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Keywords:

  • cetuximab;
  • epidermal growth factor receptor;
  • vascular endothelial growth factor receptor;
  • insulin growth factor type-1 receptor;
  • Src family kinases;
  • head and neck cancer

Abstract

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

Head and neck cancer is a challenging disease that is expected to account for greater than 500,000 new cases worldwide in 2008. Toxicity has impeded advances in chemotherapy and radiation for head and neck cancer, and the prognosis for patients with recurrent and/or metastatic disease remains poor. Over the past decade, clinical research in head and neck cancer has focused on improving the efficacy of current multimodal approaches by targeting cellular pathways associated with carcinogenesis. Blocking the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) have emerged as primary strategies that account for the success of current targeted therapies in cancer. Recent studies with cetuximab, a monoclonal antibody inhibitor of the EGFR, have demonstrated survival benefits across the range of treatment settings in advanced head and neck cancer, and it is the only targeted therapy approved for use in this malignancy. In this review, the authors present the current development status of targeted therapies, focusing on those that have potential to impact the management of head and neck cancer in the near-term future. Trials are ongoing in all stages of disease and with a variety of modalities and agents, and those trials should provide critical insight into the best way to use these agents to improve patient outcomes. Cancer 2009. © 2009 American Cancer Society.

Despite advances in local and systemic therapy, head and neck cancer remains a clinically challenging disease. For the past decade, clinical research in head and neck cancer has focused on improving on the benefits of chemotherapy and radiation by targeting the cellular pathways associated with carcinogenesis. Recent studies with cetuximab (Erbitux; ImClone Systems Inc., New York, NY/Bristol-Myers Squibb, New York, NY), a monoclonal antibody (MoAb) inhibitor of the epidermal growth factor receptor (EGFR), have demonstrated survival benefits across the range of treatment settings in advanced head and neck cancer. Cetuximab was approved by the US Food and Drug Administration (FDA) in 2006, making it the first and, currently, the only targeted biologic available for commercial use in head and neck cancer.

Other compounds that target EGFR along with novel compounds that target other cellular domains that have been implicated in carcinogenesis remain under active clinical investigation in head and neck cancer. In this review, we present the current development status of these targeted therapies, focusing on those that are in the later stages of clinical development.

Natural History of Head and Neck Cancer

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

Head and neck cancers are a biologically similar group of epithelial cancers that occur throughout the upper aerodigestive tract. The majority (90%-95%) are squamous cell carcinoma (SCCHN), and their different primary sites amid the complex anatomy of the head and neck give rise to intricate patterns of local invasion and regional spread that make treatment choices complicated. This distinction also makes primary tumors more difficult to eradicate once they have grown large enough to spread into adjacent tissues and lymph nodes. Primary tumor sites include the lip, oral cavity (mouth), nasal cavity, paranasal sinuses, pharynx, and larynx. The pharynx, larynx, mouth, and tongue each account for approximately 10,000 new cases in the US annually.1

Overall, a cure is achieved in approximately 50% of all patients with SCCHN. Approximately 33% of patients present with early-stage disease (stages I and II) and have a 5-year survival rate of approximately 80%, another 50% of patients have locally advanced (LA) disease (stages III-IVB) and have a 5-year survival rate of approximately 50%, and 10% of patients have metastatic (stage IVC) disease with only approximately 25% surviving past 5 years1 (Table 1).

Table 1. Current Treatment of Head and Neck Cancer
    Survival
SettingPatients, %*Treatment ObjectiveStandard-of-care TreatmentRate, %Years
  • *

    See Jemal 20071 and Argiris 2004.3

  • *See Jemal 2007,1 Argiris 2004,3 and Leon 2005.4

  • Chemotherapy includes the option of cetuximab as an alternative (locally advanced and refractory squamous cell carcinoma of the head and neck [SCCHN]) or adjunct (recurrent and/or metastatic SCCHN) to conventional chemotherapeutics.

Initial diagnosis     
 Early stage (stage I/II)33CureSingle modality: Radiotherapy or surgery825
 Locally advanced (stage III/IVA/IVB)52CureCombined modality: Concurrent radiotherapy and chemotherapy plus surgery if necessary525
 Metastatic (stage IVC)10PalliationChemotherapy275
Recurrent/refractory50PalliationChemotherapy33/>51/1

In contrast to many other cancers in which metastasis is the primary cause of death, local recurrence is the most common cause of treatment failure and death in patients with head and neck cancers. Greater than 50% of patients who die from head and neck cancer have locoregional disease as the only site of failure, and nearly 90% of patients with distant failure also have persistent locoregional disease.2 Because of the frequency of local recurrence, locoregional control is a key treatment objective, and localized treatment with radiotherapy and/or surgery is a critical component of initial management. The 50% of patients who develop recurrent disease have a very poor prognosis, with a median overall survival (OS) of only 6 to 9 months, and <33% remain alive at 1 year.3 Patients with recurrent and/or metastatic (RM) disease who progress after treatment have the worst prognosis, with a median OS of 3 to 4 months, and <5% remain alive at 1 year.4

Risk factors for SCCHN include cigarette, cigar, or pipe smoking and excessive alcohol consumption.5 More recently, it was demonstrated that human papillomavirus (HPV), especially HPV type 16, plays a role in the pathogenesis of a subset of SCCHNs.6 HPV-associated cancers are distinct epidemiologically, clinically, and molecularly from HPV-negative tumors and are associated with improved survival outcomes.7, 8

It is believed that epithelial cancers such as SCCHN develop from a series of genetic events that affect key molecules and biologic pathways.9 The expression of biologic markers is associated with ‘early’ events in premalignant lesions. These biomarkers of cancer progression include mutations in the ras and Bcl-2 proto-oncogenes, inactivation of the tumor-suppressor genes (eg, p53), and increased expression of the receptors involved in growth and differentiation, such as EGFR and the vascular endothelial growth factor (VEGF) receptor (VEGFR). Accumulation of chromosomal abnormalities, oncogene activation, and differences in genetic susceptibility all likely influence the prognosis for neoplastic tissues and provide the scientific basis for biologically based anticancer strategies. Two primary strategies have emerged that account for most of the success of current targeted therapies: 1) blocking growth factor-based cellular signaling (eg, EGFR-associated) and 2) blocking angiogenesis-related cellular signaling (eg, VEGFR-associated). Although many other biologic strategies continue to be studied, most late-stage clinical trials are testing agents that have activity related to either or both of these 2 strategies.

