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Status of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer

John Mendelsohn, Jose Baselga

From the University of Texas M.D. Anderson Cancer Center, Houston, TX; and Vall d’Hebron University Hospital, Universidad Autonoma, Barcelona, Spain.

Address reprint requests to John Mendelsohn, MD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030-4009; email: jmendelsohn{at}mdanderson.org.

	ABSTRACT

TOP ABSTRACT EPIDERMAL GROWTH FACTOR (EGF)... ANTI-EGFR STRATEGIES AND... CLINICAL DEVELOPMENT OF ANTI... LOW-MW EGFR TYROSINE KINASE... CHALLENGES IN THE DEVELOPMENT... REFERENCES

 
The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor of the ErbB family that is abnormally activated in many epithelial tumors. Receptor activation leads to recruitment and phosphorylation of several downstream intracellular substrates, leading to mitogenic signaling and other tumor-promoting cellular activities. In human tumors, receptor overexpression correlates with a more aggressive clinical course. Taken together, these observations indicate that the EGFR is a promising target for cancer therapy. Monoclonal antibodies directed at the ligand-binding extracellular domain and low–molecular weight inhibitors of the receptor’s tyrosine kinase are currently in advanced stages of clinical development. These agents prevent ligand-induced receptor activation and downstream signaling, which results in cell cycle arrest, promotion of apoptosis, and inhibition of angiogenesis. They also enhance the antitumor effects of chemotherapy and radiation therapy. In patients, anti-EGFR agents can be given safely at doses that fully inhibit receptor signaling, and single-agent activity has been observed against a variety of tumor types, including colon carcinoma, non–small-cell lung cancer, head and neck cancer, ovarian carcinoma, and renal cell carcinoma. Although antitumor activity is significant, responses have been seen in only a minority of the patients treated. In some clinical trials, anti-EGFR agents enhanced the effects of conventional chemotherapy and radiation therapy. Ongoing research efforts are directed at the selection of patients with EGFR-dependent tumors, identification of the differences among the various classes of agents, and new clinical development strategies.

	EPIDERMAL GROWTH FACTOR (EGF) RECEPTOR AS A TARGET FOR CANCER THERAPY

TOP ABSTRACT EPIDERMAL GROWTH FACTOR (EGF)... ANTI-EGFR STRATEGIES AND... CLINICAL DEVELOPMENT OF ANTI... LOW-MW EGFR TYROSINE KINASE... CHALLENGES IN THE DEVELOPMENT... REFERENCES

 
The EGF receptor (EGFR) was the first receptor identified of a family of receptors known as the type I receptor tyrosine kinases, or ErbB receptors. This receptor family is comprised of the following four related receptors: the EGFR itself (ErbB1/EGFR/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4).^1–3 These receptors trigger downstream signaling pathways that are not linear but consist of a rich multilayered network, which allows for horizontal interactions and permits multiple combinatorial responses that may explain the specificity of cellular outcomes to receptor activation. Deregulation of these tightly regulated ErbB receptor signaling pathways can lead to malignant transformation.

To summarize our understanding of EGFR signaling, it may be useful to first dissect the process into sequential levels starting at the cell surface, then move into intracellular-signaling pathways that lead to gene transcription and alteration in molecular activities, and finally, end with in a variety of cellular responses.¹

The cell surface is where the initial ligand-receptor and receptor-receptor interactions occur. ErbB receptors are composed of an extracellular ligand-binding domain, a transmembrane segment, and an intracellular protein tyrosine kinase domain with a regulatory carboxyl terminal segment. ErbB receptors become activated by several mechanisms. Under physiologic conditions, a variety of EGFR family ligands drive the formation of homo- or heterodimeric complexes among the four ErbB receptors, which provides for signal amplification and diversification (Fig 1).¹ In tumor cells, these receptors can be activated by additional mechanisms. First, receptor overexpression in the tumor may lead to ligand-independent receptor dimerization. In some tumors, such as in glioblastoma, mutant forms of the EGFR that arise from gene rearrangements result in ligand-independent constitutive receptor activation and impaired receptor downregulation.⁴ Heterologous ligand-dependent mechanisms are also at play as demonstrated by the finding that stimulation of G-protein–coupled receptors results in EGFR activation via metalloproteinase-mediated cleavage of precursor membrane-bound EGF ligands.⁵ Recently, a ligand-independent mechanism of EGFR activation via the urokinase plasminogen receptor has been identified.⁶ These findings indicate that tumor cells may have additional EGFR activation mechanisms beyond receptor overexpression, mutations, and autocrine ligand production.

