lunes, 15 de abril de 2013

Epidermal Growth Factor Receptor Targeting in Head and Neck Cancer: Have We Been Just Skimming the Surface?

Epidermal Growth Factor Receptor Targeting in Head and Neck Cancer: Have We Been Just Skimming the Surface?

Epidermal Growth Factor Receptor Targeting in Head and Neck Cancer: Have We Been Just Skimming the Surface?

  1. Lillian L. Siu

+ Author Affiliations

  1. Princess Margaret Cancer Centre, Toronto, Ontario, Canada

  1. Corresponding author: Lillian L. Siu, MD, Princess Margaret Cancer Centre, Drug Development Program, 610 University Avenue, Suite 5-718, Toronto, Ontario, M5G 2M9 Canada; e-mail:

Despite extensive research in squamous cell carcinoma of the head and neck (SCCHN), the epidermal growth factor receptor (EGFR) remains the only nonchemotherapeutic molecular target that has been successfully translated into a biologic therapy with clinical benefit. Targeting this transmembrane tyrosine kinase growth factor receptor in SCCHN is an attractive and rational strategy given that more than 90% of these tumors overexpress EGFR. The potential value of EGFR as a therapeutic target is also supported by the observation that poor prognostic outcomes have been correlated with increased EGFR protein expression or EGFR gene copy number amplification.13 Traditional anti-EGFR strategies include monoclonal antibodies (MABs) that block the extracellular ligand-binding domain and small molecule inhibitors that reversibly inhibit activation of the cytoplasmic tyrosine kinase. Currently, the only approved targeted therapy in SCCHN is cetuximab, the chimeric immunoglobulin G1 antibody to EGFR.

In March 2006, the US Food and Drug Administration granted approval for the addition of cetuximab to radiation therapy in locally or regionally advanced SCCHN or as monotherapy for patients with platinum-refractory, recurrent or metastatic (RM) SCCHN. This approval was substantiated by a randomized phase III trial4 and a single-arm phase II trial.5 Bonner et al4,5 demonstrated that the combination of cetuximab and radiation was superior to radiation alone in patients with stage III/IV oropharyngeal, hypopharyngeal, or laryngeal SCCHN, with clinically and statistically significant improvements in the duration of locoregional control (24.4 v 14.9 months; hazard ratio [HR], 0.68; P = .005) and overall survival (OS; 5-year OS, 45.6% v 36.4%; HR, 0.73; P = .018). An open-label, single-arm trial evaluated the efficacy of cetuximab in 103 patients with RM SCCHN who experienced disease progression on platinum-based therapy and demonstrated an objective response rate of 13% with a median duration of approximately 4 months.6 An additional indication for cetuximab was granted by the US Food and Drug Administration in November 2011 for the treatment of RM SCCHN in combination with platinum-based therapy and fluorouracil. The pivotal phase III trial, Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME), reported a difference of 2.7 months in the primary end point of OS in the first-line treatment of RM SCCHN with the addition of cetuximab to cisplatin or carboplatin plus fluorouracil (median, 10.1 v 7.4 months; HR, 0.8; P = .04).7

The success of cetuximab in locoregionally advanced or RM SCCHN has not been observed with the small molecule tyrosine kinase inhibitors (TKIs), despite their common target of EGFR. This finding has been corroborated by two well-designed studies presented in the articles accompanying this editorial. In a randomized, open-label phase II study in locally advanced SCCHN, Martins et al8 investigated the effect of the addition of the EGFR TKI erlotinib to standard cisplatin-based chemoradiotherapy on complete response rate (CRR) and progression-free survival (PFS). Given the results of the Radiation Therapy Oncology Group (RTOG) 0522 trial, wherein the addition of cetuximab to cisplatin and radiotherapy did not improve PFS or OS,9 it was not surprising that this study also failed to detect a statistically significant improvement in its primary end point of CRR in the experimental arm over the control arm (centrally reviewed CRR of 52% v 40%, respectively; P = .08).8 Although the limitations of CRR as a valid surrogate end point for long-term clinical outcome in locally advanced SCCHN were pointed out by the authors and have been described in the literature,10 the comparable PFS between the two arms (HR, 0.9; P = .71) and the consistency of the negative results with those of RTOG 0522 confirmed the lack of benefit of combining anti-EGFR therapy with concurrent chemoradiotherapy as a chemoadditive strategy in unselected patients with locally advanced SCCHN. Unfortunately, p16 testing by immunohistochemistry was performed in fewer than half of the participants in this study by Martins et al, which hampers exploratory subgroup analysis of this combination on the basis of human papillomavirus status.

Likewise conducted in an unselected population, the second study11 investigated the addition of another EGFR TKI, gefitinib, to palliative chemotherapy in patients with RM SCCHN. In this randomized, placebo-controlled phase III trial conducted by the Eastern Cooperative Oncology Group (E1302), Argiris et al11 randomly assigned 270 patients with poor prognosis to once-per-week docetaxel plus either gefitinib or placebo. Cross-over was allowed for those in the placebo arm to receive gefitinib alone after progression. Without reaching its accrual target of 314 patients, this study was closed after an interim analysis showed no benefit in its primary end point of OS between the investigational and control arms (7.3 v 6.0 months, respectively; HR, 0.93; P = .60) with a higher frequency of grade 3 to 4 diarrhea in the gefitinib arm. An important issue for this trial is the evaporating niche of patients for whom this combination would be relevant, given the results of the EXTREME trial, which were published after this trial started. Although this trial was not designed to specifically address the suitability of gefitinib and docetaxel after combination cetuximab plus chemotherapy treatment, the history of prior chemotherapy did not impact outcome on the basis of subgroup evaluation. An unplanned subgroup analysis revealed that patients younger than age 65 years experienced a marginal median OS benefit from the investigational combination (7.6 v 5.2 months; P = .04). Further consideration of this regimen as an option in young patients would require not only validation but also justification, considering the current therapeutic landscape in RM SCCHN.