Current Treatment of Head and Neck Cancer

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

SCCHN falls into 4 stages: 1) early-stage disease, 2) LA disease, 3) RM disease, and 4) platinum-refractory disease (Table 1). Cure is the primary objective of the initial therapeutic approach for patients who are diagnosed without distant metastases. For patients with early-stage SCCHN (stage I and most stage II), this objective is achieved readily with single-modality radiotherapy and/or surgery. For LA SCCHN (stages III-IVB), which tends to be highly sensitive to initial treatment strategies, a combination of local therapy (radiotherapy and/or surgery) and systemic chemotherapy usually is used. Accordingly, combined-modality therapy (ie, induction and/or concurrent) has emerged over the last decade as the standard therapy for LA SCCHN.2 Finally, the goal of therapy for patients with RM SCCHN is palliation. These patients generally are treated with chemotherapy alone, beginning with a platinum singlet or a platinum-based doublet, then proceeding to a variety of single agents upon platinum failure.

Although the treatment of SCCHN remains multidisciplinary, it continues to evolve, and much clinical research has focused on the ability of nonsurgical approaches to obviate surgery. Multiple clinical trials have demonstrated the ability of concurrent chemoradiation (CRT) to improve survival while preserving organ function,2 although the significant late toxicities of CRT may outweigh its potential benefits in many patients. Three general approaches to CRT currently are used: 1) surgery followed by adjuvant CRT, 2) definitive CRT with surgery as an optional salvage or completion treatment, and 3) induction chemotherapy followed by definitive CRT. The induction approach is of increasing interest, because it has the theoretical potential to decrease the risk of distant failure, may rapidly reduce tumor bulk, and may predict responsiveness to CRT. Phase 2 studies have yielded encouraging results, and the induction approach is the subject of several large randomized trials.10, 11

Despite much progress, toxicity has impeded advances with current approaches. Standard CRT is associated with substantial toxicity, and efforts to improve its therapeutic index through increased exposure to chemotherapy and/or radiation generally have not succeeded. Furthermore, although chemotherapy provides some benefit to patients with RM SCCHN, their prognosis remains poor. Additional treatment options are needed desperately for these patients.

For these reasons, targeted agents have been the subject of great clinical interest. The results of recent phase 3 trials have confirmed these benefits for the anti-EGFR MoAb cetuximab. However, results to date have demonstrated weak activity with these agents as monotherapies, suggesting that combinations of targeted agents and conventional therapy will be necessary to achieve improved outcomes. It is noteworthy that the necessity of combining local and systemic therapy in LA SCCHN results in a level of complexity that makes performing and interpreting clinical trials very difficult. In addition, clinical trials are testing cytotoxics, notably docetaxel and pemetrexed, with promising results. Ongoing trials should provide critical insight into the best ways to combine agents and modalities to improve outcomes further in patients with SCCHN.

Targeting the Epidermal Growth Factor Receptor

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

The EGFR is a member of the human epidermal receptor (HER)/Erb-B family of receptor tyrosine kinases that transduce extracellular signals to intracellular responses.12 In addition to maintaining normal cellular function, responses elicited through EGFR signaling include cell proliferation in malignancy, promotion of tumor cell motility, adhesion, invasion, induction of angiogenesis, and inhibition of apoptosis.13 The overexpression of EGFR has been documented in several malignancies, including SCCHN, in which its overexpression consistently is high (>90%).13, 14 Studies of tissue samples from patients with SCCHN have indicated that the expression of EGFR is higher in tumor tissue versus normal tissue15-17 and that increased levels of EGFR and its ligand transforming growth factor α are strong predictors of decreased disease-free survival.18

Given the apparent role of EGFR in tumorigenesis and the high degree to which it appears to be overexpressed in SCCHN, blockade of EGFR pathways has been investigated as a rational anticancer strategy.19 The most extensively evaluated in the clinic are the MoAbs cetuximab, panitumumab (Vectibix; Amgen, Thousand Oaks, Calif), and zalutumumab, and the low molecular weight tyrosine kinase inhibitors (TKIs) gefitinib (Iressa; AstraZeneca, Wilmington, Del) and erlotinib (Tarceva; OSI Pharmaceuticals, Melville, NY/Genentech, South San Francisco, Calif) (Table 2). Newer ‘dual TKIs’ that inhibit both EGFR and HER-2 (erbB-2) also are undergoing clinical trials in SCCHN. Of these, lapatinib (Tykerb; GlaxoSmithKline, Philadelphia, Pa) is furthest along in clinical development (Table 2). Recent research has demonstrated that the cancer-specific mutant EGFR VIII may occur in >33% of SCCHN and, thus, may provide a promising target for therapy.20 An anti-EGFR VIII vaccine (CDX-110) is undergoing phase 3 testing in glioblastoma multiforme; whether this vaccine or EGFR VIII-specific MoAbs could be effective in treating SCCHN is unknown.

