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Keywords:

  • epidermal growth factor receptor;
  • cetuximab;
  • erlotinib;
  • drug-dose response relationship;
  • drug toxicity

Abstract

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

Novel therapeutic agents that target the epidermal growth factor receptor (EGFR) constitute an important addition to the therapeutic armamentarium for the treatment of metastatic disease. EGFR-targeted agents currently approved by the U.S. Food and Drug Administration include cetuximab, a monoclonal antibody for the treatment of colorectal cancer; and the small-molecule EGFR tyrosine kinase inhibitor (TKI) erlotinib for the treatment of nonsmall cell lung cancer (NSCLC) and pancreatic cancer. Approval of the TKI gefitinib for NSCLC recently was withdrawn. Although both classes of anti-EGFR agents target the same receptor, substantial distinctions regarding their mechanism significantly affect dosing requirements, toxicity profiles, and their use as combination agents. Cancer 2006. © 2006 American Cancer Society.

The use of agents that target the epidermal growth factor receptor (EGFR) in cancer therapy was proposed more than 20 years ago. Since then, numerous therapeutic agents have been designed to target the EGFR and its signal-transduction pathway. These novel treatment options have been components of an ongoing revolution in cancer therapy and have held the promise of fulfilling significant unmet needs in many tumor types.

Of the various EGFR-targeted agents, the most promising and well studied are the monoclonal antibodies (MoAbs) and the small-molecule EGFR tyrosine kinase inhibitors (TKIs). Both classes of agents target the same receptor, but their mechanisms of receptor inhibition differ. MoAbs block the extracellular ligand-binding portion of the EGFR and interfere with its activation; in contrast, TKIs block induction of the intracellular tyrosine kinase-mediated signaling pathways. Anti-EGFR agents that have received approval for cancer therapy include the MoAb cetuximab (Erbitux™) and the TKIs gefitinib (Iressa®) and erlotinib (Tarceva®), although approval for gefitinib recently was withdrawn. Several other MoAbs and TKIs that target the EGFR also are in development.

Startling and somewhat unexpected differences between the agents are becoming apparent as the clinical experience with the EGFR inhibitors accumulates. In addition to different mechanisms of action of the 2 main classes of EGFR inhibitors, the agents vary considerably in terms of their specificity for the EGFR, which may contribute to the observed differences in efficacy and toxicity profiles. This review provides a mechanistic and clinical overview of agents that target the EGFR with a view toward exploring the clinical implications of the differing specificities of the agents.

EGFR Structure and Function

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

The human EGFR is a transmembrane glycoprotein that consists of an extracellular ligand-binding domain, a hydrophobic transmembrane region, and an intracellular tyrosine kinase domain. The EGFR is a member of the ErbB family of receptor tyrosine kinases, which includes EGFR (EGFR-1), ErbB-2 (HER-2), ErbB-3, and ErbB-4. The principal ligands of EGFR-1 are EGF and transforming growth factor α (TGF-α). Other ligands include amphiregulin, heparin-binding EGF, the poxvirus mitogens, epiregulin, and β-cellulin. Binding of ligand to the EGFR induces receptor homodimerization or heterodimerization (with other ErbB family members), which results in intracellular transphosphorylation of tyrosine residues.

Phosphorylation of the EGFR tyrosine kinase activates a complex, multilayered, downstream signaling network (Fig. 1). The major components of this network include mitogen-activated protein kinase (MAPK), which is involved in cell proliferation; phosphotidylinositol-3 kinase (PI3K), which mediates cell cycle progression and survival; and the signal transducer and activator of transcription (STAT) family of proteins, which mediates cell division, survival, motility, invasion, and adhesion. Heterodimerization of various members of the ErbB family receptors on ligand binding expands the combinatorial array of signaling events that can be initiated by a single molecule.1, 2

thumbnail image

Figure 1. The epidermal growth factor receptor (EGFR) signaling pathway. PI3K indicates phosphotidylinositol-3 kinase; JAK, Janus kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase.

