Epidermal growth factor receptor-targeted treatment for advanced colorectal carcinoma

Authors

  • Alan P. Venook M.D.

    Corresponding author
    1. Department of Medicine, University of California–San Francisco, San Francisco, California
    • Department of Medicine, University of California, San Francisco, 1600 Divisadero, Box 1705, San Francisco, CA 94115
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    • Fax: (415) 353-9959

    • Alan P. Venook is a consultant with Genentech and is a member of the Speakers Bureaus of Sanofi, Roche, Pfizer, and Genentech.


Abstract

Substantial effort has focused on the development of novel targeted agents for treating patients with late-stage colorectal carcinoma. These agents are designed specifically to inhibit biochemical processes associated with pathogenesis. Numerous molecules targeting the epidermal growth factor receptor have been investigated as therapeutic agents and appear to herald a shift in the treatment paradigm for colorectal carcinoma. Cancer 2005. © 2005 American Cancer Society.

Colorectal carcinoma (CRC) is a major cause of morbidity and mortality in most industrialized nations1 and remains among the top three most common malignancies in men and women.2 Pathologic stage is the most reliable prognostic factor for patients with CRC. When it is detected early and is localized to the bowel mucosa, CRC is treatable and generally is curable, with a 93% 5-year survival rate.1 However, the 5-year survival rate decreases to 67% with involvement of adjacent organs or lymph nodes and is only 8% in patients who have widespread, metastatic disease.1, 3 Metastatic disease is present in approximately 20% of patients with CRC at the time of their first diagnosis3 and develops in up to 50% of patients.3, 4 Although increasing numbers of options are available for the treatment of patients with advanced CRC, their long-term prognosis remains poor.

Newer therapeutic options for treating metastatic CRC (mCRC) include oral fluoropyrimidines (e.g., tegafur, capecitabine), irinotecan, oxaliplatin, and targeted biologic therapies.5 Among these, targeted biologic agents have been the subject of intensive, ongoing research.4 Novel agents are being designed specifically to inhibit the biochemical processes of pathogenesis as the molecular basis of carcinogenesis is unraveled gradually. Targets include signal-transduction pathways that regulate growth, survival, cell-cycle regulation, tumor angiogenesis, and metastasis.6 This promising new class of therapies holds the promise of enhanced chemotherapy benefits, prolonged survival, reduced toxicity, and improved quality of life for patients with advanced disease.

The epidermal growth factor receptor (EGFR) and associated signal-transduction pathways have emerged as important molecular therapeutic targets for CRC.7, 8 This article reviews the newer EGFR-targeted biologic agents, which appear to herald a shift in the CRC treatment paradigm.

EGFR IN CRC

EGFR Biology

EGFR (also known as HER [human EGF receptor] and ErbB1) is a glycoprotein composed of an extracellular ligand-binding domain, a transmembrane region, and an intracellular tyrosine kinase domain (Fig. 1).9–11 The receptor is a member of the ErbB family of receptor tyrosine kinases, including ErbB1, ErbB2 (HER-2), ErbB3, and ErbB4, and it is encoded by the c-erbB protooncogene.9–12 EGFR is expressed on normal epithelial, stromal, glial, and smooth muscle cells, and it mediates growth, development, and differentiation.11 EGFR binds to and is activated by numerous ligands, including EGFR, transforming growth factor α (TGF-α), amphiregulin, heparin-binding EGF, the poxvirus mitogens, and betacellulin.13 Ligand binding activates signal transduction through the dimerization of two ErbB receptor family members, affording dimer autophosphorylation (Fig. 1).9, 11, 13 Subsequently, kinase-mediated signaling pathways that involve Ras/mitogen-activated protein kinase, phosphoinositol-3-kinase/Akt, and Janus kinase/signal transducer and activator of transcription are engaged (Fig. 2), activating transcription factors in the cell nucleus.14, 15

Figure 1.

Epidermal growth factor receptor (EGFR) structure, activation, and inhibition strategies in clinical development. 1. Anti-EGFR antibodies target the EGFR extracellular domain. 2. Tyrosine kinase inhibitors (TKIs) target the intracellular receptor tyrosine kinase activity (K). MoAb: monoclonal antibody; P: phosphate.

Figure 2.

