Cancer cells may acquire the capacity for
autonomous and dysregulated proliferation through the uncontrolled
production of specific molecules that promote cell growth (growth
factors) or through abnormal, enhanced expression of specific proteins
(growth factor receptors) on the cell membranes to which growth factors
selectively bind. Both processes trigger a series of intracellular
signals that ultimately lead to the proliferation of cancer cells,
induction of angiogenesis, and metastasis.1
The majority of human epithelial cancers are marked by functional
activation of growth factors and receptors of the epidermal growth
factor receptor (EGFR) family. Given this phenomenon, EGFR was the first
growth factor receptor to be proposed as a target for cancer therapy. After
20 years of drug development, four EGFR antagonists are currently
available for the treatment of four metastatic epithelial cancers:
non–small-cell lung cancer, squamous-cell carcinoma of the head and
neck, colorectal cancer, and pancreatic cancer. Less information
is available about the use of EGFR antagonists in the treatment of
earlier stages of cancer. This article summarizes the mechanisms of
action of EGFR inhibitors, presents the clinical evidence of their
anticancer activity, and considers the current, and controversial,
clinical issues with respect to their optimal use in the treatment of
patients with cancer.
EGFR in Human Carcinogenesis
EGFR is a transmembrane receptor belonging to a family of four related proteins (Figure 1Figure 1
Signal Transduction Pathways Controlled by the Activation of EGFR.).2
Ten different ligands can selectively bind to each receptor. After a
ligand binds to a single-chain EGFR, the receptor forms a dimer3 that signals within the cell by activating receptor autophosphorylation through tyrosine kinase activity.3
Autophosphorylation triggers a series of intracellular pathways that
may result in cancer-cell proliferation, blocking apoptosis, activating
invasion and metastasis, and stimulating tumor-induced
neovascularization.3,4 Development of EGFR Antagonists for Anticancer Therapy
The first anti-EGFR drugs were developed in the 1980s.18 Two classes of EGFR antagonists have been successfully tested in phase 3 trials and are now in clinical use: anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors (Table 1Table 1
Functional and Pharmacologic Characteristics of EGFR Inhibitors. and Table 2Table 2
EGFR Inhibitors Currently Approved for Cancer Treatment.).4,5,10-12,18 Anti-EGFR monoclonal antibodies, such as cetuximab, bind to the extracellular domain of EGFR when it is in the inactive configuration, compete for receptor binding by occluding the ligand-binding region, and thereby block ligand-induced EGFR tyrosine kinase activation. 4,5,19 Small-molecule EGFR tyrosine kinase inhibitors, such as erlotinib and gefitinib, compete reversibly with ATP to bind to the intracellular catalytic domain of EGFR tyrosine kinase and, thus, inhibit EGFR autophosphorylation and downstream signaling. Anti-EGFR monoclonal antibodies recognize EGFR exclusively and are therefore highly selective for this receptor. In addition, various small-molecule EGFR tyrosine kinase inhibitors can block different growth factor receptor tyrosine kinases, including other members of the EGFR family, or the vascular endothelial growth factor receptor. Various irreversible EGFR tyrosine kinase inhibitors are now in early stages of clinical development.4,5,12 The mechanism (or mechanisms) of action, pharmacologic effects, and spectrum of activity of anti-EGFR monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors have differences that may be relevant for clinical activity (Table 1 and Figure 2Figure 2
Mechanisms of Action of Anti-EGFR Drugs in Cancer Cells. and Figure 3Figure 3
Mechanisms of Action of Anti-EGFR Monoclonal Antibodies in Cancer Cells.).13 Clinical Efficacy of EGFR Antagonists in Human Cancers
More than 10 EGFR-targeting agents are in advanced clinical development for the treatment of various human cancer types.5,10-12 Two anti-EGFR monoclonal antibodies (cetuximab and panitumumab) and two small-molecule, reversible EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) have been approved in several countries for the treatment of metastatic non–small-cell lung cancer, colorectal cancer, squamous-cell carcinoma of the head and neck, and pancreatic cancer (Table 2).20-24 (For relevant clinical studies supporting the use of anti-EGFR drugs in the first three conditions, see Tables 1, 2, and 3 in the Supplementary Appendix, available with the full text of this article at www.nejm.org.)Non–Small-Cell Lung Cancer