View larger version (71K): [in this window] [in a new window]   Fig 1. Mechanisms of receptor activation. Epidermal growth factor receptors and members of the receptor family (HER2/3/4) become activated by dimerization. The mechanisms that promote the formation of receptor dimers include ligand binding, receptor overexpression, and transactivation (heterodimerization). After receptor dimerization, activation of the intrinsic protein tyrosine kinase activity occurs, resulting in tyrosine autophosphorylation. These events result in the recruitment and phosphorylation of several intracellular substrates, leading to mitogenic signaling and other cellular activities.

View larger version (101K): [in this window] [in a new window]   Fig 2. Epidermal growth factor receptor signaling. The process of ligand-receptor and receptor-receptor interaction leads to activation of key intracellular-signaling pathways that regulate gene transcription, cell cycle progression, and a variety of cellular responses that promote malignant behaviors.15

Second, evidence has accumulated that increased EGFR expression correlates with a poorer clinical outcome in a number of malignancies, including bladder, breast, lung, and head and neck cancers.^15,17,19 Third, increased receptor content is often associated with increased production of ligands, such as transforming growth factor alpha, by the same tumor cells.^16,19,20 This establishes conditions conducive to receptor activation by an autocrine stimulatory pathway.

In early studies, monoclonal antibodies (MAbs) directed at the EGFR that blocked ligand binding to the receptor were shown to inhibit the growth of cancer cells bearing high receptor levels, both in culture and in nude mouse xenografts.^12–14 These observations were confirmed with other anti-EGFR MAbs.^21,22

	ANTI-EGFR STRATEGIES AND MECHANISMS OF ACTION

TOP ABSTRACT EPIDERMAL GROWTH FACTOR (EGF)... ANTI-EGFR STRATEGIES AND... CLINICAL DEVELOPMENT OF ANTI... LOW-MW EGFR TYROSINE KINASE... CHALLENGES IN THE DEVELOPMENT... REFERENCES

 
There are several potential strategies for targeting the EGFR, including MAbs that interfere with receptor signaling; MAbs serving as carriers of radionuclides, toxins, or prodrugs;²³ low–molecular weight (MW) tyrosine kinase inhibitors that interfere with receptor signaling; antisense oligonucleotides or ribozymes that block receptor translation;^24,25 and prevention of receptor trafficking to the cell surface with intracellular single-chain Fv fragments of antibodies.²⁶ Of these approaches, MAbs and the low-MW tyrosine kinase inhibitors are in the most advanced stages of clinical development and will be reviewed in detail.

The antibodies in clinical trials bind to the easily accessible extracellular domain of the receptor and compete with the ligand binding to the receptor. For example, the murine MAb 225 and its chimeric human:murine derivative cetuximab (IMC-C225, Erbitux ImClone Systems Inc, New York, NY) bind to the EGF receptor with high affinity (Kd = 0.39 nmol/L for cetuximab), compete with ligand binding, and block activation of receptor tyrosine kinase by EGF or transforming growth factor alpha.^12,13,27 In addition, MAb 225/cetuximab induces antibody-mediated receptor dimerization, resulting in receptor downregulation, and this effect may be important for its growth-inhibitory capacity.²⁸ The low-MW inhibitors, however, compete with ATP for binding to the tyrosine kinase portion of the receptor and, thereby, abrogate the receptor’s catalytic activity. Some of these small molecules can induce formation of inactive EGFR homodimers and EGFR/HER2 (ErbB1/ErbB2) heterodimers,^29,30 which impair EGFR-mediated transactivation of the potent ErbB2 tyrosine kinase. In addition, because of the more than 80% homology in the kinase domain between the EGFR (ErbB1) and HER2 (ErbB2),³ some ATP-competitive low-MW inhibitory molecules can block the catalytic activity of both receptors.³¹ These small molecules are also able to block the catalytic activity of EGFR mutants lacking the extracellular binding domain³² and should be able to prevent ligand-independent activation of EGFR kinase activity as well.

At the level of downstream receptor-dependent signaling pathways, EGFR antibodies and low-MW ATP-competitive inhibitors of the EGFR kinase seem to have similar effects. Both strategies result in an efficient blockade of the main EGFR signal transduction pathways, including the MAPK and PI3K/Akt pathways^33–38 and the Jak/Stat pathway (Fig 3).³⁹

View larger version (70K): [in this window] [in a new window]   Fig 3. Inhibition of signaling pathways by anti–epidermal growth factor receptor (EGFR) therapies. (A) In unperturbed conditions, major signaling routes of the activated EGFR consist of the Ras-Raf-MAP-kinase pathway and the phosphatidylinositol 3-kinase (PI3K) and its downstream protein-serine/threonine kinase Akt pathway. (B and C) Signal transduction via these pathways is efficiently blocked by anti-EGFR therapies as shown here in cultures of A431 cells treated with the EGFR tyrosine kinase inhibitor gefinitib (adapted from Albanell et al34).