This diagram illustrates epidermal growth factor receptor (EGFR) signal transduction. SoS: son of sevenless; GRB2: adapter protein; JAK: Janus kinase; PDK-1: pyruvate dehydrogenase kinase 1; PI3K: phosphoinositol-3-kinase; MEK: mitogen-activated protein kinase kinase; ERK: endoplasmic reticulum kinase; mTOR: mammalian target of rapamycin; NF-κB: neuronal factor κB; HIF-1α: hypoxia-inducible factor 1α; ELK-1: ets-like gene 1; STAT: signal transducers and activators of transcription; VEGF: vascular endothelial growth factor. P: phosphate; FT: farnesyl transferase.

All human epidermal malignancies express EGFR, although expression levels vary.13 Overexpression of EGFR and its ligands in some tumor types makes EGFR a particularly attractive therapeutic target.16 In CRC, expression is significantly higher in malignant colonic mucosa relative to adjacent normal mucosa,17 and 25–77% of CRC tumors express EGFR.13, 18 Dysregulation of the EGFR pathway also is associated with malignancy.19 In addition to increased expression of the receptor and its ligands individually, autocrine or paracrine loops and aberrant downstream signaling are among possible mechanisms that mediate cell cycle progression, resistance to apoptosis, angiogenesis, invasion, and migration.13, 19–22

EGFR expression predicts poor outcome in patients with CRC. mCRC cells express a five-fold increase in EGFR mRNA relative to cells with low metastatic potential.23 Furthermore, coexpression of EGF and EGFR predicts more aggressive disease.24 Patients who had CRC with < 50% EGFR-positive tumor cells showed improved survival compared with patients who had increased EGFR expression (P < 0.01).25

Targeting EGFR in CRC

Numerous strategies for inhibiting EGFR have been investigated, and several have reached clinical testing. Classes of the agents evaluated include monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs), ligand-toxin conjugates, immunoconjugates, and antisense therapies; currently, only TKIs and MoAbs are being studied in the clinic (Fig. 1) (Table 1).

Table 1. Antiepidermal Growth Factor Receptor Approaches in Clinical Developmenta
ClassPhase of development
  • FDA: United States Food and Drug Administration; CRC: colorectal carcinoma; EGF: epidermal growth factor; NSCLC: nonsmall cell lung carcinoma.

  • a

    Data were derived from Sridhar SS, Seymour L, Shepherd FA. Inhibitors of epidermal-growth-factor receptors: a review of clinical research with a focus on non-small-cell lung cancer. Lancet Oncol. 2003;4:397– 406.; and Cohen RB. Epidermal growth factor receptor as a therapeutic target in colorectal cancer. Clin Colorectal Cancer. 2003;2:246–251.

Monoclonal antibody 
 Cetuximab (IMC-C225)Phase II–III (FDA approved for CRC)
 Panitumumab (ABX-EGF)Phase I–II
 EMD 72000Phase I
 hR3Phase I
 MDX-447Phase I
 ICR62Phase I
Tyrosine kinase inhibitors 
 Gefitinib (ZD1839)Phase II–III (FDA approved for NSCLC)
 Erlotinib (OSI-774; CP-358,774)Phase III (FDA approved for NSCLC)
 EKB-569Phase I–II
 Lapatinib (GW572016)Phase I–II

Anti-EGFR MoAbs

General features of therapeutic antibodies

Antibody-based therapeutic agents are the most rapidly expanding class of pharmaceuticals.26 Early therapeutic antibodies originated from mice. To reduce immunogenicity, mouse antibody amino acid sequences must be grafted onto a human antibody scaffold.27 Such engineered MoAbs may be either chimeric or humanized.28 Chimeric and humanized antibodies contain 65–90% and approximately 95% human sequences, respectively.27 Transgenic mice and phage-display technologies now permit the de novo generation of fully human antibodies.26

Therapeutic antibodies may be classified further by antibody isotype. Antibodies of the immunoglobulin G1 (IgG1) or IgG3 isotype26 and murine IgG2a antibodies28 potentially support the immune system effector functions of antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).29 ADCC involves interactions between tumor-bound MoAb and Fcγ receptors on immune cells, such as neutrophils or macrophages, leading to the cell-mediated lysis or phagocytosis of tumor cells. CDC involves binding of a tumor-bound MoAb with complement component C1q, affording cell lysis and the attraction of effector cells.27 In vivo activation of immune effector responses has been demonstrated for the IgG1 antibodies rituximab,30 trastuzumab,30 and cetuximab.31

Various antibodies directed against EGFR are available currently the clinic. These are reviewed in detail below.