Phase 1 trials showed that gefitinib and erlotinib have important clinical activity in patients with metastatic, chemorefractory non–small-cell lung cancer.25-29 Dose-dependent and reversible diarrhea and acneiform rashes have been the most prominent side effects (maximum tolerated dose, 750 mg per day for gefitinib and 150 mg per day for erlotinib). The histologic characteristics of the rash (a neutrophilic infiltrate in perifollicular areas within the basal layer of the skin) differ from those seen in typical acne and are common to all EGFR-targeted drugs, including anti-EGFR monoclonal antibodies.30 Skin toxicity is generally observed within 2 to 3 weeks after the start of treatment and gradually resolves in most patients, even when anti-EGFR treatment is continued. The maximum tolerated dose of erlotinib (150 mg per day), based on side effects, was chosen for further study, whereas for gefitinib, relatively low doses (patients were randomly assigned to receive 250 mg or 500 mg per day), given the maximum tolerated doses, were chosen.Gefitinib was the first anti-EGFR agent that was shown, in two randomized phase 2 studies, to have clinically important antitumor activity in patients with non–small-cell lung cancer who had not had a response to one or more chemotherapy regimens, including platinum-based and docetaxel-based therapies.30-32 The two doses of gefitinib (250 mg and 500 mg) had similar antitumor activity, but toxicity was greater at the higher dose. Therefore, the lower dose was selected for further clinical studies. These trials led the Food and Drug Administration (FDA) in May 2003 to approve gefitinib as third-line therapy for patients with locally advanced or metastatic non–small-cell lung cancer after failure of both platinum-based and docetaxel-based chemotherapies.
However, a placebo-controlled, randomized phase 3 trial (the Iressa Survival Evaluation in Lung Cancer [ISEL] trial) failed to show that gefitinib was effective in improving survival.33 Neither median survival nor the rate of survival at 1 year differed significantly between patients receiving gefitinib and those receiving placebo in either the overall study population or a subgroup with a history of adenocarcinoma. Preplanned subgroup analysis showed a significant survival benefit only in patients of Asian origin and in those who had never smoked. In June 2005, on the basis of the lack of a survival benefit in the ISEL study, the FDA restricted the use of gefitinib to patients participating in a clinical trial or continuing to benefit from treatment already initiated. Currently, gefitinib is marketed in several countries in eastern Asia but is not available in the United States or the European Union.
More recently, two randomized phase 3 trials evaluated the effectiveness of gefitinib monotherapy as compared with that of standard chemotherapy (docetaxel) as second-line treatment for chemotherapy-refractory non–small-cell lung cancer. The V-15-32 trial, conducted in Japan, failed to demonstrate the noninferiority of gefitinib in terms of overall survival, which was the primary end point.34 However, in a large multicenter trial, this end point was achieved with gefitinib after platinum-based therapy had failed.35 In addition, the side-effect profile appeared to favor gefitinib.35
In a phase 2 study, the antitumor activity of erlotinib as a single agent in heavily pretreated non–small-cell lung cancer was similar to that of gefitinib.36 More important, in the BR.21 trial, a phase 3, randomized, double-blind, placebo-controlled study involving patients with pretreated non–small-cell lung cancer, erlotinib increased median survival by approximately 2 months as compared with placebo (Table 3Table 3
Efficacy of Erlotinib in Chemotherapy-Refractory Non–Small-Cell Lung Cancer.).37
Responses were significantly more frequent in women, in patients with
adenocarcinoma, and in patients with no history of smoking. However, a
significant survival advantage was observed in all patient subgroups
after treatment with erlotinib as compared with placebo. Quality-of-life
analysis supported the palliative benefit of erlotinib in extending the
time during which patients were free of symptoms (cough, dyspnea, and
pain).38
On the basis of these results, erlotinib was approved by the FDA in
November 2004 and by the European Medicines Evaluation Agency (EMEA) in
October 2005 for second- and third-line treatment of
chemotherapy-resistant, advanced non–small-cell lung cancer. Several
hypotheses have been proposed as to why the efficacy seems different for
gefitinib and erlotinib in the similar BR.21 and ISEL phase 3 studies.