1. Cell-cycle arrest.
Initial experiments with MAb 225 demonstrated that the antibody induces G1 phase arrest because of elevated levels of the cyclin-dependent kinase 2 inhibitor p27^KIP1, which results in hypophosphorylation of Rb protein.^40,41 Similarly, low-MW tyrosine kinase inhibitors of the EGFR induce an accumulation of p27^KIP1 and of hypophosphorylated Rb protein that leads to a G1 arrest.^33,42,43

2. Potentiation of apoptosis.
In some cases, G1 arrest is followed by apoptosis.⁴⁴ In DiFi colon carcinoma cells, this can be attributed to the induction of Bax and activation of caspase 8.^45,46 Activation of other proapoptotic molecules has also been reported.

3. Inhibition of angiogenesis.
Blockade of EGFR activation by cetuximab and by low-MW tyrosine kinase inhibitors results in a significant decrease in tumor-cell production of angiogenic growth factors such as basic fibroblast growth factor, vascular endothelial growth factor, and interleukin-8.^47–50 The decrease in angiogenic growth factors, in turn, correlates with a significant decrease in microvessel density and an increase in apoptotic endothelial cells in human tumor xenografts.

4. Inhibition of tumor-cell invasion and metastasis.
Cetuximab inhibits lung metastasis in mice with established human tumor xenografts.⁴⁹ Cetuximab and similar monoclonal antibodies directed against the EGFR have also been shown to inhibit the expression and activity of several matrix metalloproteinases (MMPs) that play a key role in tumor-cell adhesion, including the gelatinase MMP-9. Several studies have correlated this antibody-mediated decrease in MMP production with both a significant reduction in in vitro tumor-cell invasion and the inhibition of tumor growth and metastasis in nude mice.^48,51–53 The inhibitory effects on invasion, metastasis, and angiogenesis may explain why anti-EGFR treatment is often more effective in vivo than in cell culture.

5. Augmentation of the antitumor effects of chemotherapy and radiation therapy.
Based on an initial observation that an anti-EGFR antibody had the capacity to enhance the antitumor activity of cisplatin in a human tumor xenograft model,²² extensive studies of human tumor-cell xenografts were conducted with MAb 225 and cetuximab. The experiments demonstrated that these MAbs markedly augment the antitumor effects of different classes of chemotherapeutic agents, including cisplatin, doxorubicin, paclitaxel, and topotecan.^54–57 Subsequent studies demonstrated that the low-MW EGFR tyrosine kinase inhibitors enhance the antitumor activity of conventional chemotherapeutic agents, both in cell culture and in human tumor xenografts.^58,59 Similar findings are observed when MAbs and low-MW agents are given in combination with radiation therapy.^60,61

There is, however, evidence that the mechanisms of action and the antitumor effects of MAbs and the low-MW tyrosine kinase inhibitors are not completely overlapping. Anti-EGFR MAbs,²⁸ but not the low-MW tyrosine kinase inhibitors,³⁵ have the capacity to form receptor-containing complexes that result in receptor internalization, an important mechanism for attenuating receptor signaling. In addition, cetuximab can elicit antibody-dependent cellular cytotoxicity,⁶² an antitumor mechanism that also could be important for the action of the anti-ErbB2 MAb, trastuzumab.⁶³ In contrast, the inhibition of more than one ErbB receptor type is unique to the low-MW tyrosine kinase inhibitors. Therefore, it is not surprising that, in studies with cultured cancer cells maximally inhibited by low-MW EGFR tyrosine kinase inhibitors, the addition of anti-EGFR MAbs can result in further antitumor activity.⁶⁴ This finding sets the stage for combining anti-EGFR MAbs and low-MW tyrosine kinase inhibitors in the clinic.

	CLINICAL DEVELOPMENT OF ANTI-EGFR MONOCLONAL ANTIBODIES

TOP ABSTRACT EPIDERMAL GROWTH FACTOR (EGF)... ANTI-EGFR STRATEGIES AND... CLINICAL DEVELOPMENT OF ANTI... LOW-MW EGFR TYROSINE KINASE... CHALLENGES IN THE DEVELOPMENT... REFERENCES

 
Among available anti-EGFR MAbs (Table 1), the one furthest ahead in clinical development is the chimeric human:murine MAb cetuximab. Cetuximab is a potent inhibitor of the growth of cultured cancer cells that have an active autocrine EGFR loop and is capable of inducing complete regressions of well-established human tumor xenografts overexpressing EGFR.⁶⁵

After an initial clinical observation that the addition of cetuximab to irinotecan induced responses in patients with advanced colorectal carcinoma who had been treated with irinotecan,⁷⁰ a phase II study was performed with patients who had advanced colorectal carcinoma and progression on irinotecan treatment. In this study, 120 patients were continued on the same dose and schedule of irinotecan, and cetuximab was added on a full-dose weekly schedule (Tables 2 and 3). The combination was found to be safe, and the response rate was 22.5%, with a median duration of response of 186 days.⁷¹ A retrospective analysis of this study has revealed an interesting correlation between the occurrence of skin rash and greater response rate.⁷²