Table 2. Targeted Agents in Phase 2 or Higher Development in Head and Neck Cancer
Target(s)AgentDrug TypeCompanyNo. of Listed SCCHN Trials*Approved Indications
  • SCCHN indicates squamous cell carcinoma of the head and neck; EGFR, epidermal growth factor receptor; MoAb, monoclonal antibody; BMS, Bristol-Myers Squibb; CRC, colorectal cancer; TKI, tyrosine kinase inhibitor; NSCLC, nonsmall cell lung cancer; HER-2, human epidermal receptor 2; GSK, GlaxoSmithKline; BC, breast cancer; VEGF, vascular endothelial growth factor; MM, multiple myeloma; VEGFR, vascular endothelial growth factor receptor; IGF-1R, insulin growth factor receptor 1; RAF, tyrosine receptor protein kinase; PDGFR-β, platelet-derived growth factor receptor β; MKI, multiple kinase inhibitor; RCC, renal cell carcinoma; HCC, hepatocellular carcinoma; GIST, gastrointestinal stromal-cell carcinoma; SRC, v-scr sarcoma viral oncogene homolog; ABL, c-abl oncogene receptor tyrosine kinase; MET, met proto-oncogene (hepatocyte growth factor); CML, chronic myelogenous leukemia.

  • *

    See National Institutes of Health 2008.34

Approved     
EGFRCetuximab (Erbitux)MoAbImClone/BMS/Merck43SCCHN, CRC
Phase 3     
 EGFRErlotinib (Tarceva)TKIOSI/Genentech29CRC, NSCLC
 Gefitinib (Iressa)TKIAstraZeneca24
 Panitumumab (Vectibix)MoAbAmgen6CRC
 ZalutumumabMoAbGenmab6
 EGFR, HER-2Lapatinib (Tykerb)Dual TKIGSK6BC
 VEGFBevacizumab (Avastin)MoAbGenentech/ Roche17CRC, NSCLC, BC
 p53INGN 201 (Advexin)Gene therapyIntrogen5
Phase 2, randomized     
 ProteasomeBortezomib (Velcade)Small molecule, injectableMillennium, Takeda10MM, lymphoma
 EGFR, VEGFRVandetanib (ZD6474)Dual TKIAstraZeneca3
 IGF-1RIMC-A12MoAbImClone1
 EGFR, HER-2BIBW 2992Dual TKIBoehinger-Ingelheim1
Phase 2, single-arm     
 RAF, VEGFR, PDGFR-βSorafenib (Nexavar)MKIOnyx/Bayer6RCC, HCC
 VEGFR, PDGFR-β, c-kitSunitinib (Sutent)MKIPfizer3RCC, GIST
 VEGFRCediranib (AZD2171; RecentinTKIAstraZeneca2
 SRC, BCR-ABL, c-kit, PDGFR-βDasatinib (Sprycel)MKIBMS2CML
 SRC, ABLAZD0530MKIAstraZeneca1
 MET, VEGFR-2XL880 (GSK089)MKIExelixis/GSK1

Cetuximab

Cetuximab is a human:murine MoAb of the immunoglobulin G1 (IgG1) isotype that appears to act through multiple mechanisms; and, as an anti-EGFR MoAb, cetuximab blocks the binding of natural ligands to the EGFR, preventing EGFR dimerization, internalization, and autophosphorylation and inhibiting subsequent activation of tyrosine kinase-mediated signaling pathways. Preclinical studies demonstrated that cetuximab inhibited the growth of EGFR-expressing carcinoma cell lines through cell cycle arrest, antiangiogenesis, antiapoptosis, and inhibition of tumor cell invasion and metastasis.21-23 More recent data demonstrated that cetuximab may block the nuclear import of EGFR, preventing activation of DNA repair mechanisms that protect cells from radiation- or chemotherapy-induced DNA damage.24 This finding is consistent with animal studies, which demonstrated that cetuximab augments the antitumor effects of both radiotherapy25, 26 and conventional chemotherapeutics.27, 28 Cetuximab also may engage host-immune functions, including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, which are associated specifically with the IgG1 isotype.29

On the basis of the promising results from preclinical studies and early clinical trials, cetuximab has been studied across the continuum of advanced SCCHN. To our knowledge, 2 large phase 3 trials, 1 each in LA disease and RM disease, and 11 phase 2 studies have been completed. One large phase 3 trial in LA SCCHN is ongoing as well as numerous phase 2 studies, including 3 trials that have enrolled >400 patients with LA laryngeal cancer to specifically study the potential role of cetuximab therapy in achieving larynx preservation. The FDA has approved 2 indications for cetuximab in SCCHN: 1) in combination with radiotherapy in patients with LA or regionally advanced SCCHN and 2) as monotherapy in patients with RM SCCHN for whom prior platinum-based therapy has failed.

Locally advanced SCCHN

The LA SCCHN indication for cetuximab is based on a multinational, randomized phase 3 study comparing radiotherapy plus cetuximab with radiotherapy alone in the treatment of LA SCCHN.30 Patients were randomized to receive high-dose radiotherapy plus cetuximab (n = 211 patients) or high-dose radiotherapy alone (n = 213 patients). In the radiotherapy plus cetuximab group, cetuximab therapy consisted of 8 total doses initiated 1 week before radiotherapy at a loading dose of 400 mg/m2 over a period of 120 minutes followed by weekly 60-minute infusions of 250 mg/m2 for the duration of radiotherapy.

The results demonstrated that adding cetuximab to radiotherapy significantly prolonged both locoregional control and OS compared with radiotherapy alone. There was a 32% reduction in the risk of locoregional failure (hazards ratio [HR], 0.68; 95% confidence interval [95% CI], 0.52-0.89 [P = .005]), resulting in a nearly 10-month increase in median locoregional control with the addition of cetuximab to radiotherapy (24.4 months vs 14.9 months). There was a 26% reduction in the risk of death (HR, 0.76; 95% CI, 0.57-0.97 [P = .03]), resulting in a nearly 20-month increase in median OS with the addition of cetuximab to radiotherapy (49 months vs 29.3 months). To our knowledge, this improvement in OS is the highest yet reported in a phase 3 trial in this setting. Preservation of function also appeared to be improved with cetuximab. Although the trial was not powered to detect significance for this outcome, patients who received cetuximab plus radiotherapy had a 49% reduction in the risk of undergoing laryngectomy and a rate of larynx preservation nearly double that of the patients who received radiotherapy alone (15.4% vs 8.6%). With the exception of the expected cetuximab-related toxicities of acneiform rash and infusion-related events, the incidence of severe (grade 3-5) reactions was similar in the 2 treatment groups. It is noteworthy that the clinical benefits of adding cetuximab to radiotherapy were achieved without adversely affecting quality of life (QoL).31 On the basis of these results, cetuximab plus radiotherapy has become a valuable therapeutic option and a foundation for further clinical research in patients with LA SCCHN.