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EGFR in Malignancy

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

EGFR expression has been documented in numerous epithelial malignancies (Table 1), although the EGFR is expressed to some degree in all cells of epithelial origin.4 EGFR activation appears to promote the development and progression of malignancy, because it is implicated in proliferation, angiogenesis, metastasis, and apoptosis inhibition and resistance in to chemotherapy, or radiation therapy, or both. Exactly how the EGFR contributes to tumor growth and progression remains unclear, although it is likely that multiple mechanisms are involved.

Table 1. Epidermal Growth Factor Receptor Expression in Various Carcinomas*
Tumor TypePercentage of tumors that expressed EGFR
  • EGFR indicates epidermal growth factor receptor.

  • *

    Adapted from Grandis JR, Sok JC. Signaling through the epidermal growth factor receptor during the development of malignancy. Pharmacol Ther. 2004;102:37–46.3

Colorectal25–77
Pancreatic30–50
Bladder31–48
Prostate39–47
Ovarian35–70
Glioma40–63
Breast14–91
Lung40–80
Renal50–90
Head and neck80–100

It has been observed that autocrine loops induce constitutive activation of the EGFR.5 Therefore, high expression of EGFR ligands in conjunction with increased expression of EGFR may facilitate the development of an autocrine or paracrine growth pathway, contributing to carcinogenesis. Supporting this theory, coexpression of both EGFR and TGF-α has been correlated with a poor prognosis in many cancers.6

Genomic alterations (e.g., overexpression, mutation, deletion, rearrangement) activate the transforming capacity of receptor tyrosine kinases in malignancies. In some tumors, mutant EGFR receptors result in impaired receptor down-regulation. Of several receptor mutations known to alter receptor function or activity, the best recognized is the EGF mutant receptor vIII (EGFRvIII).7–9 Mutations may arise from germline defects or from events secondary to environmental insult. In some malignancies, viruses exploit the EGFR pathway to stimulate cell proliferation.10

MoAbs that Target the EGFR

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

EGFR-specific MoAbs bind to the extracellular domain of the receptor, competing with ligand binding. This prevents receptor tyrosine kinase activation and attenuates EGFR-mediated intracellular signaling. Numerous MoAbs to the EGFR have been developed over the past 2 decades. Cetuximab has received U.S. Food and Drug Administration (FDA) approval, and several others currently are undergoing clinical testing (Table 2). Although they were developed against the same target, different EGFR MoAbs have unique specificities, affinities, and EGFR down-regulating abilities, all of which can affect their capacity to block receptor-mediated signaling and, thus, their clinical activity.

Table 2. Epidermal Growth Factor Receptor-Specific Antibodies
AgentClass/specificityTumor typeDeveloperDevelopment stageReference
  1. MoAb indicates monoclonal antibody; EGFR, epidermal growth factor receptor; CRC, colorectal cancer; NSCLC, nonsmall cell lung cancer; SCCHN, squamous cell carcinoma of the head and neck; CR, complete response; PR, partial response; SD, stable disease; OR, overall response; EGFRvIII; epidermal growth factor mutant receptor vIII.

Cetuximab (Erbitux®)Chimeric human-murine MoAb/EGFRCRC, NSCLC, SCCHN, pancreaticImCloneApprovedImClone, 200295
Panitumomab (ABX-EGF)Human MoAb/EGFRCRC, renalAbgenixPhase IIIHecht et al., 200496
h-R3 (nimotuzumab; TheraCIM™)Humanized MoAb/EGFRSCCHN (gliomas)CIMYM BiosciencesPhase I/II (n = 24): CR, 16.7%; PR, 20.8%; SD, 50%; rash, 0%Crombet et al., 200197; Crombet-Ramos et al., 200598; CMYM press release, May 19, 2005
EMD-72000 (Matuzumab)Humanized MoAb/EGFRSCCHN, ovarian, cervical, esophageal, CRCEMD Pharmaceuticals/ Merck KgaAPhase II: Ongoing 
    Phase I (n = 22): OR, 23%; SD, 27%; rash, 64%Vanhoefer et al., 200499
    Phase I (n = 22): PR or SD, 24% (5 of 22)Tabernero et al., 2003100
    Phase I (n = 51): Optimal biologic dose, 1200 mg every 3 weeksSalazar et al., 2004101
MDX-447 (HuMax™-EGFr)Humanized MoAb (bispecific)/EGFR and CD64SCCHNMedarexPhase I/IICurnow, 1997102
Mab-806EGFRvIIIU87MG.σ2-7 (EGFRvIII-positive) glioma and epithelioid carcinoma (A431) cells and xenograftsLudwig InstitutePreclinical: Specific binding to and internalization of EGFRvIIIJohns et al., 2002103; Mishima et al., 2001104