A critical interpretation of the results of these phase II studies of cetuximab in combination with chemotherapy raises some points for discussion. First, were the patients that responded to cetuximab and irinotecan in the colorectal carcinoma study or to cetuximab plus cisplatin in the head and neck cancer studies truly refractory to the chemotherapy? In the design of the phase II colorectal trial, a minimum number of cycles of irinotecan before adding cetuximab to irinotecan was not required. However, in the larger head and neck study, patients were required to have documented progression after having received at least two cycles of platinum-based therapy before cetuximab was added to the platinum regimen.⁷¹

Second, even if the patients were chemotherapy refractory, the observed antitumor activity with cetuximab could be the result of several possibilities: cetuximab may have antitumor activity as a single agent, cetuximab may revert chemotherapy resistance, or both effects may be occurring. A follow-up phase II study has demonstrated an 11% response rate with cetuximab as single-agent therapy in advanced refractory colorectal carcinomas, so the first possibility has been addressed.⁷⁵ The second possibility will be answered by a prospective European study in which patients refractory to irinotecan are randomly assigned to receive cetuximab as a single agent or cetuximab plus irinotecan at the same dose and schedule on which they had progressed.

Additional studies with cetuximab have been conducted. A small phase III study in head and neck tumors comparing cisplatin and placebo with cisplatin and cetuximab showed a more than doubling of the response rate but only a modest and nonsignificant improvement in time to disease progression in the cetuximab arm.⁷⁶ Responses to chemotherapeutic agents administered in combination with cetuximab were observed in phase II studies of gemcitabine in patients with advanced pancreatic carcinoma⁷⁷ and docetaxel in advanced non–small-cell lung cancer (NSCLC).⁷⁸ Cetuximab can also be administered safely in patients with head and neck cancer when given in combination with radiation therapy, with 13 complete responses and two partial responses in 16 patients.⁷⁹ A phase III study of radiation with or without cetuximab in patients with advanced head and neck tumors has recently completed accrual.

Other anti-EGFR MAbs that have a similar mechanism of action to cetuximab are currently under clinical investigation. ABX-EGF (Abgenics; San Francisco, CA) is a fully human immunoglobulin-G2 anti-EGFR MAb that binds with high affinity (Kd = 50 pM), inhibits ligand-dependent receptor activation, and effectively inhibits the growth of human tumor xenografts.⁸⁰ In a phase II study of ABX-EGF in advanced renal cell carcinoma, 31 patients whose treatment had failed or who were unable to receive interleukin-2/interferon alfa completed one 8-week cycle of ABX-EGF and were assessable for response. Objective responses were seen in two patients.⁸¹

EMD 72000 is a humanized anti-EGFR monoclonal antibody that also prevents ligand-induced receptor activation and is currently in phase I studies.⁸² This antibody has a prolonged half-life that may allow for a less frequent administration schedule than the other antibodies, which are given on a weekly basis. In an ongoing trial, preliminary efficacy and pharmacodynamic data indicate that a more convenient schedule of administration of every 2 to 3 weeks may actually be feasible with EMD 72000.⁸³ Antibody h-R3 is another anti-EGFR monoclonal antibody that has entered clinical trials.⁸⁴ The safety profile of all of these antibodies has been good, and not surprisingly, acneiform skin rashes are the most frequent side effect.

Bispecific MAbs against the EGFR are also being studied as potential therapeutic tools. These antibodies have two differing antigen-binding arms and, therefore, dual specificity. One arm is specific for EGFRs, whereas the other arm binds to an immunologic effector cell. The result is an antibody that binds to EGFRs and concomitantly enhances the host’s antitumor cellular immune response. Data have been published on three bispecific antibodies. M26.1 F(ab')2, which targets EGFRs and CD3, reduces tumor-cell growth when coated with human lymphocytes.⁸⁵ MDX-447 targets EGFRs and CD64 (immunoglobulin-G receptor), and preliminary data from an ongoing phase I/II trial show immunologic activity, good tolerability, and some biologic response in treatment-refractory patients.^86,87 H22-EGF, which targets EGFRs and CD64, reduces tumor-cell growth and enhances immunologically mediated cellular cytotoxicity in preclinical studies.⁸⁸

	LOW-MW EGFR TYROSINE KINASE INHIBITORS

TOP ABSTRACT EPIDERMAL GROWTH FACTOR (EGF)... ANTI-EGFR STRATEGIES AND... CLINICAL DEVELOPMENT OF ANTI... LOW-MW EGFR TYROSINE KINASE... CHALLENGES IN THE DEVELOPMENT... REFERENCES

 
There are a large number of low-MW inhibitors of EGFR tyrosine kinase that are under clinical development (Table 4). In an attempt to classify these antireceptor agents, we have grouped them by their degree of receptor specificity (restricted to the EGFR or also inhibiting other ErbB kinases) and by their reversibility or irreversibility of action.