Cetuximab

Cetuximab (Erbitux®; ImClone Systems Inc., Princeton, NJ) is a human:murine, chimeric anti-EGFR IgG1 MoAb that is indicated for use in combination with irinotecan for the treatment of patients with mCRC who have EGFR-expressing tumors that are refractory to irinotecan-based therapy or as monotherapy in irinotecan-intolerant patients with mCRC who have EGFR-expressing tumors.32 Mechanisms of action of cetuximab include inhibition of cell cycle progression,33 induction of apoptosis,34, 35 inhibition of angiogenesis,36, 37 and decreased invasion and metastatic spread.38 Cetuximab has been studied in clinical trials as a single agent, in combination with second-line treatment of patients with refractory CRC, and as an addition to front-line combinations such as 5-fluorouracil (5-FU), leucovorin, and oxaliplatin FOLFOX-4.39 Preclinical studies have shown that the antitumor activity of cetuximab is potentiated combined with cisplatin, paclitaxel, doxorubicin, topotecan, gemcitabine, 5-FU, or radiation.40

Although cetuximab is the only EGFR inhibitor that has been approved by the U.S. Food and Drug Administration (FDA) for patients with CRC, its development has been somewhat circuitous. Because of the expectation that many biologics lack efficacy as monotherapy, cetuximab was tested first in combination therapy. An initial observation suggesting that cetuximab had the ability to make irinotecan-resistant patients responsive to irinotecan led to a strategy of adding cetuximab to irinotecan in such patients. Although the benefit of such a strategy was confirmed later, the original study failed to convince the FDA of meaningful efficacy, which led to the succession of clinical trials listed below. Therefore, the activity of cetuximab as monotherapy was demonstrated after its activity in combination was apparent.

Treatment with cetuximab plus irinotecan afforded a 22.5% partial response (PR) rate for a median of 186 days as a second-line agent in patients (n = 120 patients) who had progressive disease and tumors that were refractory to irinotecan and 5-FU. The median survival in those patients was 232 days.41, 42 Single-agent cetuximab afforded a 9% PR rate and 37% stable disease or minor responses in patients with EGFR-expressing tumors (n = 57 patients) who had disease progression on an irinotecan-based regimen.43 The median survival of those patients was 6.4 months. The most frequently reported adverse events (AEs) were acne-like rash and asthenia. Single-agent cetuximab has been compared directly with cetuximab plus irinotecan in patients with EGFR-detectable, irinotecan-refractory mCRC.44 Of 577 patients screened, 474 patients (82.1%) had EGFR-positive tumors, and 329 of those patients met all inclusion criteria and were randomized 2:1 to receive cetuximab plus irinotecan (n = 218 patients) or cetuximab monotherapy (n = 111 patients). Patients who had disease progression on cetuximab monotherapy were allowed to cross over to the cetuximab plus irinotecan arm. Response rates were 17.9% in the combination therapy arm and 10.8% in the monotherapy arm. The median time to disease progression was significantly greater for combination therapy versus monotherapy (4.1 months and 1.5 months, respectively; P < 0.001). The difference in overall survival between the 2 arms was not statistically significant (8.6 months for combination therapy; 6.9 months for monotherapy). However, this result may have been due to the crossover study design: Fifty-six patients in the monotherapy group received additional irinotecan after they had disease progression on cetuximab monotherapy.

In patients with previously untreated mCRC, several studies have evaluated cetuximab added to front-line irinotecan/5-FU/leucovorin (IFL). In a single study, 11 patients (44%) achieved a PR, and 5 patients achieved a minor response.45 The median time to disease progression and the median survival were not reached. Frequently reported AEs were diarrhea, neutropenia, and rash. In another trial, 4 of 13 patients with mCRC achieved a confirmed PR; 1 patient demonstrated stable disease, and information on 7 patients was pending.46 In a European study, 52% of 21 evaluable patients with mCRC achieved a PR, and 43% had stable disease, affording a tumor growth control rate of 95%47 with no unexpected toxicities.

