IgG2 monoclonal antibody with a higher binding affinity for EGFR than cetuximab. It inhibits tyrosine phosphorylation in a dose-dependent manner because it blocks the EGF binding site on the receptor and causes rapid internalisation of EGFR.[26] In xenograft models, ABX-EGF resulted in complete eradication of some tumours with high EGFR expression. ABX-EGF may also be synergistic with chemotherapy. [27] In a phase I trial of 43 patients with NSCLC, dose-dependent acneiform skin rash was transient and biological activity was observed even at low doses. [28] Phase II trials with ABX-EGF in patients with kidney, colorectal, prostate, and lung cancer are underway. A trial combining ABX-EGF with paclitaxel and carboplatin is being done in patients with advanced NSCLC.

EMD 72000, a humanised monoclonal antibody that selectively binds EGFR, has shown antiproliferative effects against head and neck squamous carcinoma cell lines.[29] In murine models, the extent of tumour regression after treatment with EMD 55900 (the murine version of the antibody) correlated directly with the extent of EGFR expression. Also, in mice treated simultaneously with TNF small alpha, Greek (0·5 small mu, Greek g/g) and EMD 55900 or 72000, increased antitumour effects including complete tumour eradication were observed. [30] In phase I trials in patients with tumours expressing EGFR, the maximum tolerated dose of EMD 72000 on a weekly schedule was 1600 mg per week. Headache and fever were dose limiting at higher doses. Of 158 patients evaluable for tumour response, five showed partial remission, and four had stable disease. [31]

MAb ICR62 is a rat monoclonal antibody that blocks binding of EGF and TGF small alpha, Greek to EGFR. In vitro, it inhibits growth of tumour cells that overexpress EGFR and in xenograft models eradicates EGFR-expressing tumours.[29] MAb ICR62 has also been shown to have additive effects when given in combination with cisplatin. [29] In a phase I trial of 20 patients with squamous-cell cancers of lung and head and neck that expressed EGFR, no serious toxic effects were observed with doses up to 100 mg a day. Four patients showed human anti-rat antibody (HARA) responses, and biopsy samples taken from four patients who received doses of MAb ICR62 of 40 mg or greater showed localisation of the antibody to tumour-cell membranes. [32]

h-R3 is a humanised monoclonal antibody (IgG1), directed against EGFR. In xenograft models of human lung adenocarcinoma, radiolabelled h-R3 was preferentially taken up into tumour tissue over normal tissue.[33] A phase I dose escalation study of h-R3 in patients with locally advanced head and neck cancer showed that the antibody was well tolerated and that it may act synergistically with radiation therapy. [34] With recent advances in radioimmunotherapy techniques, h-R3 may be useful in targeting radiotherapy specifically to tumour sites.

The class I IgG receptor or CD64 receptor on cytotoxic effector cells can initiate the destruction of tumour cells. MDX-447 is a bispecific antibody comprised of humanised Fab anti-CD64 and humanised Fab anti-EGFR.[35] In vitro, MDX-447 recognises the CD64 receptor and EGFR, thereby targeting cytotoxic effector cells to tumour cells expressing EGFR, resulting in cell lysis. [36] MDX-447 given alone and with granulocyte colony-stimulating factor is being evaluated in phase I/II trials of patients with tumours that overexpress EGFR. Main toxic effects include fever, chills, blood pressure lability, and myalgia. Of 36 evaluable patients, nine had stable disease for 3–6 months. The optimum dose and the maximum tolerated dose have yet to be defined. [35] MDX-H210, is another bispecific antibody with humanised Fab anti-CD64 and humanised Fab anti-HER2. [35] Three phase II trials of MDX-H210 are being done in patients with tumours that overexpress HER2.

Antibodies to HER2

Trastuzumab, a monoclonal antibody against the extracellular domain of HER2, was originally developed for use in breast cancers, in which overexpression of HER2 occurs most frequently, generally because of gene amplification.[7] HER2 is a marker of more aggressive disease, lower rates of oestrogen-receptor expression, higher rates of recurrence, and a worse overall prognosis. [8 and 37] A phase III trial of first-line treatment of patients with metastatic breast cancer with overexpression of HER2 found that the addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (4·6 months vs 7·4 months), higher objective response rate (32% vs 50%), lower death rate at 1 year (33% vs 22%), and longer median survival (20·3 months vs 25·1 months; table 3). Cardiac dysfunction was seen in patients receiving simultaneous trastuzumab and anthracyclines. [7 and 8]