Cetuximab

Cetuximab (IMC-225, Erbitux™; ImClone Systems, Princeton, NJ) was approved by the FDA in February 2004 for the treatment of patients with EGFR-positive metastatic colorectal cancer (CRC), either as monotherapy in irinotecan-intolerant patients or in combination with irinotecan for the treatment of patients with tumors refractory to irinotecan-based therapy. It also was approved in December 2005 by the Swiss agency Swissmedic for the treatment of patients with previously untreated, advanced squamous cell carcinoma of the head and neck in combination with radiation. Cetuximab is a chimeric human:murine immunoglobulin G1 (IgG1) MoAb that binds to the EGFR with a 2-log higher affinity than the natural ligands TGF-α and EGF.11 Binding of cetuximab to the EGFR promotes receptor internalization and subsequent degradation without receptor phosphorylation and activation.12 This results in receptor down-regulation, reducing the availability of EGFR on the cell surface and effectively preventing activation of EGFR-associated, downstream signaling pathways. Cetuximab also binds to the mutant receptor EGFRvIII, inducing internalization of 50% of antibody-receptor complexes after 3 hours, and an 80% reduction in phosphorylated EGFRvIII.13 The half-life of cetuximab in humans, which is approximately 7 days,14 allows once-weekly dosing and is amenable with standard chemotherapy regimens.

The antitumor activity of cetuximab was demonstrated initially in preclinical models, with mechanisms of action including inhibition of tumor cell proliferation, G0/G1 cell-cycle arrest, induction of apoptosis, inhibition of angiogenesis, inhibition of invasion/ metastases, and enhancement of radiosensitivity.15–17 In addition, cetuximab is of the IgG1 antibody isotype, which has the potential for mediating antibody-dependent, cell-mediated cytotoxicity (ADCC) and complements fixation.18 More recently, it was shown that cetuximab blocks the transport of EGFR into the nucleus, where, otherwise, it would form a complex with DNA-dependent protein kinase to activate DNA repair mechanisms that confer resistance to chemotherapy-induced or radiation-induced damage.19

Cetuximab was tolerated well in early clinical studies. The most frequently occurring adverse events included fever and chills, asthenia, transaminase elevation, nausea, and skin toxicities.14 Less than 4% of patients developed antichimeric antibodies in Phase I studies, suggesting low immunogenicity. A relatively small number of patients (1.5%) experienced severe (Grade 3 or 4) infusion reactions, usually within minutes of the initial infusion.21

Cetuximab has demonstrated efficacy in Phase II clinical trials in patients with refractory, metastatic CRC, either alone or in combination with irinotecan. In the largest combination trial, the safety and efficacy of cetuximab plus irinotecan were compared with single-agent cetuximab in 329 patients with EGFR-detectable, irinotecan-refractory, metastatic CRC.21 Patients were randomized either to receive cetuximab (a standard regimen of an initial intravenous infusion of 400 mg/m2 followed by weekly intravenous infusions of 250 mg/m2) plus irinotecan at the same dose and schedule on which they had been progressing, or to receive cetuximab alone. The response rate for the combination arm was 22.9% (95% confidence interval [95% CI], 17.5–29.1%), and the median time to progression was 4.1 months. The response rate for single-agent cetuximab was 10.8% (95% CI, 5.7–18.1%), and the median time to progression was 1.5 months. Another Phase II, open-label clinical trial examined cetuximab as monotherapy in 57 EGFR-positive patients with irinotecan-refractory, metastatic CRC.22 In that study, 5 patients (9%; 95% CI, 3–19%) achieved a partial response, and 21 patients had stable disease or minor responses. The median survival was 6.4 months.