A Phase II study evaluated the activity of single-agent cetuximab in patients with EGFR-detectable mCRC refractory to fluoropyrimidine-based chemotherapy plus irinotecan and in combination with oxaliplatin.48 A total of 248 patients (median age, 59 years; male:female ratio, 55:45 patients; Eastern Cooperative Oncology Group performance status [PS] 0:1, 42:57 patients) were enrolled in that study. Patients were received treatment with cetuximab at standard doses (400 mg/m2 loading dose over 2 hours, then 250 mg/m2 over 1 hour weekly). Commonly encountered AEs were skin rash and fatigue/malaise. One patient experienced a Grade 3 allergic reaction that required discontinuation of study treatment. PRs were observed in 12% of patients. Stable disease was observed in 34% of patients for at least 6 weeks, affording a disease control rate of 46%. Significantly, 9 patients with EGFR-undetectable CRC were enrolled, and 2 of those patients achieved a PR.

Therapeutic antibodies can induce hypersensitivity and other infusion-related reactions. Cetuximab infusion reactions typically are seen after the first dose and may be associated with minor fever, chills, and dyspnea. Hypotension, urticaria, and rapid onset of airway obstruction (Grade 3/4) occur in 3% of patients, although these rarely occur with fatal outcome (< 1 in 1000 episodes). These reactions are considered anaphylactoid and are unlikely to be IgE-mediated. Premedication with an H1 antagonist (e.g., diphenhydramine IV or similar agent) is recommended. Premedication regimens consist of 25–50 mg diphenhydramine HCl but vary with respect to pretreatment interval, administration route, and infusion rate. A suggested regimen consists of 10 mg of liquid cetirizine, 150 mg of ranitidine, and 625 mg of acetaminophen given 30 minutes prior to infusion. Initiating the cetuximab infusion at 2.5 mL per minute for 15 minutes and increasing to a maximum of 5 mL per minute also may be beneficial. There is no evidence to suggest that a test dose (20 mg of cetuximab for 10 minutes) reliably can identify patients who are at risk for severe reactions.

The most common toxicity associated with cetuximab treatment is acneiform rash. Rash occurs in approximately 75% of cetuximab-treated patients and resolves upon discontinuation of treatment. In studies across multiple malignancies, rash intensity predicted increased survival.42, 49 Lack of a maximum tolerated dose for cetuximab and correlation between rash and response suggest the possibility of dose escalation in patients who fail to develop rash at the onset of therapy. Confirming this observation in larger studies and, prospectively, investigating the value of tailoring dosing to maximize efficacy will be required.

Preclinical studies have demonstrated that anti-EGFR agents may have little activity when the level of EGFR expression is below a threshold level.50–52 Consequently, cetuximab is indicated only for the treatment of patients who have tumors that demonstrate EGFR expression,32 typically as determined by immunohistochemical (IHC) assay.53 However, there does not appear to be a relation between EGFR staining intensity and tumor response, and the reported percentages of EGFR-detectable tumors have varied.41, 48 Despite the efforts of the American Joint Committee on Cancer to develop a standardized EGFR IHC detection system54 and the availability of an FDA-approved EGFR test kit,53 grading IHC tests often is ambiguous; and a variety of factors affect the cut-off point for receptor positivity and afford significant variability in interinvestigator scoring.55 It is interesting to note that some patients who were assigned EGFR-nondetectable tumor status had demonstrated benefits from cetuximab therapy.48 Clearly, further study is required.

Several important questions remain regarding the role of cetuximab in the treatment of mCRC. Although cetuximab is approved for the second-line treatment of patients with irinotecan-refractory mCRC, the potential role of this agent in the treatment of patients with disease in earlier stages remains understudied. For example, further evaluation is needed of cetuximab in adjuvant or first-line metastatic settings in combination with various agents, such as oxaliplatin, and in patients with EGFR-negative CRC. To this end, Tabernero et al. recently reported the results of the Phase II ACROBAT trial evaluating the efficacy of full-dose cetuximab combined with full-dose FOLFOX-4 in patients with first-line mCRC.39 An 81% response rate (5% CR, 76% PR) was reported in 42 patients available for analysis. The regimen was well tolerated and warranted testing in a larger group of patients. A Phase III trial (EXPLORE) of FOLFOX plus cetuximab in patients who failed a first-line irinotecan-containing regimen also is under way.56 Particularly promising results have been obtained for cetuximab in the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN).57