One possible explanation is dosing: erlotinib was used at the maximum
tolerated dose, whereas gefitinib was provided at a much lower dose.39 On the basis of preclinical data demonstrating that anti-EGFR drugs potentiate the antitumor activity of cytotoxic drugs, four phase 3, double-blind, placebo-controlled, randomized clinical trials examined the combination of erlotinib or gefitinib with chemotherapy as first-line treatment for non–small-cell lung cancer. Two standard platinum-based, dual-drug regimens were used in combination with erlotinib or gefitinib.40-43 Neither a survival advantage nor a benefit with respect to the response rate or time to progression was seen with the addition of gefitinib or erlotinib to chemotherapy in any of these trials. One possible reason that these trials failed to demonstrate any advantage of gefitinib or erlotinib is that they were conducted in unselected patients with non–small-cell lung cancer.44 Since only a subgroup of EGFR-positive patients with non–small-cell lung cancer have tumors that are dependent on the EGFR pathway, few patients with this type of cancer would have a clinical benefit from the addition of an anti-EGFR drug to chemotherapy.44 In addition, a retrospective subgroup analysis suggested that the addition of erlotinib to carboplatin and paclitaxel significantly prolonged survival only in the subgroup of patients who had never smoked.42
Cetuximab treatment is said to have relatively few side effects. The most common adverse events include skin toxicity (flushing, an acnelike rash, and folliculitis), fever and chills, asthenia, transient elevations in aminotransferase levels, and nausea.45 Approximately 1.5% of patients have infusion reactions, which include allergic reactions requiring discontinuation of therapy; this rate is in keeping with the use of a chimeric human–mouse monoclonal antibody. Whereas cetuximab is marginally active as a single agent in advanced non–small-cell lung cancer, most phase 2 studies suggest that adding cetuximab to platinum-based therapies is of clinical benefit.46-50 A large, multicenter, randomized, phase 3 study in which cetuximab was added to standard platinum-based chemotherapy (cisplatin and vinorelbine) has recently been completed (ClinicalTrials.gov number, NCT00148798). A more thorough evaluation of the role of cetuximab in the treatment of advanced non–small-cell lung cancer awaits publication of the results of this trial.
Colorectal Cancer
Cetuximab has been evaluated in both chemotherapy-refractory and untreated metastatic colorectal cancer. In phase 2 studies, cetuximab monotherapy was associated with response rates of 9 to 12%. Response rates of approximately 20% were achieved when cetuximab was used in combination with irinotecan in patients who had not had a response to previous therapy with irinotecan.51-53 A multicenter, randomized, phase 2 trial evaluated the activity of cetuximab given alone or with irinotecan in patients who had not had a response to irinotecan monotherapy (Table 4Table 4
Efficacy of Cetuximab in Chemotherapy-Refractory Colorectal Cancer.).54
The cetuximab–irinotecan combination was significantly more effective
than cetuximab monotherapy in terms of the response rate and rate of
progression-free survival. However, the median survival was similar with
the two approaches, mainly because of the crossover of patients from
cetuximab monotherapy to the combination group on treatment failure. On
the basis of these results, cetuximab was approved by the FDA in
February 2004 for use in patients with metastatic colorectal cancer,
either in combination with irinotecan (for patients who do not have a
response to irinotecan alone) or as monotherapy (in patients who cannot
tolerate irinotecan). The EMEA has approved cetuximab only in
combination with irinotecan.A multicenter, randomized, phase 3 trial examined the combination of cetuximab plus irinotecan as second-line treatment for colorectal cancer in patients who had not had a response to an oxaliplatin-based regimen. Cetuximab plus irinotecan was significantly better than irinotecan alone in improving response rates, increasing progression-free survival, and improving the quality of life.55 However, no differences were seen in overall survival, probably because almost half the patients crossed over to cetuximab treatment after the failure of irinotecan monotherapy. Recently, a randomized phase 3 trial comparing the use of cetuximab with best supportive care for patients in whom all available drugs, including fluoropyrimidines, oxaliplatin, and irinotecan, had failed showed that cetuximab increased progression-free survival, overall survival, and quality of life (Table 4).56 Cetuximab appears to be the only drug that does so with colorectal cancer who have had unsuccessful courses of all currently available chemotherapies.