Single-arm studies of cetuximab plus CRT in LA SCCHN have produced encouraging efficacy with possibly higher toxicity than what was observed with CRT alone. A large phase 3 study, Radiation Therapy Oncology Group (RTOG) 0522 (NCT00265941), currently is ongoing to test this strategy (Table 3).32-34 Patients in RTOG 0522 are being randomized to treatment with concurrent boost radiotherapy (1.8 grays [Gy] per day during Weeks 1-6; a boost of 1.6 Gy 4-6 hours later during Weeks 5 and 6; 70 Gy total to macroscopic disease) and cisplatin at a dose of 100 mg/m2 intravenously during Weeks 1 and 4, with or without cetuximab at a dose of 400 mg/m2 intravenously during Week 1, followed by 250 mg/m2 during Weeks 2 through 10.

Table 3. Survival Results in Selected Cetuximab Clinical Trials in Advanced Squamous Cell Carcinoma of the Head and Neck
SettingReferenceStudy TypeNo. of PatientsRegimenOS, MonthsHR (95% CI)P
  1. OS indicates overall survival; HR, hazards ratio; 95% CI, 95% confidence interval; platinum, cisplatin or carboplatin; 5-FU, 5-fluorouracil; EXTREME, Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer.

Locally advancedBonner 200630Phase 3211Radiotherapy plus cetuximab490.74 (0.57-0.97).03
   213Radiotherapy29.3  
Recurrent and/or metastatic (first-line)Vermorken 200737 (EXTREME)Phase 3222Platinum/5-FU plus cetuximab10.10.797 (0.644-0.986).0362
   220Platinum/5-FU7.4  
Platinum-refractoryVermorken 200711Single-arm phase 2103Cetuximab monotherapy5.9
 Baselga 200539Single-arm phase 296Platinum plus cetuximab6.1
 Leon 20054Retrospective151Various3.6

Recurrent and/or metastatic SCCHN

Building on the results of earlier studies,35, 36 the Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer or ‘EXTREME’ study confirmed the benefit of adding cetuximab to chemotherapy in patients with previously untreated (first-line) RM SCCHN.37, 38 To our knowledge, this phase 3 trial is the first in this setting in >25 years to yield significantly improved survival compared with standard platinum-based chemotherapy alone. In total, 442 patients with RM SCCHN who were not amenable to local therapy and had not received systemic therapy in this disease setting were randomized to treatment with either cetuximab plus platinum-based chemotherapy (cisplatin or carboplatin plus 5-fluorouracil [5-FU]; n = 222 patients) or platinum-based chemotherapy alone (n = 220 patients). Patients received cetuximab at a dose of 400 mg/m2 followed by 250 mg/m2 weekly until progression or unacceptable toxicity and either carboplatin (area under the serum concentration-time curve, 5; Day 1) or cisplatin (100 mg/m2 intravenously; Day 1) plus 5-FU (1000 mg/m2 intravenously; Days 1-4) every 3 weeks for a maximum of 6 cycles or the same dose and schedules of platinum plus 5-FU without cetuximab.

The study met both its primary endpoint of improving OS and its secondary efficacy endpoints of improved progression-free survival (PFS) and an increased objective response rate (ORR). The addition of cetuximab to platinum-based chemotherapy reduced the overall risk of death by 20% (HR, 0.797; 95% CI, 0.644-0.986 [P = .036]) and prolonged the median OS by 36.5% or 2.7 months (10.1 months vs 7.4 months). The risk of disease progression was reduced by 46% (HR, 0.538; 95% CI, 0.431-0.672 [P < .0001]), and the median PFS was prolonged by 70% or 2.3 months (5.6 months vs 3.3 months). The ORR was increased by 83% (35.6% vs 19.5%; P = .0001). These substantial clinical benefits were achieved with no decrease in QoL associated with the addition of cetuximab to chemotherapy. Grade 3 and 4 adverse events were similar between the study arms, and acne-like rash and infusion reactions were limited to the patients who received cetuximab. The prolonged survival and acceptable safety profile demonstrated in the trial make cetuximab plus platinum-based chemotherapy an important treatment option for these patients and suggest that cetuximab added to platinum-based chemotherapy may represent a new standard of care in the first-line treatment of patients with RM SCCHN.

Platinum-refractory SCCHN

Having failed standard earlier line therapies, patients with platinum-refractory disease have few good treatment options; therefore, most novel therapies for SCCHN are tested first in this setting. Although there is no recognized standard treatment, cetuximab monotherapy is the only therapy with an approved indication for platinum-refractory SCCHN. Three large, single-arm, phase 2 trials have been reported testing cetuximab as monotherapy and in combination with platinum chemotherapy in this setting.39-41 For comparable groups of patients, these studies have reported an OS of approximately 6 months that compared favorably to the 3.6 months observed in a historic control group of 151 patients.4 It is worth noting that the results for cetuximab monotherapy41 and cetuximab plus cisplatin39 were similar, suggesting that there may be little advantage to combining the 2 agents. Grade 3 and 4 adverse events generally were similar across the 3 trials and were consistent with the toxicity profiles of the individual agents.