Panitumumab

Panitumumab (ABX-EGF; Amgen Inc.) is a fully human IgG2 anti-EGFR MoAb that is in clinical testing for a variety of tumors. ABX-EGF was derived from transgenic mice,50 offering potentially slower clearance than mouse-derived MoAbs.6 In a Phase I study, 43 patients with CRC, renal carcinoma, prostate carcinoma, nonsmall cell lung carcinoma (NSCLC), pancreatic carcinoma, and esophageal tumors58 (interim data; n = 15 patients) received ABX-EGF therapy. Two patients (1 patient with esophageal carcinoma and 1 patient with CRC) demonstrated stable disease for 7 months and 4 months, respectively. One patient with prostate carcinoma demonstrated a minor response. Toxicities included acneiform rash. No patient developed an infusion-related reaction, serious AE, or human antihuman antibodies.

Interim results are available from a multicenter Phase II study of ABX-EGF in patients with mCRC who previously failed therapy with a fluoropyrimidine and irinotecan, with oxaliplatin, or with both.59 In total, 148 patients are enrolled in 2 cohorts based on EGFR expression levels. At the time of last follow-up, enrollment was complete. All patients were available for evaluation after 8 weeks; 15 patients (10.1%) had confirmed PRs, and 54 patients (36%) had stable disease, as determined by investigator assessment. Skin rash was the most common AE. One patient had a Grade 3 infusion reaction that may have been related to ABX-EGF.

EMD 72000

EMD 72000 (EMD Pharmaceuticals, Durham, NC), which is a humanized IgG1 anti-EGFR MoAb, has completed Phase I clinical testing in EGFR-positive solid tumors. Patients (n = 22 patients) with chemotherapy-refractory esophageal, colorectal, head and neck, and cervical tumors received EMD 72000 weekly.60, 61 Objective response (23%) and stable disease (27%) were demonstrated at all dose levels. AEs included rash (64%). EMD 72000 administered to 22 patients with colon, gastric, or renal tumors demonstrated PRs in 2 patients and a minor response in 1 patient.39 Two patients achieved stable disease. A recently reported, Phase I, pharmacokinetic/pharmacodynamic study showed near-complete EGFR signaling suppression at the 1200-mg dose level.62

Other anti-EGFR MoAbs in development

Other MoAbs directed against EGFR have undergone clinical testing. The humanized MoAb hR3 (CIMYM Inc., Mississauga, Ontario, Canada) has shown activity in SCCHN in a Phase I trial.63 ICR62, which is a rat MoAb, also has demonstrated some effect in Phase I trials in patients with SCCHN and NSCLC64; and a Phase I trial of MDX-447 (Medarex, Inc., Princeton, NJ), which is a bispecific anti-EGFR, anti-CD64 humanized antibody, demonstrated efficacy in patients with solid EGFR-positive tumors.65, 66

TKIs

TKIs are small molecules that inhibit EGFR tyrosine kinase.67 Most TKIs are reversible inhibitors; however, irreversible TKIs have been developed, and some of these agents are targeted to inactivate the kinase activity of multiple ErbB receptor family members. Although the majority of TKIs are in preclinical or early clinical testing, several are in Phase II/III evaluation for various epithelial tumors, including CRC.

Gefitinib

Gefitinib (Iressa™; AstraZeneca Pharmaceuticals LP, Wilmington, DE) is a reversible TKI that has demonstrated primarily cytostatic effects in human CRC cell lines.68, 69 Combined administration of gefitinib with topotecan, raltitrexed, or paclitaxel potentiated activity. Phase I studies of gefitinib monotherapy in patients advanced malignancies, including CRC, revealed durable PRs and stable disease.70, 71 In a Phase I study of gefitinib plus 5-FU/leucovorin in patients with mCRC (n = 17 patients), 1 patients achieved a complete response (CR), and 4 patients achieved PRs.72 Acneiform rash, diarrhea that may be dose limiting, mucositis, and neutropenia were common AEs. In the second part of a Phase I/II trial, 27 patients with mCRC received gefitinib.73 Four of 24 evaluable patients demonstrated a minor response (tumor shrinkage), and no objective responses were observed. A Phase I trial of gefitinib combined with oxaliplatin/5-FU/leucovorin (IFOX) was undertaken in patients with advanced epithelial tumors, including CRC.74