A logical question arises from the results of these two clinical trials: Should any more studies be performed in SCCHN with EGFR TKIs? A comparison of the biologic and pharmacologic properties between anti-EGFR MABs and TKIs may be informative. On the basis of existent evidence in SCCHN, the large MABs are superior to small molecule TKIs, which may reflect the underlying mechanisms through which EGFR drives tumor growth or treatment resistance. In non–small-cell lung cancer, the reverse is true—TKIs are superior in clinical activity to the MABs—which presumably is explained in part by the presence of EGFR mutations in the kinase domain where TKIs exert their effects.1214 The role of EGFR pathway dependence or addiction and other related molecular networks may be differentially affected by MABs in comparison with TKIs in SCCHN, which potentially accounts for different therapeutic responses. In addition, immune-effector mechanisms such as cetuximab-mediated antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and complement-dependent cell-mediated cytotoxicity may play an influential role in the observed clinical activity and may partially explain why biomarkers focused on EGFR protein expression or gene amplification are not predictive. The immunologic mechanism of ADCC results from the Fc fragment of the MABs interacting with Fc gamma receptors on macrophages and natural-killer cells. Fc gamma receptors are subject to polymorphisms that influence the strength of the Fc receptor and Fc target binding and potentially underpins the variability in efficacy between different MABs.15 TKIs lack such a mechanism of action, which distinguishes them from the MABs. The comparative pharmacokinetic profiles may further explain the different efficacy between MABs and TKIs in SCCHN, including longer half-lives of MABs (mean half-life of cetuximab, 112 hours; mean half-life of erlotinib, 36 hours), variable bioavailability of EGFR TKIs,16 higher interpatient variability for TKI degradation resulting from cytochrome P450 polymorphisms, and lower TKI specificity for EGFR in comparison with MABs.17 Unless there are distinctively favorable pharmacologic properties offered by a novel EGFR TKI and/or the identification of a validated predictive biomarker for a sensitive or resistant patient subgroup, there is minimal incentive for further patient and clinical trial resources to be invested in yet another trial of an EGFR TKI in SCCHN.

Despite cetuximab's approval for various indications in SCCHN, its incremental benefit in the clinical setting is, at best, modest. This underscores the continued need to develop other targeted therapies and to more comprehensively elucidate resistance mechanisms to EGFR inhibition. One strategy aimed at overcoming EGFR resistance includes the use of irreversible, broader pan-ErbB receptor TKIs (ie, ErbB1, 2, and 4) such as afatinib and dacomitinib. These two agents have shown promise as single agents in phase II trials in both platinum-refractory and untreated RM SCCHN settings, respectively.18,19 ErbB3 has emerged to become a key target in the therapeutic strategy to overcome EGFR resistance, given that not only can it allosterically activate the kinase domain of its heterodimerized partners, such as EGFR and ErbB2, but it also acts as a potent activator of the phosphatidylinositol 3-kinase (PI3K)/AKT survival pathway. Novel approaches focusing on the inhibition of ErbB3 and its heterodimerization partners are being actively developed in early phase trials. Besides the strategy to more effectively interrogate the ErbB pathway, therapeutic resistance to EGFR inhibition may occur as a result of crosstalk and/or upregulation of compensatory escape mechanisms, with the PI3K/AKT pathway being a prime target. EGFR-independent AKT activation has been demonstrated in SCCHN cell lines to be driven by activating mutations in PIK3CA.20 Upregulation of this pathway may also be influenced by amplifications in PIK3CA and AKT2 and activating mutations in PTEN, which have been reported in SCCHN tumor specimens.21 Characterizing aberrations in the PI3K/AKT pathway may delineate a functionally distinct molecular genotype of SCCHN and presents attractive therapeutic targets for AKT inhibitors and PI3K antagonists that are either pan-isoform or isoform-specific.22

At present, the lack of validated predictive biomarkers precludes effective patient selection for specific molecularly targeted therapies and stalls the advances of experimental therapeutics in SCCHN. Theoretically, next-generation and massively paralleled sequencing may spawn molecular profiles that would shed light on relevant predictive biomarkers. Stransky et al23 performed whole exome sequencing in 74 paired tumor and normal samples to reveal a diverse mutational landscape in SCCHN. Although pathways involved in squamous differentiation were consistently shown to be aberrant, disappointingly there were no new and easily druggable targets. It is unlikely that genomic sequencing alone will represent a panacea to the therapeutic challenges in SCCHN. Comprehensive characterization that encompasses a broader omics-based molecular evaluation as well as immune function assessments is urgently needed. Clearly, our current knowledge of EGFR as a therapeutic target in SCCHN is merely skimming the surface of a problem that is exceedingly complex.


Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Lillian L. Siu, Roche, Pfizer, Bristol-Myer Squibb, Boerhinger-Ingelheim Expert Testimony: None Other Remuneration: None


Administrative support: Lillian L. Siu

Manuscript writing: All authors

Final approval of manuscript: All authors


  • See accompanying articles on pages 1405 and 1415


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