Phase I studies have demonstrated that daily administration of gefinitib is safe, with dose-dependent pharmacokinetics but with a high degree of interpatient variability.^91–93 The most common side effects were an acneiform skin rash, generally mild and reversible on cessation of treatment, and diarrhea. In these early studies, the effects of gefinitib on EGFR activation and receptor-dependent events in the skin, an EGFR-dependent tissue, were analyzed.⁹⁴ Gefinitib significantly suppressed EGFR phosphorylation, inhibited MAPK activation, reduced keratinocyte proliferation, and increased p27^KIP1 levels and apoptosis. Marked reduction in EGFR phosphorylation was observed at doses well below the doses that produce unacceptable gastrointestinal toxicity, a finding that strongly supports the use of an optimal biologic dose instead of the maximally tolerated dose for these types of agents. Clinical responses were observed in patients with NSCLC.^91–93

Phase II studies with two dose levels of gefinitib (250 and 500 mg/d) have now been completed in patients with NSCLC who had progressed after first- or second-line chemotherapy for advanced disease. The first study was conducted in 210 patients previously treated with one or two chemotherapy regimens and showed an 18.7% response rate and marked improvement in disease-related symptoms (Table 5).⁹⁵ Interestingly, the 250-mg/d dose was as active as the 500-mg/d dose and had a lower frequency of adverse events. In the second study of 216 patients for whom at least two prior chemotherapy regimens had failed, tumor response rates of 11.8% and 8.8% were observed for the 250 and 500 mg/d groups, respectively.⁹⁶ The results of these trials have led to the regulatory approval of gefinitib in Japan for NSCLC.

Single-agent phase II studies with gefinitib have also been conducted or are ongoing in other tumor types, including head and neck, colon, prostate, gastric, and breast cancers. In tumors of the head and neck, a phase II study has shown an 11% response rate.¹⁰¹ A study in patients with previously treated colorectal carcinoma who were administered gefinitib at a (high) dose of 750 mg has recently been reported. Although some evidence of antitumor and biologic activity was observed, there were no documented responses.¹⁰² In a study in hormone refractory prostate cancer, patients were randomly assigned to receive either gefinitib at 250 or 500 mg/d.¹⁰³ A total of 40 patients were treated; no objective or prostate-specific antigen responses were seen, and nine patients or more had a best response of treatment failure, meeting the protocol criteria for stopping the study.

On May 5, 2003, the FDA approved gefitinib 250 mg/d as monotherapy treatment for patients with locally advanced or metastatic NSCLC after failure of both platinum-based and docetaxel chemotherapies. The drug was not recommended for use in combination with chemotherapy. The basis for approval was a randomized study on patients who had experienced treatment failure with both chemotherapeutic agents, which compared placebo, 250 mg/d and 500 mg/d. Partial response occurred in 15 of 142 assessable patients, for a response rate of 10.6% (95% confidence interval, 6.0%-16.8%), and the median duration of response was 7.0 months (range, 4.6 to 18.6+ months). The higher dose did not improve the response rate and casued increased toxicity. It was noted that interstitial lung disease had occurred at an overall incidence of 1% in patients receiving gefitinib, and approximately one third of the cases were fatal, with higher rates in Japan than in the United States. This information is from the package insert provided by the company.

Erlonitib (OSI-774, formerly known as CP-358, 774, Tarceva; Genentech, San Francisco, CA) is an orally-available quinazoline that is a selective inhibitor of EGFR. A phase I study with increasing daily doses of erlonitib demonstrated that the maximum-tolerated dose was 150 mg/d. At this recommended dose level, erlonitib resulted in a steady-state serum concentration higher than the concentration required to achieve full receptor inhibition in preclinical models. Similar to gefinitib, erlonitib inhibited EGFR-dependent processes in skin and tumor biopsies.¹⁰⁴ Clinical responses were seen in phase II studies conducted in patients with NSCLC, head and neck tumors, and ovarian carcinoma (Table 4).^105–107 In NSCLC, 57 patients who had histologically documented stage IIIB/IV EGFR-positive disease and who had failed prior systemic therapy were treated with erlonitib at a dose of 150 mg/d. There were two complete remissions and five partial remissions, for an overall response rate of 12%. In addition, the median survival time in that study was of 9.3 months, and the 1-year survival rate was an impressive 40%.¹⁰⁵ Ongoing trials in NSCLC include phase III first-line combination therapy in stage IIIB/IV NSCLC and phase III studies in refractory NSCLC. In addition, there is an ongoing 700-patient phase III study in refractory NSCLC being conducted by the National Cancer Institute of Canada in which patients are being randomly assigned to receive erlonitib versus placebo, with survival as the primary end point.