On the basis of these encouraging results, trastuzumab was evaluated in patients with NSCLC overexpressing HER2––overexpression is less frequent and believed to be the result of polysomy of chromosome 17 and not the gene amplification seen in breast cancer.[38] HER2 overexpression in NSCLC is most commonly found in adenocarcinomas and large-cell carcinomas and is predictive of poorer outcomes ( figure 2). [8, 9, 10, 11 and 12] In a randomised trial of patients with HER2-positive advanced NSCLC, the addition of trastuzumab to gemcitabine and cisplatin failed to increase response rates or increase progression-free or overall survival ( table 3). [39] However, only 2% of patients with NSCLC who were screened for entry into this trial were found to have HER2-positive tumours by fluorescence in-situ hybridisation (FISH), which is superior to immunohistochemistry in predicting response to trastuzumab in breast cancer. [37] Five of the six patients who had HER2-positive tumours (as determined with FISH) responded to treatment. Nonetheless, it seems that trastuzumab is unlikely to improve treatment outcome for most patients with NSCLC.

2C4 is an antibody against the ectodomain of HER2 at a site distinct from that of trastuzumab. It acts specifically by inhibiting the association of HER2 with other members of the EGFR superfamily and it does not cross react with trastuzumab. Preclinical information suggests that 2C4 will inhibit the growth of both androgen-dependent and androgen-independent prostate tumours grown as xenografts in athymic mice. A phase I study of 2C4 given every 3 weeks is being done.[40]

Conjugates of the monoclonal antibody to EGFR MAb 528 and mammalian pancreatic ribonuclease (an endogenous protein possessing antitumour activity) have been evaluated in preclinical studies. This immunoconjugate showed dose-dependent cytotoxicity against EGFR-expressing squamous cancer cells but not against EGFR-deficient small-cell-lung cancer cells.[41] Immunoconjugates of cetuximab and the ricin A chain (a potent inhibitor of protein synthesis) and EGF and Pseudomonas endotoxin are also at the preclinical stage.[42]

EGFRvIII has a constitutively active tyrosine kinase and unlike wild-type EGFR, does not bind ligand or undergo receptor dimerisation.[43 and 44] Since it is preferentially expressed in tumour tissue, EGFRvIII may serve as a highly specific target for therapy. A murine homologue of human EGFRvIII has been created and Y10––an IgG2a murine monoclonal antibody that recognises the human and murine equivalents of this variant receptor––has been investigated. [45] In that in-vitro study, Y10 was found to inhibit DNA synthesis and cellular proliferation, and induce complement-mediated and antibody-dependent cell-mediated cytotoxicity; phase I trials have not yet begun. [45] Ua30:2, another antibody to EGFRvIII has been studied in glioma tissue sections and has shown no measurable cross-reactivity to wild-type EGFR. However, clinical evaluation of this agent has not yet begun. [43] MAb806, also an antibody to EGFRvIII, is being evaluated in preclinical studies. [46] A phase I randomised study of an EGFRvIII peptide vaccine with granulocyte macrophage colony-stimulating factor vs keyhole limpet haemocyanin as adjuvant therapy in patients with EGFRvIII-expressing cancers is being done.

Vaccination against EGF

Another novel approach against the EGFR signal transduction cascade involves inducing an active immune response against the EGF ligand.[47] YMB2000 is an EGF vaccine that is a conjugate of recombinant EGF (rEGF) made in yeast, and recombinant P64K protein made in Escherichia coli. rEGF alone is not antigenic but in preclinical studies of rEGF conjugated to P64K an immune response to both proteins has been observed.[48] Although there is a theoretical risk of inducing autoimmunity, human safety and immunogenicity studies have shown seroconversion rates of 60% without evidence of significant toxic effects. Secondary reactions were mild and limited to erythema and itching at the site of injection. [47] Patients who developed a high antibody response showed a trend towards improved survival. There is currently a randomised phase II study assessing the safety and immunogenicity of human EGF vaccine in patients with stage III/IV NSCLC. Secondary objectives include the preliminary assessment of efficacy (survival benefit, objective response) and quality of life.

Tyrosine kinase inhibitors

The most active tyrosine kinase inhibitors are small molecules that compete with and prevent binding of adenosine triphosphate to the intracellular tyrosine kinase region. These agents cause tumour regression by increasing apoptosis and by inhibiting cellular proliferation and angiogenesis. The two compounds that are at the most advanced stage of development are gefitinib and erlotinib both of which target EGFR.