Phase 2 studies57,58 indicate that cetuximab combined with both irinotecan and oxaliplatin-based chemotherapies may have a role in the first-line treatment of metastatic colorectal cancer, with a 10 to 20% absolute increase in response rates reported. Such a response could be clinically relevant, particularly for the management of metastatic disease limited to the liver, since reductions in the number and size of metastases after administration of the drug might present the opportunity for potentially curative surgery. Recently, a multicenter, randomized, phase 3 study evaluated the combination of cetuximab with a standard chemotherapeutic regimen of fluorouracil, leucovorin, and irinotecan (FOLFIRI) in previously untreated metastatic colorectal cancer. Cetuximab plus FOLFIRI significantly increased response rates, prolonged progression-free survival, and increased the number of patients who could undergo potentially curative surgical removal of liver metastasis by a factor of approximately three.59
Another monoclonal agent is panitumumab, a fully human anti-EGFR monoclonal antibody.22 As seen with cetuximab, skin toxicity and diarrhea are the most common side effects of this agent. A randomized phase 3 clinical trial compared the use of panitumumab with the best supportive care in patients with colorectal cancer who had previously been treated unsuccessfully with a fluoropyrimidine, oxaliplatin, and irinotecan. A 10% response rate was reported, together with a significant reduction in the risk of tumor progression.60 However, no difference was observed in overall survival, probably because of the preplanned crossover to panitumumab in the treatment group receiving the best supportive care. On the basis of these results, panitumumab was approved by the FDA in September 2006 as monotherapy for the treatment of metastatic colorectal cancer with disease progression after chemotherapy regimens consisting of a fluoropyrimidine, oxaliplatin, and irinotecan.
Squamous-Cell Carcinoma of the Head and Neck
The combination of cetuximab and radiotherapy was initially tested in patients with previously untreated, locally advanced squamous-cell carcinoma of the head and neck. In a randomized, multicenter, phase 3 clinical trial, patients were treated with radiotherapy alone or in combination with cetuximab (Table 5Table 5
Efficacy of Cetuximab in Squamous-Cell Carcinoma of the Head and Neck.).61,62
Radiotherapy plus cetuximab significantly prolonged progression-free
survival, duration of locoregional control, and overall survival. A
randomized phase 3 trial of cisplatin plus cetuximab as compared with
placebo in patients with previously untreated, metastatic squamous-cell
carcinoma of the head and neck showed a significantly higher response
rate in the group that received cisplatin plus cetuximab.63
However, no significant difference in overall survival was observed,
possibly because of the relatively small study sample. A recent larger,
randomized, multicenter phase 3 trial showed that the addition of
cetuximab to platinum- and fluorouracil-based chemotherapy in the
first-line treatment of recurrent or metastatic squamous-cell carcinoma
of the head and neck may be helpful, since progression-free survival and
overall survival were significantly prolonged (Table 5).62
This phase 3 study is unique in showing a survival benefit for a novel
treatment as compared with platinum-based chemotherapy in the treatment
of this disease.Several phase 2 studies evaluated cetuximab alone or in combination with cisplatin in the treatment of platinum-resistant squamous-cell carcinoma of the head and neck, a cancer in which no specific therapy has been effective; such patients have a very short life expectancy. The overall response rate with cetuximab monotherapy was 10 to 13%, with a disease-control rate of approximately 40 to 46%.64-67 Cetuximab was approved by the FDA in February 2006 for use in combination with radiotherapy to treat patients with locally advanced, unresectable squamous-cell carcinoma of the head and neck. It was also approved as monotherapy for metastatic disease in patients who have not had a response to chemotherapy. In March 2006, the EMEA approved cetuximab in combination with radiotherapy for the treatment of locally advanced disease.