A Phase II trial currently is evaluating the efficacy and toxicity of IFOX in patients with advanced CRC.75 Patients are stratified as follows: no prior therapy for metastatic disease > 6 months since any adjuvant therapy (Group A), and prior therapy for metastatic disease (Group B). Interim data (42 patients) showed that, in Group A, 18 of 23 patients (78%) achieved a PR versus 6 of 19 patients (32%) in Group B. Observed Grade 3 and 4 toxicities included diarrhea, nausea, neutropenia, and emesis.76

Preliminary data suggest that gefitinib-based therapy has modest efficacy in heavily pretreated patients with CRC.77 However, gefitinib in combination with capecitabine, irinotecan, and oxaliplatin may be feasible. Further studies are required. Recently, EGFR mutations were associated strongly with response to gefitinib in patients with NSCLC.78, 79 Although these mutations have not been found in CRC,80 evidence of mutations conferring sensitivity to anti-EGFR therapy is emerging. For example, cyclin D1 gene polymorphism81 and heterozygous mutations in exons 18 and 1948 have been associated with clinical outcomes in cetuximab-treated patients with mCRC. Although extensive follow-up work is required, optimized anti-EGFR therapy in selected patients with mutation-positive tumors is a tantalizing possibility.

Erlotinib

Erlotinib (OSI-774, formerly CP-358,774; Tarceva®; OSI Pharmaceuticals, Inc. [Melville, NY], Genentech, Inc. [South San Francisco, CA], and Roche Pharmaceuticals [Nutley, NJ]), is a reversible TKI that is being evaluated in solid tumors, including colon, head and neck, ovarian, and lung tumors. In human cell lines and murine xenografts, erlotinib inhibited EGFR phosphorylation and cellular proliferation, interrupted cell cycle progression at G1, and induced apoptosis.82

Several trials have evaluated erlotinib monotherapy in the treatment of mCRC. In a Phase I study in pretreated patients with advanced lung, prostate, colon, head and neck, breast, renal, and liposarcoma malignancies, AEs were mild.83 In another Phase I study evaluating erlotinib in 40 patients with lung, colorectal, and head and neck malignancies, 1 of 7 patients with CRC showed a 30% reduction in liver metastasis that was sustained for 11 months.84 Two patients with CRC experienced stable disease for at least 5 months. Diarrhea and acneiform rash were dose limiting. An interim report from a Phase II study in mostly pretreated patients with mCRC (n = 30 patients) showed 8 of 25 patients (32%) with stable disease and 12 patients (48%) with progressive disease.85 No objective responses were observed.

Erlotinib combined with chemotherapy also is being evaluated. In a Phase Ib trial of erlotinib combined with capecitabine and oxaliplatin in previously treated patients with mCRC (n = 23 patients), 5 patients achieved a PR, and 14 patients had stable disease.86 Interim data from another Phase II study (n = 20 patients) showed an overall response rate of 20%, and 64% of patients had stable disease.87 Similar to cetuximab, rash severity appears correlated with increased survival.88 Phase II studies in lung, ovarian, and head and neck tumors are underway, and a Phase III trial in patients with lung carcinoma is planned.89 Despite acceptable tolerance of monotherapy and the above-listed combination regimens, Messersmith et al. recently reported on a Phase I trial of erlotinib plus reduced-dose infusional 5-FU and leucovorin (FOLFIRI) (n = 6 patients); the trial was closed early due to toxicity.90 Dose-limiting toxicity included Grade 3 diarrhea despite supportive measures and Grade 3 emesis that required hospitalization. Although rash is not considered a dose-limiting toxicity per se, unusual Grade 2 rash seen in 4 patients required dose reduction or interruption of treatment. It is unknown whether increased rash severity would correlate with better outcome for some patients.