Gefitinib

Gefitinib (ZD1839, Iressa) is an oral EGFR-specific anilinoquinazoline which reversibly inhibits autophosphorylation, resulting in reduced c-FOS mRNA––a transcription factor forming part of the AP1 complex––and a shift of cells from S phase into G0/G1.[49] Preclinical studies showed that gefitinib can inhibit and even induce complete regression of well-established A431 xenografts and potentiate the cytotoxic effects of ionising radiation and chemotherapy. [50, 51 and 52] In phase I studies of gefitinib given in doses of 150–1000 mg per day, the most frequent adverse events were nausea, vomiting, an acneiform rash, and diarrhoea, the latter two effects becoming dose limiting at the maximum tolerated dose of 800 mg per day. [53] The skin is particularly susceptible to the effects of gefitinib largely because the EGFR is highly expressed in keratinocytes and in cells of eccrine and sebaceous glands. [54] Antitumour activity was observed at all dose concentrations but there was no evidence of a dose-response association. The doses chosen for phase II/III investigations were 250 mg and 500 mg per day, at which antitumour activity and pharmacokinetics consistent with preclinical activity were common. [53]

The results of two large randomised phase II trials, (IDEAL 1 and 2) have now been reported. In the IDEAL 1 trial, 210 patients with NSCLC who had failed one or two chemotherapy regimens (at least one platinum-based therapy) were randomly assigned to receive 250 mg or 500 mg per day of gefitinib. There were no differences between the two doses with respect to response rate, time to progression, or median survival. Response rates were also similar whether gefitinib was used as second-line (17·9%) or third-line treatment (19·8%). The frequency of rash and diarrhoea were greater in patients who received 500 mg per day.[55] In the IDEAL 2 study, 216 patients who had failed two or more chemotherapy regimens containing platinum and docetaxel received 250 mg or 500 mg gefitinib per day. The response rates were 12% and 9% and median survival was 6·1 and 6·0 months, respectively. An increased incidence of adverse events in patients receiving 500 mg per day was also seen. [56] The results are presented in table 4 and can be compared with results from the TAX 317 trial in which patients with stage IIIB/IV NSCLC who had failed cisplatin-based chemotherapy were randomly assigned to receive best supportive care or 75 mg/m² docetaxel.[57] Compared with the results that can be achieved with second-line chemotherapy, the response rates, survival, and toxicity profiles in the IDEAL 1 and 2 trials are very encouraging. On the basis of these two trials, gefitinib was approved in Japan in 2002, and more than 20000 patients have now been treated. Interstitial lung disease has been reported from Japan as an unexpected side-effect of gefitinib and is currently being investigated further. However, an analysis of the incidence of interstitial lung disease in the patient databases of the two placebo-controlled first-line trials of gefitinib in NSCLC [58 and 59] has shown that the rates of this toxic effect were the same in the active treatment and the placebo groups (0·9% and 1·1%, personal communication, George Blackledge and Steve Averbuch, AstraZeneca). These observations suggest that interstitial lung disease may not be a toxic effect that is specifically related to gefitinib therapy.

Table 4. Results of trials of second-line and third-line treatment of non-small-cell lung cancer
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Two randomised, placebo-controlled, phase III trials (INTACT 1 and 2) of gefitinib in chemotherapy-naive patients with stage IIIB/IV NSCLC have been reported (table 5). The trials combined gefitinib (250 or 500 mg per day) or placebo with either gemcitabine and cisplatin (INTACT 1) or paclitaxel and carboplatin (INTACT 2).[58 and 59] In both trials the toxic effects of gefitinib combined with chemotherapy were comparable to chemotherapy alone, with the exception of additive dose-dependent diarrhoea and skin rash. However, the results of the INTACT trials were disappointing because the addition of gefitinib to chemotherapy failed to show improved response or survival. An explanation for this result may be that chemotherapy and gefitinib are targeting the same cell population and that the chemotherapy response masks that of gefitinib. Alternatively, chemotherapy may directly or indirectly affect EGFR function or expression thereby reducing the effects of gefitinib. Finally inhibition of EGFR may reduce cellular proliferation, thereby making chemotherapy less effective. [58]

Table 5. Results of trials of gefitinib in the first-line treatment of non-small-cell lung cancer
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The European Organization for Research and Treatment of Cancer plans to study docetaxel (75 mg/m²) with and without gefitinib (250 mg per day) in patients with NSCLC who have failed one cisplatin-based regimen. The study will begin when phase I testing of the docetaxel and gefitinib combination is complete. Gefitinib is also being studied in patients with earlier stage NSCLC. An intergroup trial led by the Southwest Oncology Group is evaluating gefitinib in patients with inoperable stage IIIA/B NSCLC. Patients with stable or responsive disease after concurrent chemotherapy and thoracic radiation followed by consolidation docetaxel are randomly assigned to receive gefitinib or placebo as maintenance therapy for up to 5 years.