Mature results were reported recently from a Phase III trial of radiation therapy with or without cetuximab in 424 patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN).23 In that study, the addition of cetuximab to high-dose radiation resulted in a statistically significant improvement in overall survival compared with patients who received radiation alone. The median survival was 49 months in the cetuximab plus radiation arm versus 29 months with radiation alone, and there was a 26% reduction in the risk of mortality in the combination arm (P = .03). Locoregional disease control also improved significantly in patients who received cetuximab plus radiation therapy.23 Moreover, the addition of cetuximab to radiation therapy appeared to improve larynx preservation in the 171 patients who had laryngeal and hypopharyngeal carcinomas.24 Cetuximab did not exacerbate the Grade 3 or 4 toxicities of radiation therapy, except for the expected acneiform rash and infusion reactions. That clinical trial was the first to our knowledge that demonstrated a statistically significant increase in survival associated with EGFR inhibition in patients with SCCHN. To our knowledge to date, cetuximab is the only EGFR-specific agent administered in combination therapy that has increased survival in a curative setting without exacerbating the toxic effects of radiation.

Cetuximab also has demonstrated clinical activity in combination with docetaxel in patients with chemotherapy refractory NSCLC.25 The combination resulted in a partial response rate of 28% (13 of 47 patients) and stable disease in 8 of 47 patients (17%). The treatment was tolerated well, with toxicities as expected from chemotherapy and cetuximab.

Cetuximab's specificity for the EGFR may result in fewer overlapping toxicities than other combination therapies. Preclinical and clinical data support cetuximab combinations with a wide variety of chemotherapeutic agents26 and radiation therapy.27 Numerous ongoing studies are evaluating cetuximab combination therapy for a wide variety of indications (available at URL: www.clinicaltrials.gov [accessed March 2006]).

Until recently, positive testing by immunohistochemistry for EGFR expression was a patient-selection criterion for most cetuximab clinical studies. It was determined, however, that the intensity of EGFR staining did not correlate with clinical response to cetuximab28 and that some patients who tested negative for EGFR expression responded to cetuximab treatment,21, 29 and others who tested EGFR-positive did not.30 Consequently, current National Comprehensive Cancer Network guidelines for CRC management recommend against using EGFR expression by immunohistochemistry to select patients for cetuximab treatment regimens.31

Other EGFR-specific antibodies in development

Panitumumab (ABX-EGF; Abgenix, Fremont, CA) is a fully human, high-affinity MoAb to EGFR that has shown antitumor effects in preclinical models.32 Panitumumab blocks ligand binding and causes receptor internalization,33 although not degradation, suggesting that it may be recycled to the cell surface.34 Panitumumab has shown activity in clinical trials in patients with various advanced cancers, including renal carcinomas and metastatic CRC.35, 36 The principal toxicity was skin rash; other toxicities included pruritis, dyspnea, fatigue, diarrhea, abdominal pain, and asthenia.

Other EGFR-specific MoAbs in clinical development include EMD72000 (matuzumab; EMD Pharms/Merck KgaA) and hR3 (TheraCIM™; CIMYM Biosciences, Ontario, Canada). MDX-447 (Medarex, Princeton, NJ) is a dual EGFR and CD64 inhibitor,37 and MAB-806 (Ludwig Institute, Victoria, Australia) targets the mutant EGFRvIII (Table 2).

TKIs

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

Numerous small molecules that inhibit the EGFR tyrosine kinase are in various stages of clinical testing (Table 3). EGFR TKIs block receptor tyrosine kinase activity by binding at or near the adenosine triphosphate (ATP) binding site on the intracellular kinase domain. Although these small molecules usually are designed to inhibit EGFR selectively, they generally have low specificity compared with MoAbs and partially may inhibit other receptor tyrosine kinases. This less stringent specificity has the potential to result in less predictable clinical effects. The TKIs are administered orally and readily are diffusible, and it is believed that gastrointestinal toxicities associated with EGFR TKIs are related to EGFR inhibition in the gut. Frequent administration is required to maintain serum concentrations for continuous TK inhibition. The 2 TKIs that have been approved by the FDA, gefitinib and erlotinib, are used frequently at or near their maximum tolerated dose, and gastrointestinal toxicities often limit further dose escalation.