Pancreatic Cancer
A single-group phase 2 study suggested that cetuximab was promising when used in combination with gemcitabine for the treatment of advanced pancreatic cancer.68 However, a more recent randomized phase 3 study failed to show a significant survival advantage with this combination as compared with standard treatment (gemcitabine monotherapy).69 In contrast, another randomized phase 3 trial, which compared the combination of erlotinib (100 mg per day) and gemcitabine with gemcitabine alone, showed a significant improvement in response and survival rates (hazard ratio for death, 0.82; 95% confidence interval, 0.69 to 0.99; P=0.04; 1-year survival rate, 23% vs. 17%, P=0.02), and both the FDA and EMEA have approved this regimen for first-line treatment of pancreatic cancer.70 Although the increase in survival could be considered modest in absolute terms, it showed that there is a significant advantage in adding an anticancer drug to gemcitabine in the treatment of metastatic pancreatic cancer — a unique finding.Predicting the Response to Anti-EGFR Drugs
Since only a subgroup of patients with cancer have a clinical benefit from treatment with EGFR inhibitors, there is an urgent need for identification and clinical validation of useful criteria for selecting patients for such treatment. A series of studies suggests that considering certain clinicopathological characteristics, as well as specific gene alterations, might help to identify patients whose cancers could be either sensitive or resistant to anti-EGFR therapy.Clinical and Pathological Predictors
Most clinical studies of gefitinib or erlotinib in non–small-cell lung cancer suggest that Asian ethnic background, female sex, the absence of a history of smoking, and a tumor with histologic features of adenocarcinoma are potential predictors of a positive clinical response to anti-EGFR therapy. 20,23,71 However, the presence or absence of cutaneous toxic effects, such as an acnelike rash, and their severity are the most important clinical correlates of the efficacy of anti-EGFR therapy. In fact, a significant positive correlation between cutaneous toxicity and rates of response, progression-free survival, and overall survival has been noted in virtually all trials of erlotinib, cetuximab, or panitumumab in advanced non–small-cell lung cancer, colorectal cancer, squamous-cell carcinoma of the head and neck, and pancreatic cancer. 53,54,72 It is conceivable that the effects in skin not influenced by cancer reflect the extent of EGFR blockade achieved in the tumor, in which case the rash would correlate with EGFR saturation or with a relevant drug concentration within the tumor.EGFR Protein Expression
EGFR expression as determined by immunohistochemical methods was the first biomarker investigated as a potential predictor of response. However, most studies have failed to show any relationship between EGFR expression and the clinical activity of anti-EGFR drugs.24,51 Cetuximab has also been shown to have clinical activity in patients with colorectal cancer that is negative for EGFR.73 Similarly, in a prospective phase 2 clinical trial, the response to treatment with panitumumab in patients with metastatic colorectal cancer was similar whether EGFR protein expression was high, low, or negative, as assessed by immunohistochemical methods.74 Collectively, these data suggest that immunohistochemical testing for EGFR is not an optimal method for identifying patients who may have a response to treatment with anti-EGFR drugs.Somatic EGFR Gene Mutations
The discovery that certain somatic mutations within the tyrosine kinase, ATP-binding domain of the EGFR gene are associated with a response to EGFR tyrosine kinase inhibitors in non–small-cell lung cancer suggested that the selection of patients through molecular screening might be feasible.75,76 Approximately 90% of EGFR mutations affect small regions of the gene within exons (18 to 24) that code for the EGFR tyrosine kinase domain. The most common mutations are an in-frame deletion in exon 19 around codons 746 to 750 (accounting for 45 to 50% of EGFR mutations) and a missense mutation leading to a substitution of arginine for leucine at codon 858 (L858R) in exon 21 (35 to 45% of EGFR mutations).6 Somatic EGFR mutations are found in approximately 5 to 15% of unselected white