In a large intergroup trial led by the National Cancer Institute of Canada Clinical Trials Group (NCI-CTG), patients with completely resected stage IB, II, and IIIA NSCLC are being randomly assigned postoperatively to receive 250 mg per day gefitinib or placebo for up to 2 years. This trial aims to establish a tumour bank that can hopefully be used to answer some fundamental questions about patient selection for anti-EGFR therapy. Currently it is not known whether EGFR expression or overexpression is necessary for response or clinical benefit from treatment. Although trials in advanced disease will attempt to answer these questions, the studies may lack statistical power because not all patients have tumour samples available for analysis. A smaller trial of identical design is currently on hold in Japan pending further examination of the potential for gefitinib to cause interstitial lung disease.

Phase I and II studies of gefitinib with other chemotherapy regimens and with thoracic irradiation are ongoing in several centres. Gefitinib is also being evaluated in patients with premalignant dysplastic lesions detected at bronchoscopy to determine whether these changes may be reversible. Studies are also under development to evaluate gefitinib in other tumour types including breast cancer and head and neck cancer.

Erlotinib

Erlotinib (Tarceva, CP-358774, OSI 774) is another anilinoquinazoline derivative and orally active EGFR inhibitor that can induce both cell-cycle arrest in G1 and apoptosis. It inhibits EGFR autophosphorylation with a selectivity more than 1000-times greater than other tyrosine kinase inhibitors and reduces EGFR-associated phosphotyrosine by about 70% 24 h after a single 100 mg/kg dose.[60] Erlotinib also interferes with signalling via the variant receptor EGFRvIII. [61] In mouse xenograft models, concurrent erlotinib and cisplatin chemotherapy produced increased antitumour activity over that of cisplatin alone, with no increase in toxic effects. [62] Phase I studies showed that diarrhoea, rash, nausea, headache, emesis, and fatigue were the most frequent side-effects. At doses of 200 mg per day, diarrhoea was dose limiting but manageable with loperamide or a reduction in dose to 150 mg per day. The 150 mg per day dose was selected for subsequent studies because of its safety and tolerability profile and pharmacokinetic parameters. [60] By contrast, the 250 mg and 500 mg doses of gefitinib chosen for clinical trials were much lower than the maximum tolerated dose for gefitinib, which is 800 mg per day, raising questions about appropriate dosing of anti-EGFR therapies.

In a phase II trial of erlotinib in patients with NSCLC who had been treated previously and whose tumours showed more than 10% EGFR expression, the most common adverse effect was a maculopapular acneiform rash. The response rate was 14%, time to progression was 2·1 months, median survival was 9·0 months, and 1-year survival was 40%. Tumour response and survival did not correlate with the extent of EGFR expression (table 4). [63] Survival in this erlotinib trial was similar to the C225 trial in that it correlated most closely with the development of rash.

The preclinical synergy of erlotinib with platinum-based chemotherapy and non-overlapping toxic effects provided the rationale for combining erlotinib with chemotherapy. Phase I studies of erlotinib with gemcitabine and cisplatin and paclitaxel and carboplatin showed that erlotinib could be safely added to these combinations at a dose of 100 mg per day.[63 and 64] Two trials of 1000 patients given gemcitabine and cisplatin and paclitaxel and carboplatin with or without erlotinib have completed accrual but results have not yet been published.

A randomised phase III trial of single-agent vinorelbine or erlotinib is under development for patients with poor performance status. The Eastern Co-operative Oncology Group is planning to evaluate docetaxel with or without erlotinib in patients with NSCLC who have failed one cisplatin-based regimen. The NCIC-CTG evaluated erlotinib in patients with NSCLC who had a poor performance status, patients declining second-line treatments, and as third-line treatment. Because there is no proven role for chemotherapy in these clinical settings, patients in this trial were randomly assigned at a ratio of 2:1 to receive erlotinib 150 mg per day or placebo. This trial completed accrual in February 2003 but results have not yet been published.