Table 3. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Other Epidermal Growth Factor Receptor-Targeted Agents
AgentTumor typeDeveloperDevelopment stageReference(s)
  1. TKI indicates tyrosine kinase inhibitor; NSCLC, nonsmall cell lung cancer; PR, partial response; SD, stable disease; FOLFOX4, combined 5-fluorouracil, leucovorin, and oxaliplatin; CR, complete response; PD, progressive disease; FOLFIRI, combined 5-fluorouracil, leucovorin, and irinotecan; DLT, dose-limiting toxicity; MTD, maximum tolerated dose; NA, not applicable.

Quinazoline TKI
ZD1839 (Gefitinib; Iressa®)NSCLCAstraZenecaApproved for NSCLCIressa® product insert; AstraZeneca, 2005105
OSI-774 (Erlotinib; Tarceva®)NSCLC; pancreaticOSI, Genentech, RocheApproved for NSCLC; Phase III for pancreatic cancerTarceva® product insert; OSI Pharmaceuticals, 2004106
GW-572016 (Lapatinib)Breast, NSCLCGSKPhase II/III, Breast cancer (n = 40): PR, 35%; SD, 35%; NSCLCRoss et al., 200580
Canertinib (CI-1033)SCC, skinPfizerPhase I/IIShin et al., 200175; Garrison et al., 200174
EKB-569ColorectalWyeth-AyerstPhase I/II and FOLFOX4 (n = 25): CR, 0%, PR, 48%; SD, 48%; PD, 4%; with FOLFIRI (n = 41): CR, 4%; PR, 39%; SD, 34%; PD, 17%Tejpar et al., 2004107; Casado et al., 2004108
PD153035Glioma, breast, SCCHN, mesotheliomaTocris CooksonPreclinical: [DOWNWARDS ARROW] growth and metastasisCole et al., 2005109
Pyrrolotriazine TKI
BMS 599626Solid (nonhematologic)Bristol-Myers SquibbPhase I: No DLT; Grade 1 and 2 adverse eventsGarland et al., 2005110
PKI-166Prostate, renalNovartisPhase I: MTD and DLT determinationHoekstra et al., 2002111
AEE788Glioma, colon, thyroidLymphoSignPreclinical, Phase IPark et al., 2005112; Yokoi et al., 2005113
Pyridopyrimidine TKI
ARRY-334543Breast, lung, epidermal carcinomasArray BioPharmaPreclinical/Phase IMiknis et al., 200582
PD158780NeuroepitheliomaNAPreclinicalSridhar et al., 2003114; Fallon et al., 200484

Gefitinib

Gefitinib (ZD1839, Iressa®; AstraZeneca, Wilmington, DE), which was approved by the FDA in 2003, is a small-molecule, reversible inhibitor of EGFR tyrosine kinase activity. After accelerated approval was grated based on the tumor response rate, gefitinib originally was indicated as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC who had previously received or were not suitable for chemotherapy. However, because of the disappointing final data from 2 studies (Iressa Survival Evaluation in Lung Cancer [ISEL] and S0023), which failed to show a significant survival benefit in patients NSCLC,38, 39 the indication for gefitinib subsequently was limited to patients either who currently are receiving and benefiting from it or who previously received and benefited from it and to patients enrolled in select clinical trials.40

Gefitinib selectively inhibits the EGFR tyrosine kinase and has approximately 100-fold greater potency against EGFR compared with other tyrosine or serine/threonine kinases. Unlike cetuximab, gefitinib does not induce EGFR internalization or degradation in CRC cells, nor does it reduce EGF binding sites or EGFR protein content. In preclinical studies, gefitinib inhibited tumor cell growth and enhanced the antitumor effects of chemotherapy.41–43 The most common adverse events of gefitinib observed in early clinical studies included skin rash, diarrhea, nausea, and emesis.41 Acute lung injury also has been reported,44 and gastrointestinal toxicities may be dose limiting.45