In ovarian carcinoma, 34 patients were treated with erlonitib, and two patients had a confirmed response (overall response rate, 6%), two patients had unconfirmed responses, and 14 patients had stable disease for more than 2 months.¹⁰⁶ In a multicenter head and neck cancer trial, 124 patients with locally recurrent or metastatic disease who had been previously treated were given erlonitib at the recommended dose of 150 mg/d. Six patients had confirmed responses, for an overall response rate of 5%.¹⁰⁷ In a phase II ongoing study in colorectal carcinoma, no clinical responses have been reported to date.¹⁰⁸ At present, phase II studies with erlonitib are underway in other tumor types, including breast cancer, and phase IB studies are exploring the feasibility of combining erlonitib with a variety of conventional chemotherapeutic agents.

Class 2: Irreversible EGFR-Specific Tyrosine Kinase Inhibitors
This class is represented by EKB-569, an EGFR tyrosine kinase inhibitor that binds irreversibly to EGFR and has an IC₅₀ of 38.5 nmol/L in vitro.¹⁰⁹ To demonstrate that EKB-569 bound covalently to EGFR, ¹⁴C-labeled EKB-569 was synthesized and incubated with cellular membranes from cell lines expressing the receptor, the reaction was terminated under reducing conditions, and continued binding of labeled EKB-569 to the EGFR was observed. EKB-569 exerts far less inhibition of the tyrosine kinase activities of other members of the EGFR family, displaying an IC₅₀ 30 times higher for HER2 than for EGFR. In the A431 human tumor xenograft model, a single dose of EKB-569 resulted in a 50% inhibition of receptor phosphorylation at 24 hours despite a serum half-life of 2 hours, a finding consistent with its reported irreversibility.¹⁰⁹ In an initial phase I study EKB-569 has been reported to be safe both on an intermittent and a continuous-dose schedule.¹¹⁰ The observed side effects were skin rashes and diarrhea, which are very similar to the side effects observed with other compounds of this type.

Class 3: Reversible PAN-HER (human EGF receptor family) Tyrosine Kinase Inhibitors
In those situations where coexpression of the EGFR (ErbB1) and the HER2 (ErbB2) occurs,¹⁶ an inhibitor that simultaneously targets both receptors may have therapeutic advantages. GW2016, currently under clinical development, inhibits the kinase activity of the two receptors with an IC₅₀ of 10 nmol/L for EGFR and an IC₅₀ of 9 nmol/L for HER2. However, GW2016 does not inhibit HER4 well, with an IC₅₀ that is more than 30-fold higher.^111,112

A relevant question is whether a dual inhibitor may have greater efficacy than a receptor-specific tyrosine kinase inhibitor, taking into consideration the observation that EGFR-specific tyrosine kinase inhibitors can prevent activation of HER2 in vivo (see previous). If these agents directly target HER2 in addition to EGFRs, then they could have an improved activity profile in tumors, such as breast cancer, that are HER2-dependent. However, this improved activity could also be at the cost of additional toxicities.

Class 4: Irreversible EGFR Family Tyrosine Kinase Inhibitors
CI-1033 is a 4-anilinoquinazoline that irreversibly inhibits in vitro the three catalytically active members of the EGFR family: EGFR, HER2, and HER4. Irreversibility is achieved by virtue of the compound’s ability to covalently modify a specific cysteine residue in the ATP binding site of these receptors (cys-773).¹¹³ CI-1033 is currently under phase I evaluation.¹¹⁴ Reported adverse events include an acneiform rash, diarrhea, thrombocytopenia, and one episode of a reversible hypersensitivity reaction. One clinical response was observed in a patient with advanced squamous cell carcinoma.¹¹⁴

At the present time, it is not known whether these different classes of oral low-MW receptor tyrosine kinase inhibitors and the different compounds within the classes will have different activities and/or toxicity profiles. It also is not known whether irreversibility of action will be advantageous in the clinic. Because these agents are given orally on a daily basis, the point can be made that irreversible inhibitors of phosphorylation could produce more substantial receptor inhibition. However, the comparative effects of irreversible and reversible inhibitors on receptor degradation and synthesis and on cell biology are unknown.

	CHALLENGES IN THE DEVELOPMENT OF ANTI-EGFR AGENTS

TOP ABSTRACT EPIDERMAL GROWTH FACTOR (EGF)... ANTI-EGFR STRATEGIES AND... CLINICAL DEVELOPMENT OF ANTI... LOW-MW EGFR TYROSINE KINASE... CHALLENGES IN THE DEVELOPMENT... REFERENCES

 
The finding that anti-EGFR agents have clinical antitumor activity and a low toxicity has validated the EGFR as a target for cancer therapy. However, there is clearly a need to optimize the utilization of these agents because their single-agent activity is modest, the results of phase II combination studies with conventional chemotherapy have varied, and two large phase III trials combining one of these agents with chemotherapy in NSCLC showed no improvement in response over chemotherapy alone. Challenges include how to improve patient selection, identification of the differences among the various classes of agents, a reassessment of the predictive value of the currently used preclinical models, and new study designs.