CI1033 (PD183805)

CI1033, another 4-anilinoquinazoline derivative, is a highly specific irreversible tyrosine kinase inhibitor that is unique because it targets all four members of the EGFR superfamily and the constitutively active variant form EGFRvIII. CI1033 inhibits receptor signalling by selectively binding to a specific cysteine residue in the ATP pocket of the kinase domain.[65] It does not however, interfere with other tyrosine kinase receptors, such as platelet-derived growth factor, basic fibroblast growth factor, or the insulin receptor, even at high concentrations. [65] Data from three phase I trials showed that the most common side-effects are emesis, diarrhoea, and rash but generally CI1033 is well tolerated. [66, 67, 68, 69 and 70] A phase II study in patients with advanced ovarian cancer and a randomised phase II trial in patients with NSCLC after first or second-line chemotherapy evaluating different doses and schedules of CI1033 are being done.

GW572016

GW572016 is a 6-thiazolyquinazoline reversible kinase inhibitor of EGFR and HER2 kinases. In human xenograft studies, GW572016 has shown dose-dependent kinase inhibition, and seems to selectively target tumour cells overexpressing EGFR or HER2.[69] GW572016 has been tested in two phase I clinical trials in healthy patients. The most common adverse events were gastrointestinal symptoms, rash, and headache. [70 and 71]

EKB569

EKB569 is a 3-cyanoquinoline selective irreversible kinase inhibitor. It binds covalently and equipotently inhibits growth of cells overexpressing EGFR and HER2 but has little effect on cells with low levels of these receptors.[72] In a phase I trial, the most common adverse events were mild and reversible diarrhoea, rash, nausea, stomatitis, vomiting, and anorexia. At doses of 125 mg, grade 3 diarrhoea was dose limiting. EKB569 may be particularly effective clinically because it showed sustained tyrosine kinase inhibition that persisted even after the drug had cleared from the plasma. [73]

PKI166

PKI166, a pyrrolopyrimidine derivative, is a tyrosine kinase inhibitor that inhibits EGFR and HER2. It has antitumour activity in vivo in several EGFR overexpressing xenograft models. In nude mice implanted with human pancreatic carcinoma cells, PKI166 treatment reduced tumour volume by 45%, gemcitabine by 59%, and the combination of the two reduced tumour volume by 85%. Furthermore, mice given the combination treatment showed decreased lymph node and liver metastases and improved survival. A concomitant decrease in vascular endothelial growth factor and interleukin 8 was also observed suggesting that PKI166 has an antiangiogeneic effect.[74] Phase I trials of PKI166 have found elevations in liver enzymes to be dose limiting. Other less severe toxic effects included vomiting, diarrhoea, fatigue, and skin rash. The recommended phase II dose will be either 600 or 750 mg given in a 2-week on and off cycle. [75]

PD158780

PD158780 is a 4-[ar(alk)ylamino] pyridopyrimidine derivative that reversibly inhibits EGFR superfamily tyrosine kinases. Unlike gefitinib and erlotinib that target only EGFR, PD158780 is a potent inhibitor of auto and transphosphorylation of all four members of the EGFR superfamily. This agent is not yet in clinical trials.[76]

TAK165

TAK165 is a new tyrosine kinase inhibitor that targets HER2 specifically. In HER2 positive BT474 human breast tumours in mice, tumour regression was observed after 14 days of oral TAK165. This effect seemed to be mediated by inhibition of HER2 tyrosine kinase signalling and by inactivation of HER2 downstream molecules such as AKT, which is known to be antiapoptotic.[35] A phase I study of oral TAK165 given once daily to patients with advanced tumours that express HER2 is being done. [77]

Conclusion

During the past decade, several molecules that contribute to proliferation, invasion, and metastasis of cancer cells have been identified. Members of the EGFR superfamily are overexpressed in many tumours and are associated with poor prognosis. Therefore, they have become an important target for novel anticancer therapies, especially in the treatment of lung cancer where new and less toxic approaches are desperately required.

The two main classes of compounds specifically targeting EGFR include monoclonal antibodies and tyrosine kinase inhibitors. Cetuximab, an anti-EGFR antibody, has been found to control disease in patients with head and neck cancer and colorectal cancer in combination with chemotherapy. However, clinical trial results are not yet complete in patients with NSCLC. By contrast, trastuzumab, an anti-HER2 antibody that has shown significant clinical benefit in patients with breast cancer, is unlikely to have a major role in the treatment of NSCLC. The EGFR tyrosine kinase inhibitors gefitinib and erlotinib have shown promising antitumour activity against cisplatin-resistant NSCLC in phase I and phase II trials. However, results of recent phase III trials of gefitinib in combination with chemotherapy were disappointing and emphasise that we do not yet know the best way to incorporate this class of agents into our current treatment regimens.