In Phase II and Phase III studies, gefitinib demonstrated single-agent activity (tumor responses) in patients with metastatic SCCHN at a dose of 500 mg per day,46 but not at a dose of 250 mg per day,47 and in patients with NSCLC (Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL] trials).48, 49 It had only limited activity in patients with glioblastoma50 and CRC,51, 52 and it was not active against advanced renal cell carcinoma.53 The large, confirmatory, Phase III ISEL trial in 1692 patients with advanced NSCLC who had received 1 or 2 prior chemotherapy regimens failed to demonstrate a survival benefit from gefitinib monotherapy (250 mg per day), as noted previously.38 Similarly, gefitinib monotherapy did not improve survival in patients with Stage III NSCLC after completion of induction and consolidation chemotherapy and radiation therapy.39 Furthermore, gefitinib did not enhance the activity of standard chemotherapy in patients with advanced NSCLC in the Iressa NSCLC Trial Assessing Combination Treatment (INTACT) studies.54

Only 9% to 19% of patients in the IDEAL trials achieved a tumor response to gefitinib monotherapy,48, 49 and EGFR expression did not correlate with antitumor activity.55 However, an analysis of tumor samples from NSCLC patients who had a response to gefitinib revealed somatic mutations in the EGFR tyrosine kinase domain from 8 of 9 patients compared with no mutations in patients who did not respond to gefitinib.8 EGFR mutations were associated with progression-free survival and were identified in 14 of 78 patients (18%) and in 32 of 312 patients (10%) with improved outcomes in the IDEAL and INTACT studies, respectively.56 The mutations were heterozygous, suggesting a dominant oncogenic effect,56 and were clustered in exons 18 through 21 (positions 746–753) near the ATP cleft of the tyrosine kinase domain in the gefitinib binding pocket. Mutations at this site could result in structural changes that affect interactions among EGFR, ATP, and gefitinib. These results were confirmed in a separate study of patients with NSCLC from Japan and the U.S.9 A small subset of NSCLC tumor variants with a second type of EGFR mutation (a threonine-to-methionine substitution at position 790 or at T790M) recently was correlated with gefitinib resistance.57, 58 Other mechanisms of resistance have been demonstrated in gefitinib-resistant clones derived from most non-T790M-bearing cells in clinical specimens.59

Erlotinib

Erlotinib (OSI-774, CP-358,774, Tarceva®; OSI Pharmaceuticals in collaboration with Genentech and Roche Pharmaceuticals) is an orally administered, selectively potent, reversible TKI that was approved by the FDA in 2004 for the treatment of patients with locally advanced or metastatic NSCLC and in 2005 for use in combination with gemcitabine as first-line treatment for patients with locally advanced, unresectable, or metastatic pancreatic cancer. Erlotnib has minimal inhibitory action against the HER-2 receptor,60 but it also inhibits EGFRvIII tyrosine kinase activity.61 In tumor models, the degree of its antitumor effect is related to the degree of inhibition of tyrosine kinase autophosphorylation, and high doses of erlotinib are needed to achieve maximum inhibition and optimal antitumor effect.62 In mice with human HN5 head and neck carcinoma xenografts, erlotinib reduced intratumoral EGFR autophosphorylation63 by 75% to 85% for at least 12 hours and by 25% to 40% after 24 hours. Similar to gefitinib, erlotinib had no effect on EGFR expression or surface receptor density.63 In a Phase I clinical study of patients with advanced solid malignancies, the average half-life at doses ranging from 50 mg per day to 200 mg per day was approximately 24 hours after a single dose and 31 hours after multiple once-daily doses.64