In summary, a large body of clinical trial evidence confirms the benefits of incorporating cetuximab into therapy across the treatment spectrum of advanced SCCHN (Table 3). Adverse effects are predictable and manageable, consisting primarily of rash and infusion reactions, and do not appear to exacerbate the toxicities of chemotherapy and radiotherapy. Although it is unclear how this finding may impact clinical use of cetuximab, Chung et al recently demonstrated an association between geographic variations in the frequency of infusion reactions and preexisting IgE antibodies to galactose-α-1,3-galactose that cross-react with cetuximab.42

Further elucidation of the role of cetuximab in the management of SCCHN awaits the completion of ongoing trials that are addressing its use as an addition to standard CRT and induction regimens, as a component of adjuvant and neoadjuvant approaches, and as a foundation for targeted agent combinations that might eliminate or reduce the use of conventional chemotherapy. It is noteworthy that the substantial clinical experience with cetuximab in SCCHN also provides a benchmark against which to compare other novel biologics that are being tested in this disease.

Other anti–EGFR MoAbs

Two other anti-EGFR MoAbs, panitumumab (Vectibix, Amgen) and zalutumumab (HuMax-EGFr; GenMab MN Inc., Brooklyn Park, Minn), are being tested in late-stage clinical trials (Tables 2 and 4), whereas the development of a fourth such antibody, matuzumab (EMD 72,000), has been discontinued. Both panitumumab and zalutumumab are fully human MoAbs that, similar to cetuximab, bind to the extracellular domain of EGFR. The ongoing trials with these MoAbs should answer the question of whether either provides a clinical advantage over cetuximab in SCCHN.

Table 4. Targeted Agent Randomized Trials Currently Recruiting in Head and Neck Cancer
SettingIdentification No.TreatmentNo. of PatientsPrimary Endpoint
  1. NCT, national clinical trials; EPOC, Erlotinib Prevention of Oral Cancer; CRT, concurrent chemoradiotherapy; ±, with or without; DFS, disease-free survival; SOC, standard of care; PFS, progression-free survival; DAHANCA, Danish Head and Neck Cancer Group; RT, radiotherapy; LRC, locoregional control; RTOG, Radiation Therapy Oncology Group; 5-FU, 5-fluorouracil; OS, overall survival; SPECTRUM, Study of Panitumumab Efficacy in Patients with Recurrent and/or Metastatic Head and Neck Cancer; INGN, Introgen Therapeutics Inc.; BSC, best supportive care; CARISSA, Postoperative Radiotherapy with Cisplatin Alone or in Combination With Iressa in Upper Aerodigestive Tract Carcinomas; NA, not available; CRR, complete response rate; CONCERT2, Radiotherapy Plus Panitumumab Compared to Chemoradiotherapy With Unresected, Locally Advanced Squamous Cell Carcinoma of the Head and Neck; EORTC, European Organization for Research and Treatment of Cancer; ORR, objective response rate; PARTNER, Panitumumab Added to Regimen for Treatment of Head and Neck Cancer Evaluation of Response; IMC-A12, insulin-like growth factor 1 receptor inhibitor (monoclonal antibody); BIBW, a dual inhibitor of epidermal growth factor receptor and human epidermal growth factor 2.

Phase 3    
 PreventionNCT00402779 (EPOC)Erlotinib vs placebo150Incidence of oral cancer
 Adjuvant (high risk)NCT00424255CRT ± lapatinib680DFS
 NCT00412217Erlotinib vs SOC300PFS
 Locally advancedNCT00496652 (DAHANCA 19)RT/CRT ± zalutumumab600LRC
 NCT00265941 (RTOG-0522)CRT (cisplatin/RT) ± cetuximab720DFS
 Recurrent/metastaticNCT00588770 (ECOG-E1305)Cisplatin/docetaxel/5-FU ± bevacizumab400OS
 NCT00460265 (SPECTRUM)Cisplatin/5-FU ± panitumumab650OS
 NCT00041626Cisplatin/5-FU ± INGN 201288OS
 RefractoryNCT00088907 (ECOG-E1302)Docetaxel ± gefitinib330OS
 NCT00382031BSC ± zalutumumab273OS
Phase 2    
 AdjuvantNCT00169221 (CARISSA)RT/cisplatin ± gefitinib140NA
 Locally advancedNCT00703976RT/pemetrexed/cetuximab ± bevacizumab80PFS
 NCT00468169Induction chemotherapy[RIGHTWARDS ARROW]RT + cisplatin/cetuximab or 5-FU/cetuximab110PFS
 NCT00410826RT/cisplatin ± erlotinib204CRR
 NCT00500760RT/cisplatin ± panitumumab150LRC
 NCT00387127RT/cisplatin ± lapatinib100CRR
 NCT00547157 (CONCERT2)RT/cisplatin vs RT/panitumumab150LRC
 Locally advanced larynx, hypopharynxNCT00498953 (EORTC-24051)Induction docetaxel/cisplatin/5-FU [RIGHTWARDS ARROW]RT/carboplatin ± lapatinib133Organ preservation
 NCT00169247Induction docetaxel/cisplatin/5-FU [RIGHTWARDS ARROW]RT/cisplatin or RT/cetuximab156Organ preservation
 Locally advanced oropharynxNCT00251381RT/cetuximab ± cetuximab×12 wks90LRC
 Recurrent/metastaticNCT00103259 (ECOG-E1304)Bortezomib ± irinotecan102ORR
 NCT00454779 (PARTNER)Cisplatin/docetaxel ± panitumumab110PFS
 NCT00617734IMC-A12 ± cetuximab90PFS
 RefractoryNCT00661427Cetuximab 500 vs 750 mg/m2 ever 2 wks70ORR
 NCT00392665Erlotinib/bevacizumab vs erlotinib/sulindac82PFS
 NCT00514943BIBW 2992 vs cetuximab80NA
 NCT00459043Docetaxel ± vandetanib72ORR