Many questions remain unanswered regarding patient selection for EGFR-targeted therapy. It is not clear whether it is necessary for tumours to express or to overexpress the receptor for treatment benefit and some studies suggest that response to treatment correlates better with the development of the characteristic acneiform rash than with the level of EGFR expression. Furthermore, the best method for determining this expression has yet to be determined. Our increasing knowledge of the molecular biology of NSCLC may help to identify other biomarkers that will help predict response or resistance to novel biological agents.

Another important issue is dosage, duration, and schedule of anti-EGFR therapies. In contrast with conventional therapies, toxic effects and antitumour activity of biological therapies may not be linked and specific biological assays and pharmacologically guided studies may be required to determine the most effective dose. Duration of therapy has not been addressed in any trial to date, which may be of considerable importance if the trial of gefitinib in patients with stage IIIA inoperable NSCLC or the adjuvant trials in patients with early stage resected NSCLC are positive. Furthermore, it is also not known whether EGFR inhibitors should be given concurrently with chemotherapy or used as maintenance therapy after cessation of chemotherapy in responding patients. The negative INTACT 1 and 2 trial results suggest that it might be appropriate to assess the latter approach in clinical trials. Finally, the use of combined anti-EGFR therapy with agents that target more than one member of the EGFR superfamily, combinations of EGFR targeting agents, or combinations with other biological agents with different mechanisms of action, have yet to be addressed clinically.

Most clinical trials to date with anti-EGFR agents have shown activity in preclinical settings in vitro and in vivo. However, as has been the case in the past with chemotherapy agents, the preclinical models have not always been able to reliably predict human clinical response. This discrepancy may be because of redundancy in EGFR signalling systems contributung to resistance, similar targets shared by chemotherapy and anti-EGFR agents masking clinical responses, or changes in receptor concentrations induced by chemotherapy. Alternatively, study design and study endpoints for biological therapeutic strategies may need to be adjusted in ways that facilitate better prediction of response. The generation of pretreatment and post-treatment tumour banks may enable us to better understand these therapies at the molecular level and to tailor treatment accordingly.

Perhaps the greatest issue surrounding the use of EGFR inhibitors will be the one of cost. Gefitinib, the only anti-EGFR agent to be licensed for NSCLC, was approved in Japan in July 2002. The cost in Japan is US$60 per 250 mg pill, which equates to a total cost of more than US$20000 a year. Lung cancer is the second most common malignant disease in men and women in the Western world and this treatment alone could place a severe burden on the health-care systems of all countries regardless of whether the systems are publicly or privately funded or both. There have been no costing or cost-effectiveness studies of anti-EGFR therapy and these are needed urgently.

It is expected that EGFR-directed therapies will be established as effective novel treatments for patients with lung cancer and other malignant diseases once we understand how best to use them. For example, it has been postulated that in the elderly or those with poor performance status, anti-EGFR monotherapy may be equally efficacious and better tolerated than conventional treatments. Clearly, considerable research is still required but the wealth of knowledge gained from these early biological therapy trials cannot be understated and these studies offer hope for new and effective therapies in the future.

Search strategy and selection criteria

Data for this review were identified by searches of Cancerlit, MEDLINE, Current Contents, PubMed and abstracts from the Proceedings of the American Society of Clinical Oncology, the American Association for Cancer Research, and the European Society of Medical Oncology meetings from 1998 to 2002 with the search terms "NSCLC", "EGFR", "cetuximab", "IMC-C255", "ABX-EGF", "EMD 72000", "Mab ICR 62", "h-R3", "MDX-447", "MDX-H210", "trastuzumab, Herceptin", "2C4", "immunoconjugates", "anti-EGF vaccine", "YMB2000", "Y10", "Mab806", "gefitinib, ZD1839, Iressa", "erlotinib, OSI774, Tarceva", "CI-1033", "GW572016", "EKB 569", "PD153035", "PD168393", "PKI166", "PD158780", and "TAK 165". Reference lists of relevant articles and investigator brochures for the investigational agents included in this review were also searched. Only papers published in English between 1980 and 2002 were included.

Conflicts of interest

LS and FAS have received honoraria from and have stocks in AstraZeneca. FAS is a consultant for OSI Pharmaceuticals.

References

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Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer

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