Other TKIs

Additional oral TKIs that are undergoing clinical evaluation include the reversible dual EGFR/Her-2 TKI GW572016 (lapatinib) and the irreversible EGFR TKI EKB-569. Both of these agents have shown promising results in early clinical testing.

EKB-569 was tolerated well in patients with advanced solid tumors of the colon, lung, breast, head, and neck.91 In a Phase I/IIa study of EKB-569 in combination with FOLFOX-4 (n = 29 patients; average age, 61 years; age range 46–70 years; PS 1, 29%; PS 0, 71%), 4 of 11 patients who completed ≥ 4 cycles achieved a PR, 6 patients had stable disease, and 1 patient had progressive disease.92 Grade 3/4 AEs included neutropenia and diarrhea. In a Phase I/IIa study of EKB-569 in combination with FOLFIRI (n = 47 patients; median age, 61 years; age range 19–77 years; PS 1, 33%; PS 0, 66%), 39 evaluable patients showed a response rate of 38% and a clinical benefit rate of 85%.93 Ongoing trials of EKB-569 include an oral cancer prevention study and a Phase I trial in combination with CCI-77994 for the treatment of advanced solid tumors.

The TKI lapatinib also has been tolerated well95 and has been evaluated clinically in both monotherapy and combination therapies. In a dose-escalation study (EGF10003) in patients with EGFR-positive and/or HER-2-positive who had solid tumors (n = 64 patients, including 22 patients with CRC), 22 patients who had various types of tumors demonstrated stable disease, and 1 CR that was sustained for > 16 months was observed in a patient with EGFR-positive SCCHN.96 The final results are available from a Phase Ib study (EGF10004) of lapatinib in heavily pretreated patients with metastatic disease (n = 67 patients).97 Inclusion criteria for that study were EGFR or HER-2 overexpression on IHC, HER-2 gene amplification, or evidence of activated EGFR or HER-2 receptors demonstrated by IHC. Four PRs were observed in patients with breast carcinoma; and 23 patients with other tumor types, including colon, demonstrated disease stabilization for 8–41 weeks. Lapatinib also has been evaluated in Japanese patients (six patients) with evidence of activity that warranted a Phase II study.98 Uniformly, monotherapy has been tolerated well. Combination therapies that have shown activity in a variety of solid tumors, including CRC, are lapatinib plus FOLFOX4,99 lapatinib plus paclitaxel,100 and lapatinib plus capecitabine.101

PD158780 is another multitargeted TKI. This agent, which is a reversible inhibitor of the entire ErbB family of receptor tyrosine kinases, currently is in preclinical testing.89, 102

Potential Applications

Administered alone, many targeted agents demonstrate primarily cytostatic activity. Optimal clinical benefit may require combinations with chemotherapy, radiation therapy, or other targeted approaches. Administration with cytotoxics to achieve tumor eradication, followed by long-term maintenance biologic therapy, may be one possible treatment model.40, 103

Combinations of biologic therapies are undergoing preclinical evaluation. In combination with an antivascular endothelial growth factor (anti-VEGF) antibody, cetuximab has decreased tumor vascularity and increased apoptosis in CRC cells.104 Cetuximab plus VEGF antisense oligonucleotides and cetuximab plus protein kinase A type I antisense oligonucleotides and radiation also demonstrated activity in CRC cells.105, 106

Perspective

The evolution of the EGFR inhibitors described in this review, as well as the identification of VEGF as a meaningful target (e.g., bevacizumab), have added new tools to the armamentarium of treatments for CRC. Of course, these advances parallel the dramatic improvement in chemotherapy for the same patient population. Indeed, the advances need to be kept in context: The biologic agents appear to be most effective when combined with these chemotherapeutics.

What does all of this mean? Clearly, the improvement in survival of patients with advanced CRC with both chemotherapy and biologic combinations is heartening, but the greater impact potentially would come in the adjuvant setting, in which a higher percentage of cured patients would be the objective.

To that end, current clinical trials are exploring the use of cetuximab and other anti-EGFR agents (Table 2), as well as bevacizumab, in combination with chemotherapy in patients with Stage II or Stage III rectal carcinoma. Until such results are available, these research questions remain unanswered, but they represent the greatest opportunity to make an impact in these patients.