Panitumumab is the subject of 2 randomized trials each in LA SCCHN and RM SCCHN (Table 4). In the LA setting, the phase 2 Radiotherapy Plus Panitumumab Compared to Chemoradiotherapy With Unresected, Locally Advanced Squamous Cell Carcinoma of the Head and Neck or ‘CONCERT2’ trial (National Clinical Trials [NCT] no. NCT00547157) will evaluate 150 treatment-naive patients for locoregional control after treatment with either standard CRT (radiotherapy plus cisplatin) or radiotherapy plus panitumumab.34 In a complementary phase 2 trial (NCT00500760), 150 treatment-naive patients are being randomized to receive standard CRT with or without panitumumab, again with locoregional control as the primary endpoint.34 In RM SCCHN, the phase 3 Study of Panitumumab Efficacy in Patients with Recurrent and/or Metastatic Head and Neck Cancer or ‘SPECTRUM’ trial (NCT00460265) is randomizing 650 treatment-naive patients to cisplatin/5-FU with or without panitumumab, with OS as the primary endpoint.34 A second chemotherapy regimen is being tested in the phase 2 Panitumumab Added to Regimen for Treatment of Head and Neck Cancer Evaluation of Response or ‘PARTNER’ trial (NCT00454779) in which 110 treatment-naive patients are being randomized to receive docetaxel and cisplatin with or without panitumumab.34 PFS is the primary endpoint of that trial.

Zalutumumab is the subject of 2 large phase 3 trials, 1 in LA SCCHN and the other in the platinum-refractory setting (Table 4). The Danish Head and Neck Cancer Group recently initiated an open-label phase 3 trial (NCT00496652) that will assess locoregional control and survival in 600 patients with LA SCCHN randomized to receive either radiotherapy or CRT with or without zalutumumab.34 Another trial (NCT00382031) compares zalutumumab plus best supportive care (BSC) versus BSC alone in 273 patients with previously treated SCCHN that is refractory to or intolerant of standard platinum-based chemotherapy.34

Tyrosine kinase inhibitors

EGFR TKIs bind intracellularly to EGFR tyrosine kinase and inhibit phosphorylation, thereby blocking downstream signaling pathways. The most clinically advanced TKIs are erlotinib and gefitinib, both of which are administered orally, once daily. Although these compounds have been studied extensively in SCCHN, primarily as monotherapy, to our knowledge, neither has met a primary endpoint in a late-stage clinical trial in this disease to date. For example, in the recently reported phase 3 Iressa Versus Methotrexate or ‘IMEX’ trial, which randomized 486 patients with refractory SCCHN to receive gefitinib versus methotrexate, no difference in OS, the primary endpoint of the trial, was observed. The median OS was 5.6 months, 6 months, and 6.7 months; and the 1-year survival rates were 16.7%, 17.8%, and 26.5%, for the gefitinib at 250 mg, gefitinib at 500 mg, and methotrexate comparator arms, respectively.43 Despite disappointing results, these agents are being tested in several ongoing trials that may help delineate roles for them in the management of SCCHN (Table 4).

Both agents are being studied in early-stage as well as advanced disease. In the only late-stage prevention trial ongoing in SCCHN (NCT00402779), the ability of erlotinib monotherapy to reduce the incidence of oral cancer is being studied in the high-risk setting of oral leukoplakia with loss of heterozygosity in the intraepithelial neoplasia of patients with a history of curatively treated oral cancer and in patients with no history of oral cancer.34 Correlative analyses of this trial likely will provide an improved understanding of the role of EGFR and other biologic factors in the early pathogenesis of SCCHN. In the adjuvant setting, in what to our knowledge is 1 of the few trials testing maintenance therapy in the curative setting (NCT00412217), 300 patients at high risk for recurrence after surgery will receive erlotinib monotherapy versus standard-of-care therapy, with PFS as the primary endpoint.34 A similar population of 140 high-risk patients is being randomized to postoperative CRT with or without gefitinib in the phase 2 Postoperative Radiotherapy with Cisplatin Alone or in Combination With Iressa in Upper Aerodigestive Tract Carcinomas or ‘CARISSA’ trial (NCT00169221).34

In advanced SCCHN, a phase 2 study (NCT00410826) is randomizing 204 patients with LA SCCHN to CRT with or without erlotinib, with complete response as the primary endpoint.34 In the refractory setting, a phase 3 trial is assessing the OS of 330 patients randomized to docetaxel with or without gefitinib. Kim et al recently reported the results of a single-arm phase 2 study in patients with RM SCCHN who were treated with the combination of docetaxel, cisplatin, and erlotinib. Among the 47 patients now evaluable for efficacy, there is a response rate of >60%, and the median OS and PFS are 11 months and 6 months, respectively.44 These encouraging results suggest the potential of combining a taxane, cisplatin, and an anti-EGFR agent in the RM setting.

Dual kinase inhibitors

It is believed that EGFR/HER-2 heterodimers may potentiate receptor signaling and resistance to EGFR inhibitors. Lapatinib (Tykerb; GlaxoSmithKline), a dual kinase inhibitor that targets both EGFR and HER-2 and may block dimerization, has been tested in SCCHN and reportedly has a favorable safety profile but little activity as a single agent in RM SCCHN.45 Currently, this agent is being evaluated in a phase 3 trial (NCT00424255) as adjuvant therapy in combination with CRT in almost 700 patients with high-risk LA SCCHN and in a randomized phase 2 trial (NCT00387127), also in combination with radiotherapy and cisplatin, in 100 patients with LA SCCHN.34 Another trial (NCT00498953) in 133 patients with LA SCCHN of the larynx and hypopharynx (N = 133 patients) is testing lapatinib in an induction model with combination chemotherapy (docetaxel/cisplatin/5-FU) followed by CRT with or without lapatinib, with organ preservation as the primary endpoint.34

Another dual inhibitor of EGFR and HER-2, BIBW 2992, may hold promise for activity against tumors resistant to other EGFR inhibitors because of its potent and irreversible binding of EGFR and HER-2. This agent is being studied in 80 patients in a randomized phase 2 trial (NCT00514943) comparing it with cetuximab in patients who have refractory SCCHN.34

Targeting Angiogenesis

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

Angiogenesis is required for tumor progression and metastasis, and inhibiting this process by blocking the proangiogenic factor VEGF and its receptors (VEFGR) has become an intensive focus of clinical investigation. VEGF expression is up-regulated in many tumors, favoring tumor vascularization and growth.46-48 Many ongoing trials are testing the potential role of angiogenesis inhibitors in SCCHN in combination with conventional approaches and with other targeted agents.