Erlotinib has shown some activity as a single agent in Phase II clinical trials in patients with previously treated, advanced SCCHN65 and NSCLC.66, 67 Results were reported recently from a large, randomized, placebo-controlled trial of erlotinib in patients with advanced NSCLC after failure of first-line or second-line chemotherapy.67 Patients (n = 731) were randomized 2:1 to receive erlotinib 150 mg/day or placebo. The overall response to erlotinib was 8.9% (vs. <1% in the placebo group; P < .001), with a median response duration of 7.9 months (vs. 3.7 months in the placebo group). Statistically significant and clinically relevant differences were observed for overall survival (6.7 months vs. 4.7 months; P < .001) and progression-free survival (2.2 months vs. 1.8 months; P < .001) in patients who received erlotinib and placebo, respectively. In that study, rash and diarrhea were the most frequent symptoms, and 5% of patients discontinued erlotinib because of toxicity compared with 2% of patients on placebo.

Erlotinib in combination with chemotherapy has demonstrated benefit in patients with pancreatic cancer. In a Phase III trial that involved 569 patients with advanced pancreatic carcinoma, the addition of erlotinib to gemcitabine improved overall survival and progression-free survival compared with gemcitabine alone.68 The difference in overall survival favored the erlotinib arm, with a hazard ratio of 0.81 (95%CI, 0.67–0.97). Progression-free survival rates also improved significantly with erlotinib, with a hazard ratio of 0.76 (P = .003). Results from that trial are the first to our knowledge that demonstrate a clinical benefit from an EGFR TKI used in combination with chemotherapy. It should be noted, however, that erlotinib, like gefitinib, did not confer a survival benefit in combination with standard chemotherapy in 2 trials in patients with advanced NSCLC.69, 70

Canertinib

Canertinib (CI-1033; Pfizer Pharmaceuticals, Groton, CT) is an irreversible, pan-ErbB TKI that alkylates a cysteine residue in the ATP-binding pocket of EGFR and HER-2, inhibiting autophosphorylation. Because it irreversibly inhibits the receptor tyrosine kinases, canertinib inhibition persists until new receptors are generated. Canertinib inhibited receptor tyrosine kinase phosphorylation and activity in tumor xenografts in preclinical studies.71 Tumor samples that were treated with canertinib showed a 44% median decrease in EGFR phosphorylation.72 Canertinib also has been shown to induce polyubiquitination and degradation of HER-2, possibly through the HER-2-associated chaperone complex pathway.73 Increased preclinical activity of irreversible TKIs, compared with reversible TKIs, may be related to this additional mechanism of receptor degradation.73 In Phase I studies, the most common toxicities of canertinib were nausea and emesis, diarrhea, and skin rash. Dose-limiting hypersensitivity reactions also have been observed.74, 75

Other TKIs

EKB-569 (Wyeth-Ayerst, Madison, NJ) is an irreversible dual inhibitor of the EGFR and HER-2 tyrosine kinases, and it inhibits the growth of tumor cells that overexpress EGFR or HER-2 in vitro and in vivo.76 Dose-limiting toxicities in Phase I studies were diarrhea and elevations in liver transaminases.77, 78 In Phase II studies, EKB-569 currently is being tested alone as second-line or later stage treatment in patients with advanced CRC or advanced NSCLC (available at URL: http://www.clinicaltrials.gov [accessed February 22, 2006]).

PKI-166 (Novartis International, Basel, Switzerland), GW572016 (GlaxoSmithKline, Research Triangle Park, NC), and ARRY-334543 (Array BioPharma, CO) are 3 new dual-EGFR/ErbB-2-reversible EGFR TKIs in development. GW572016 currently is undergoing Phase I and II trials, including trials as first-line therapy for breast cancer and NSCLC.79, 80 It also is being studied in combination with trastuzumab, an MoAb to Erb-2, for metastatic breast cancer.81 ARRY-334543 is an orally active, selective, and ATP-competitive dual-EGFR/ErbB-2 inhibitor that blocks the Akt pathway and inhibits the growth of EGFR or ErbB-2-overexpressing human tumor xenografts.82 It recently was approved for testing in humans.