patients and in 25 to 35% of unselected Asian patients with non–small-cell lung cancer. These mutations seem to be limited to non–small-cell lung cancer, since they have rarely been detected in other types of human cancer. Somatic mutations in the EGFR gene are most frequently detected in a subpopulation of patients with this form of cancer who have one or more of the following characteristics: histologic features of adenocarcinoma and, in particular, nonmucinous bronchioloalveolar carcinoma; an absence of a history of smoking; an absence of K-RAS gene mutations; Asian ethnicity; and female sex.77-80 The likelihood of EGFR mutations decreases as the exposure to tobacco smoke increases, leading to the hypothesis that lung adenocarcinoma in patients who have never smoked is a distinct form of non–small-cell lung cancer with a high frequency of EGFR mutations and increased sensitivity to EGFR tyrosine kinase inhibitors.81,82 The association between EGFR mutations and a response to erlotinib or gefitinib has been retrospectively confirmed in several clinical studies.6 It has been also suggested that this association translates into improved survival.6 However, in larger randomized studies, such as the BR.21 trial, a similar survival advantage was observed for patients treated with erlotinib, independently of the presence of EGFR mutations or of a wild-type EGFR gene, indicating that the presence of EGFR mutations is not the only biomarker for predicting a survival benefit of treatment with small-molecule EGFR tyrosine kinase inhibitors in patients with non–small-cell lung cancer.83Increased EGFR Copy Number
The EGFR gene is rarely amplified in human cancers. However, fluorescence in situ hybridization (FISH) shows an increased EGFR copy number with balanced polysomy in a high proportion of cancer cells in approximately 25 to 40% of patients with non–small-cell lung cancer, squamous-cell carcinoma of the head and neck, or colorectal cancer. A single-group, phase 2 trial of treatment with gefitinib in advanced, chemotherapy-refractory non–small-cell lung cancer was the first to show that patients with FISH-positive tumors had significantly higher rates of response and survival than patients with FISH-negative tumors.84 In the BR.21 trial, patients with FISH-positive tumors (approximately 40% of the patients) who were randomly assigned to receive erlotinib had significantly longer survival as compared with patients with FISH-positive tumors who received placebo. In the patients with FISH-negative tumors, there was no significant difference in survival.83 Similar results were observed in the ISEL trial, which confirmed that patients with FISH-positive tumors who were treated with gefitinib had higher response rates and longer survival than patients receiving placebo.85 No difference in survival was seen in FISH-negative patients, irrespective of treatment. However, FISH analysis failed to demonstrate any difference in progression-free survival or overall survival in a phase 3 trial that compared gefitinib with docetaxel as second-line therapy for advanced non–small-cell lung cancer (the Iressa Non–Small-Cell Cancer Trial Evaluating Response and Survival against Taxotene [INTEREST]).36The predictive role of increased EGFR copy numbers has also been evaluated in patients with metastatic colorectal cancer in a series of retrospective studies. The first report on the correlation between positive results for EGFR and a response to therapy with cetuximab or panitumumab involved a small cohort of patients (31 patients) with advanced, chemotherapy-refractory colorectal cancer.86 Recently, a FISH analysis of EGFR in tumor samples from patients enrolled in the phase 3 study comparing the use of panitumumab with best supportive care was reported.87 In the group treated with panitumumab, patients with normal EGFR copy numbers had a shorter median progression-free survival and overall survival than patients with high EGFR copy numbers. Moreover, in the group treated only with best supportive care, no correlation between EGFR copy numbers and survival was observed, suggesting a predictive rather than a prognostic role of this genetic feature in patients with metastatic colorectal cancer who are treated with anti-EGFR monoclonal antibodies.
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