The most well developed angiogenesis inhibitor, the anti-VEFG MoAb bevacizumab (Avastin; Genentech), has FDA-approved indications in advanced colorectal, lung, and breast cancer and is in late-stage development in SCCHN. In an ongoing phase 3 trial conducted by the Eastern Cooperative Oncology Group (ECOG) (NCT00588770), 400 patients with treatment-naive RM SCCHN are being randomized to docetaxel/cisplatin/5-FU with or without bevacizumab, with OS as the primary endpoint.34 In LA SCCHN, bevacizumab is being tested in a phase 2 trial (NCT00703976) randomizing 80 patients to radiotherapy/pemetrexed/cetuximab with or without bevacizumab, with PFS as the primary endpoint.34

Cediranib (Recentin; AstraZeneca), an oral, highly potent, and selective VEGF signaling inhibitor of all 3 VEGFRs, has demonstrated activity across a broad range of solid tumors and currently is in late-stage development for colorectal and ovarian cancers. Cediranib is being tested in the RM SCCHN setting as a monotherapy in a single-arm phase 2 trial (NCT00458978), with the overall response rate as the primary endpoint.34

Preclinical and early clinical evidence suggests that combining anti-EGFR and antiangiogenesis may provide a more active cancer treatment than either strategy alone. It has been demonstrated that EGFR activation up-regulates VEGF, which, in turn, has been correlated with resistance to anti-EGFR agents.49 In addition, in vitro studies have demonstrated that the dual inhibition of VEGFR and EGFR increases apoptosis, decreases cell proliferation and vascular permeability, and improves cytostatic activity.50 In a phase 1/2 study, Vokes et al combined erlotinib with escalating doses of bevacizumab (maximum, 15 mg/kg every 3 weeks) in patients with refractory SCCHN (n = 48 patients; phase 2 cohort).51 With the highest dose of bevacizumab, 14% of patients achieved an objective response, and 54% had stable disease. The median PFS and OS were 3.8 months and 6.8 months, respectively. Several additional early-stage clinical trials are ongoing that are testing combinations of angiogenesis and EGFR inhibitors in SCCHN, primarily in the RM setting.

Multitargeted kinase inhibitors

Several novel oral agents are in clinical development that affect multiple pathways and may provide a simpler approach to blocking multiple targets. These agents include the oral kinase inhibitors sorafenib, sunitinib, and vandetanib.

Sorafenib (Nexavar; Onyx Pharmaceuticals, Emeryville, Calif/Bayer Healthcare, Morristown, NJ) is an oral kinase inhibitor that has been approved for metastatic renal cell carcinoma and unresectable hepatocellular carcinoma. It affects multiple signaling pathways that are associated with tumor angiogenesis and cell growth and proliferation and inhibits the activity of VEGFR and the platelet-derived growth factor receptor (PDGFR) as well as the RAF/MEK/extracellular signal-regulated kinase pathway. Promising early clinical results were obtained in RM SCCHN with sorafenib monotherapy in treatment-naive patients, yielding a median OS and time to progression of 8 months and 4 months, respectively.52 A nonrandomized phase 2 trial (NCT00494182) in a similar RM SCCHN patient population currently is evaluating the efficacy and safety of the combination of paclitaxel, carboplatin, and sorafenib.34

Sunitinib (Sutent; Pfizer Inc., New York, NY), which is approved by the FDA for renal cell carcinoma, is an oral inhibitor of several receptor tyrosine kinases, including b-Raf and c-Raf kinase, VEGFR-2, VEGFR-3, and PDGFR-β. By inhibiting the activity of these receptors, it is believed that sunitinib, such as sorafenib, exerts anticancer effects through the inhibition of both angiogenesis and cell proliferation. Sunitinib monotherapy currently is being tested in a 37-patient, single-arm, phase 2 study (NCT00408252) in refractory SCCHN.34

Vandetanib (Zactima; AstraZeneca) is a selective dual inhibitor of the EGFR and VEGF pathways. It is being studied in combination with docetaxel in a 72-patient, randomized, phase 2 trial (NCT00459043) in refractory SCCHN.34

Other Potential Targets

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

Insulin growth factor type-1 receptor

The insulin growth factor type-1 receptor (IGF-1R) is widely over expressed on human epithelial tumors.53, 54 Binding of its ligand IGF stimulates signaling cascades that include the insulin receptor substrate 1/phosphoinositide 3 kinase/AKT (protein kinase B)/mammalian target of rapamycin (mTOR) pathway and the growth factor receptor-bound protein 2/son of sevenless/Ras/mitogen-activated protein kinase pathway, and preclinical studies have demonstrated that blockade of IGF-1R causes apoptosis of tumor cells, inhibits tumorigenesis, and prevents tumor invasion and metastasis.53

Interactions between different families of receptors may be integral to the regulation of their signaling in normal tissue and cancer tissue.55 For example, IGF-1R and EGFR heterodimers activate IGF-1R and its downstream mediators, in turn stimulating mTOR-mediated de novo EGFR synthesis and antiapoptotic survivin proteins, thereby promoting resistance to erlotinib.56, 57 In this model, the inactivation of IGF-1R increases sensitivity to erlotinib. Through similar mechanisms, gefitinib appears to inhibit nonsmall cell lung cancer cell proliferation and induces apoptosis when IGF-IR signaling is suppressed, suggesting that combined targeting of IGF-1R and EGFR may be effective in enhancing antitumor activity.58

The MoAb IMC-A12 (ImClone Systems) is the only IGF-1R inhibitor currently undergoing clinical testing in SCCHN. In a randomized phase 2 trial (NCT00617734) that addresses the potentially important interactions described above, IMC-A12 is being evaluated as a single agent and in combination with cetuximab in patients with refractory SCCHN.34 Up to 90 patients will be enrolled in the study, and PFS will be the primary endpoint.