Patient Selection
The clinical activity of these agents has been observed mostly in unselected patient populations with various types of cancer. The majority of the studies have merely required EGFRs to be present in the tumor or have not preselected at all for receptor expression. The level of EGFR expression required in the tumor to obtain clinical benefit from these therapies remains unknown at the present time. Furthermore, it is possible that, in some cancer cells, regardless of the level of EGFR expression, the critical downstream signals may be activated via other receptors, such as insulin-like growth factor 1 or G-protein–coupled receptors, or by other pathways.^5,6,115

Although it may be tempting to establish a parallel between anti-EGFR agents and the anti-HER2 MAb trastuzumab (Herceptin; Genentech), which has activity only on cells displaying high expression of the HER2 target, the biology of EGFR is quite different from HER2. EGFR has a series of well-known ligands, and ligand binding to the receptor triggers both homo- and heterodimer formation. In contrast, HER2 is a ligand-less receptor. Its activation requires heterodimerization with another receptor in the family or spontaneous homodimerization because of the high levels of receptor overexpression. In addition, the data with cetuximab in colorectal carcinoma show that response rates were comparable in patients expressing 1+, 2+, or 3+ levels of EGFR.⁷¹ The same holds true in patients with head and neck carcinomas, with similar response rates to cetuximab in patients with tumors expressing different levels of EGFR.⁷⁴ No data are available in patients treated with low-MW inhibitors of EGFR, but in cell lines, there is not a linear correlation between EGFR expression and response to tyrosine kinase inhibitors,⁵⁸ as opposed to the linear relationship between receptor number and growth inhibition in breast cancer cell lines treated with trastuzumab.¹¹⁶

It is likely that factors other than high receptor number determine whether a particular tumor will be responsive to antireceptor therapy, based on its dependence on the EGFR pathway to drive its proliferation and function. Therefore, it will be critical in future clinical trials to analyze not only the level of EGFR expression in the tumor but also the level of expression of its ligands, such as transforming growth factor-alpha or EGF, which are required for the maintenance of an active EGFR autocrine loop. In addition, the expression levels of the other members of the same receptor family and the expression levels and levels of tyrosine phosphorylation of EGFRs and downstream molecules, such as MAPK, PI3K, Akt, p27, and Stat3, should be measured. The results can be correlated with clinical susceptibility to the antireceptor therapy to identify markers that can predict tumors potentially sensitive to these agents. In cell culture, inhibition of phosphorylation of EGFR and MAPK is necessary but may not be sufficient for cell growth inhibition; cell lines, such as MDA-468, that have a mutant PTEN phosphatase and a high basal level of phosphorylated Akt are more resistant to tyrosine kinase inhibitors.³⁵

To date, only limited data are available from clinical trials assessing the levels and phosphorylation status of molecules in these signaling pathways. In a phase I study of EMD 72000 in patients with advanced colorectal carcinoma, inhibition of EGFR phosphorylation was observed in all tumors, irrespective of response. In one responding tumor, for which biopsies before and after therapy are available, the level of basally phosphorylated Akt was low and disappeared completely with treatment with EMD 72000. On the contrary, progressing tumors had higher basal phosphorylated Akt, and this did not decrease with treatment.⁸³ In preliminary data from a phase II study of gefinitib in breast cancer, only patients that had low levels of phosphorylated Akt had a decrease in the proliferation marker Ki-67 (J. Baselga, personal communication).

The latter studies exemplify an approach that may enable the physician to clearly identify which patient cancers are susceptible to EGFR inhibitors. This will require repeated biopsies for assays of levels and phosphorylation status of molecules in signaling pathways, both before treatment and after initiation of treatment. In addition, measurement of KI-67 levels and apoptosis levels could be used to document inhibition of cell proliferation and induction of cell death, which are likely predictors of susceptibility to EGFR inhibition and, therefore, may prove to be early markers predicting clinical response.

Validation of this approach to selecting appropriate patients for anti-EGFR treatment will necessitate collection of a great deal of data on tissue biopsies and clinical responses, and this will require substantial financial support from sponsors of clinical trials. However, this may be the necessary and most cost efficient way to determine the proper utilization of agents such as these, which have produced significant clinical benefit in a minority of unselected patients in recent clinical trials.

Furthermore, taking into consideration the vast complexity of the EGFR signaling network, instead of limiting the search to these known downstream potential markers, it may be necessary to analyze larger arrays of gene and protein expression levels, both at baseline and after initiation of therapy. Such an approach will also require the performance of repeated tumor biopsies in patients participating in these trials. New technologies, including gene-expression profiling in archived paraffin-embedded tumors, may allow for easier prospective and retrospective correlations with clinical benefit.