Table 2. Current Clinical Trials of Antiepidermal Growth Factor Receptor Agents in Colorectal Carcinoma
Agent/settingCombinationPhasePrimary objectivesSecondary objectivesProjected accrual
  1. EGFR: epidermal growth factor receptor; mCRC: metastatic colorectal carcinoma; ±: with or without; TTP: time to progression; OR: overall response; QOL: quality of life; chemo: chemotherapy; CRC: colorectal carcinoma; MTD: maximum tolerated dose; RR: response rate; 5-FU: 5-fluorouracil; OX: oxaliplatin; LV: leucovorin; OS: overall survival; AEs: adverse events; CRR: clinical response rate; CA: carcinoma; I: irinotecan; DFS: disease-free survival; FOLFOX4: oxaliplatin, LV, and FU; ORR: overall response rate; NCI: National Cancer Institute; PK/PD: pharmacokinetic/pharmacodynamic; PET: positron emission tomography.

Cetuximab     
 EGFR, mCRCMonotherapy ± best supportive careIIISurvivalTTP, OR, QOL, health utilities, cost, safety60
 EGFR-negative, chemotherapy-refractory CRCMonotherapyII500
 Unresectable mCRC, other tumorsErlotinib, bevacizumabI/IIMTD, toxicity, RR, survivalActivity, toxicity37–70
 EGFR+ CRC, liver metastases5-FU, OX, LVIIRR, OS, EGFR levels, QOL, toxicity63–73
 Irinotecan-refractive mCRCBevacizumab ± irinotecanIITTP, OR, OSSafety, tolerability, AEs, molecular markers150
 Locally advanced/recurrent rectal CANeoadjuvant 5-FU and pelvic irradiationIISafetyPathologic CRR26
 Unresectable Stage IV CRCBevacizumab, 5-FU, LV, OX,IIRR, PFS, OSSafety40–67
 Resected Stage III CRCAdjuvant 5-FU, I, LV, OXIIIOSDFS, toxicity, QOL4800
 Previously treated EGFR+ mCRCFOLFOX4IIISafety/efficacy1100
 EGFR+ mCRCIrinotecanIIISafety/efficacy1300
Panitumumab     
 mCRCAMG 706IMTD, safety
 Solid tumorsGemcitabine, cisplatin, AMG 706IMTD, safety
 Solid tumorsMonotherapyISafetyPharmacokinetics
 NCI: mCRC unresponsive to 5-FU, I, OXMonotherapyIIORRResponse time, patient-reported outcomes, safety300
 Amgen: EGFR-negative mCRC or recurring on 5-FU, I, OXMonotherapyIIResponse
 Amgen: EGFR+ mCRC progressing on 5-FU, I, OXMonotherapyII
Gefitinib     
 Solid tumors5-FU, LV, OXIIORR, OS < TTPGenetic markers30–81
 Solid tumorsDocetaxelIMTD, safety, PK/PD3–42
 Solid tumorsCalcitriol, dexamethasoneIMTD, safetyPK/PD, response21–36
 mCRCCapecitabine, OXI/IIMTD, RRSafety, 1-yr survival, PFS, OS3–24 (I), 26 (II)
Erlotinib     
 Solid tumorsTrastuzumab, paclitaxelISafety, toxicity, PK/PDActivity40
 Stage III or IV CRCBevacizumab, FOLFOX4IMTD, toxicity, activityPK/PD, EGFR, activation, PET markers38
EKB-569     
 Advanced solid tumorsCCI-779IMTD, toxicity, RR30–42

In conclusion, newer chemotherapies offer prolonged survival for patients with advanced or metastatic colon carcinoma. However, chemotherapy, surgery, and radiation for these patients rarely provide curative benefits or significant long-term survival. Knowledge regarding the role of growth factors, their receptors, and related signaling pathways in carcinogenesis is expanding significantly. Targeted agents blocking signaling pathways that have been implicated in the growth and metastasis of CRC have been developed and have demonstrated favorable clinical activity in patients with advanced disease. These agents may be administered safely in combination with traditional cytotoxic agents. The integration of targeted agents within an overall treatment strategy for patients with CRC requires further investigation. It is likely that these agents will change the management of colon carcinoma and will provide new hope to patients with advanced or recurrent disease.

Ancillary