SRC Family Kinases

Src kinases are involved in the regulation of a variety of normal cellular signal transduction pathways. Increased Src activity up-regulates several signaling cascades associated with tumor development and progression, leading to increased cell growth, migration, and invasion. The levels of Src expression or activation in epithelial tumors generally correlate with disease progression.59 Several agents with Src kinase inhibitory activity, including the oral agents dasatinib and AZD0530, are in phase 2 development (Table 2).

Dasatinib (Sprycel; Bristol-Myers Squibb) is a potent inhibitor of multiple oncogenic kinases—BCR-ABL, SRC, cKIT, PDGFR, and ephrin A—and is the furthest advanced of the agents targeting Src kinases in clinical development. Because of its ability to inhibit BCR-ABL, dasatinib initially was developed in leukemia, for which it was approved by the FDA in 2006. Because dasatinib has demonstrated in vitro activity against cells that are resistant to EGFR inhibition, it is of considerable interest in SCCHN and other tumor types in which anti-EGFR agents are active.60 The agent currently is in clinical testing for many solid tumors, including SCCHN, in which it is being evaluated in 2 single-arm phase 2 trials in the RM setting.

Proteasome

The proteasome is a multicatalytic proteinase complex that plays a critical role in the intracellular degradation of proteins responsible for regulated cell growth.61, 62 In preclinical cancer models, proteasome inhibitors have demonstrated antitumor effects associated with the induction of apoptosis and the sensitization of malignant cells and tumors to the proapoptotic effects of conventional cytotoxics and radiation therapy.61, 62 This preclinical activity has been translated successfully to the clinic with the injectable small-molecule proteasome inhibitor bortezomib (Velcade; Millennium Pharmaceuticals, Cambridge, Mass). Currently approved for treating recurrent multiple myeloma and mantle cell lymphoma, bortezomib is being tested in numerous clinical trials in solid tumors. In a randomized phase 2 ECOG trial (NCT00103259), 102 patients with RM SCCHN are being randomized to bortezomib with or without irinotecan, with objective response as the primary endpoint.34 Bortezomib also is being studied in single-arm phase 2 trials in SCCHN in combination with docetaxel and with cetuximab and radiation.

p53

The tumor-suppressor gene p53 plays a crucial role in cell cycle control and apoptosis in response to foreign DNA synthesis, and its dysfunction has been implicated as a causative factor in many cancers. Mutations of p53 have been identified in 43% of invasive SCCHNs,63 and their frequency is increased when there is a history of tobacco use, with or without alcohol consumption.64 Novel p53-targeted approaches that have been investigated in SCCHN include ONYX-015, which is no longer under development, and INGN 201.

INGN 201 (Ad-p53; Advexin) is a gene therapy in which a replication-defective adenovirus serotype 5 vector with a p53 combinational DNA insertion is administered directly into the tumor to replace mutated p53 genes with wild-type (normal) p53 genes. A phase 3 trial in refractory SCCHN has been completed, and a phase 3 trial in RM SCCHN is ongoing. On the basis of completed phase 3 results, which are not yet published, application for approval of INGN 201 as monotherapy for refractory SCCHN was filed with the FDA and the European Medical Evaluation Agency (EMEA) (Table 4). In practice, the logistical issues associated with ensuring effective intratumoral administration of this type of therapy may limit its feasibility. Should either the FDA or EMEA application be approved, INGN 201 would be the first gene therapy approved by a regulatory agency for any indication.

DISCUSSION

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

In summary, 1 targeted agent, the anti-EGFR MoAb cetuximab, has been approved for commercial use in SCCHN, and several others are in late-stage clinical trials. The majority of the latter include compounds that target EGFR and others directed against angiogenesis targets as well as many that are active against multiple targets that are involved in both tumor proliferation and angiogenesis. Additional novel compounds under investigation in SCCHN include the p53 gene therapy INGN 201, the anti-IGF-1R MoAb IMC-A12, and bortezomib, a proteasome inhibitor. Many of these agents have proven anticancer efficacy and safety, with approved indications in other tumor types. Whether similar benefits will be observed in SCCHN awaits the results of ongoing trials.

By demonstrating improved survival across the treatment spectrum of advanced SCCHN, cetuximab has proven the targeted therapy paradigm in this disease. Ongoing clinical trials will define further the role of cetuximab in the management of patients with SCCHN. In addition to serving as a benchmark against which to measure the clinical trial results of other targeted agents in SCCHN, cetuximab also may provide a good foundation upon which to build rational biologic combination therapies that potentially may obviate or reduce the need for conventional cytotoxics. Indeed, although they were not covered in this review, there are many early-stage clinical trials that are exploring this biologic combination approach. Finally, as in other tumor types, there is great interest in SCCHN for identifying potential biomarkers that are predictive of treatment outcomes. This is an area of active research in SCCHN that eventually could improve risk:benefit and cost:benefit ratios through a personalized medicine approach to therapy. These efforts, combined with the rich pipeline of ongoing clinical trials, promise advances in the near future that should further improve the benefits of therapy for patients with SCCHN.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References

Supported by ImClone Systems Incorporated.

Dr. Kim has received research support from Sanofi Aventis, Genentech, Eli Lilly, ImClone, and OSIP.

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  1. Top of page
  2. Abstract
  3. Natural History of Head and Neck Cancer
  4. Current Treatment of Head and Neck Cancer
  5. Targeting the Epidermal Growth Factor Receptor
  6. Targeting Angiogenesis
  7. Other Potential Targets
  8. DISCUSSION
  9. Conflict of Interest Disclosures
  10. References
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