Two other new TKIs, PD153035 and PD158780 (Parke-Davis, Ann Arbor, MI), currently are in preclinical development. PD153035 is a dual inhibitor of EGFR and ErbB-2 tyrosine kinase members of the EGFR family. The latter agent can delay the growth of breast and epidermoid tumor xenograft but has yet to be tested clinically.83, 84

The Economics of Targeted Therapy

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

The cost of treatment with targeted agents can be substantial and should be considered. A 1-month course of treatment with cetuximab costs (in U.S. dollars) on the order of $10,000, not including the cost of other chemotherapeutic agents required for adjuvant therapy.85 Treatment with small-molecule TKIs, such as gefitinib, costs from $2000 to $3000 per month.86 Combinations of targeted therapies currently under investigation, such as cetuximab with bevacizumab,87 also are expected to result in considerable cost increases.

Changes in the healthcare marketplace, such as managed care, have led to scrutiny of the cost-effectiveness of treatment modalities in the U.S.88 The costs related to cancer treatment are difficult to assess, but they are substantial and are increasing dramatically,89 with an average annual increase of 16% in total charges from $17.9 million in 1995 to $27.9 million in 1998.90 The largest component of these costs was antineoplastic therapy (67%), which accounted for 76% of the cost increase during this period in which newer, more expensive drugs replaced older, less expensive drugs. Drugs with the greatest impact on cost between 1995 and 1998 included paclitaxel, irinotecan, and carboplatin.

The clinical utility of these agents must be defined before their cost-benefit ratio can be determined. Just as there is a need to justify more expensive chemotherapy agents with superior clinical efficacy over alternative treatments,91 targeted treatments also must demonstrate their worth. In addition, the cost of managing toxicities with these agents must be considered. Although they are not expected to exacerbate the toxicities of traditional chemotherapy or radiation therapy, differences in toxicity profiles between targeted agents could have a substantial impact on the cost of therapy, not to mention the potential for reduced efficacy if dose-limiting toxicities are observed.

Pharmacogenomics and individualized care may be possible routes to cost containment for targeted therapies by using the knowledge of genetic variations to customize therapy to improve responses and reduce toxicity.92 Whereas gene expression profiling remains largely investigational, there have been numerous promising reports in a variety of tumor types.93 Examples that illustrate the potential uses of pharmacogenomics in cancer therapy include the EGFR mutations that correlate with response to gefitinib in NSCLC patients8, 9 and cyclin D1 A870G polymorphisms, which may predict clinical outcome in patients with metastatic CRC who receive cetuximab.94

DISCUSSION

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

Novel therapeutic agents that target the EGFR constitute an important development in the treatment of metastatic disease. EGFR-targeted agents currently approved by the FDA include cetuximab, an MoAb for the treatment of CRC, and erlotinib, a small-molecule TKI for the treatment of NSCLC and pancreatic cancer. These agents have substantial differences in dosing requirements, toxicity profiles, and utility as combination agents.

MoAbs that target the EGFR are highly specific and will affect only EGFR-expressing cells. In contrast, the TKIs may inhibit tyrosine kinases other than EGFR, with unclear clinical implications. Receptor internalization and ADCC, mechanisms that are attributed to MoAbs but not to most TKIs, may provide an added clinical benefit through continuous, constant blockade of EGFR signaling; the reversible TKIs gefitinib and erlotinib may allow only incomplete signal inhibition. Irreversible TKIs in development, however, hold the promise of permanent or longer lasting kinase inhibition. Antibody-based therapeutics have relatively narrow toxicity profiles, which allow their combination with a wide range of chemotherapeutic agents without exacerbating toxicity, and the gastrointestinal toxicities of TKIs may be dose limiting. Cost-reduction strategies for these expensive, novel therapies may involve pharmacogenomics, individualized care, increased trial participation, and further study of specific patient populations.

Acknowledgements

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES

I gratefully acknowledges the literature research and editorial contributions of Todd Billeci, Bless Castro, and Bridget O'Keeffe in the development of this article

REFERENCES

  1. Top of page
  2. Abstract
  3. EGFR Structure and Function
  4. EGFR in Malignancy
  5. MoAbs that Target the EGFR
  6. TKIs
  7. The Economics of Targeted Therapy
  8. DISCUSSION
  9. Acknowledgements
  10. REFERENCES
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