Differences Among the Various Classes of Agents
Emerging data from the clinic indicate that, although these agents target the same receptor, they may have different activity profiles. Although an acneiform rash is seen in patients treated with each anti-EGFR agent, gastrointestinal toxicity is limited to the oral, low-MW tyrosine kinase inhibitors. Interestingly, differences in activity may be tumor-dependent. In advanced colorectal cancer, consistent single-agent activity has been observed with the MAbs cetuximab and EMD 72000,^75,82,83 whereas the tyrosine kinase inhibitors gefinitib and erlonitib have been shown to be inactive to date.^102,108 Likewise, antitumor activity has been reported in renal cell carcinoma with the MAb ABX-EGF⁸¹ but not with cetuximab and gefinitib. However, in head and neck tumors, activity has been reported with the MAb cetuximab^73,74 and with the tyrosine kinase inhibitors erlonitib and gefinitib.^101,107

The implication of these findings is that different agents (or classes of agents) may have to be tested separately in individual tumor types. This differential activity profile could also be an indication that these agents do not have completely overlapping mechanisms of action, and it provides a rationale for studying, in the clinic, combined treatment with different anti-EGFR compounds such as tyrosine kinase inhibitors and MAbs. In support of this approach, preclinical studies with a panel of cell lines have shown that once maximal growth inhibition is achieved with one type of agent (MAbs or tyrosine kinase inhibitors), the addition of the other agent results in additional antiproliferative effects.⁶⁴ Some of the known differences between low-MW tyrosine kinase inhibitors and mAbs that could account for the different responses seen in the clinic are listed in Table 6.

The interpretation of preclinical data becomes more complex in combination studies with chemotherapy. Although several combinations of anti-EGFR agents with chemotherapy demonstrate additive or synergistic interactions in xenograft models, this may not translate to similar effects in the clinic. This point is well exemplified by the recent negative outcome of two large phase III studies of chemotherapy with or without gefinitib in patients with advanced chemotherapy-naïve NSCLC, despite the existence of preclinical data demonstrating additive effects. There could be many explanations for this apparent lack of concordance between the laboratory and the clinic. It is possible that, to predict an effect in the clinic, there must be true synergy in the preclinical models, as in the preclinical studies with cetuximab and cisplatin⁵⁵ or trastuzumab and paclitaxel¹¹⁸ in which a complete and sustained eradication of well-established xenografts was obtained. Another potential and likely explanation is that the permanent cancer cell lines that are being used in cell culture and xenograft models may be too distant from, and therefore not predictive of, the behavior of primary human tumor cells.

New Study Designs
The implication of the disparity between preclinical and clinical results is that new models resembling more closely the clinical reality are needed for testing these types of anticancer agents. In fact, effective and proven preclinical models do not exist today, despite years of effort. Therefore, it may become necessary to redefine the scope and goals of phase I/II clinical trials with anti-EGFR agents. Once safety is determined, the pharmacologic and pharmacokinetic studies that are the hallmark of these types of trials must be combined with pharmacodynamic studies in each patient, examining effects on the molecular targets and the downstream pathways felt to be most relevant to documenting clinical activity. The importance of these targets and pathways as surrogate markers has been discussed. If such studies can identify likely responders to anti-EGFR therapy, they could greatly reduce the number of negative phase III trials, which involve large patient numbers and consume huge financial resources. This is the true meaning of tailored therapy that targets the individual patient. Other approaches to combining chemotherapy and antireceptor agents must also be explored, such as sequential administration, which is typical in the administration of chemotherapy followed by hormonal therapy for the treatment of breast cancer.

In summary, future research efforts will have to be directed at identifying more efficient and effective ways of differentiating these agents from each other, integrating these agents with conventional treatments, and finding ways of better predicting whether prolongation of life for an individual patient will be achieved. However, we submit that the largest and most important challenge has already been positively resolved; a series of advanced cancers have demonstrated objective partial responses to monotherapy with a variety of anti-EGFR agents in some patients. For those patients, anti-EGFR therapy has offered an attractive and relatively nontoxic therapy. If these agents are similar to other anticancer therapies previously studied, it is reasonable to expect that future clinical trials will demonstrate prolongation of life for many in the subset of patients who achieve objective responses and that concurrent or sequential combination treatment with chemotherapy or radiation therapy will increase efficacy.

	NOTES

 
Supported in part by the Spanish Health Ministry grant "Fondo de Investigación Sanitaria" (01/0040–02; J.B).

J.M. is on the Board of Directors of ImClone Systems Inc (New York, NY) and holds stock options.

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Submitted January 22, 2002; accepted April 22, 2003.

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