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Logo of ottDove Medical PressThis ArticleSubscribeSubmit a ManuscriptSearchFollowDovepressOncoTargets and Therapy
 
Onco Targets Ther. 2016; 9: 1927–1943.
Published online 2016 April 4. doi:  10.2147/OTT.S93720
PMCID: PMC4831599

Molecularly targeted therapy for the treatment of head and neck cancer: a review of the ErbB family inhibitors

Abstract

The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with locally advanced disease, which requires site-specific combinations of surgery, radiation, and chemotherapy. Despite aggressive therapy, survival outcomes remain poor, and treatment-related morbidity is not negligible. For patients with recurrent or metastatic disease, therapeutic options are further limited and prognosis is dismal. With this in mind, molecularly targeted therapy provides a promising approach to optimizing treatment efficacy while minimizing associated toxicity. The ErbB family of receptors (ie, epidermal growth factor receptor [EGFR], ErbB2/human epidermal growth factor receptor [HER]-2, ErbB3/HER3, and ErbB4/HER4) is known to contribute to oncogenic processes, such as cellular proliferation and survival. EGFR, specifically, is upregulated in more than 90% of HNSCC, has been implicated in radiation resistance, and correlates with poorer clinical outcomes. The central role of EGFR in the pathogenesis of HNSCC suggests that inhibition of this pathway represents an attractive treatment strategy. As a result, EGFR inhibition has been extensively studied, with the emergence of two classes of drug therapy: monoclonal antibodies and tyrosine kinase inhibitors. While the monoclonal antibody cetuximab is currently the only US Food and Drug Administration–approved EGFR inhibitor for the treatment of HNSCC, numerous investigational drugs are being evaluated in clinical trials. This paper will review the role of the ErbB family in the pathogenesis of HNSCC, as well as the evidence-based data for the use of ErbB family inhibition in clinical practice.

Keywords: head and neck cancer, epidermal growth factor receptor, monoclonal antibody, tyrosine kinase inhibitor

Introduction

Head and neck cancer is the seventh most common cancer worldwide.1 In the United States, head and neck squamous cell carcinoma (HNSCC) accounts for 3% of cancers diagnosed annually and 2% of cancer-related deaths.2 The 2014 estimates for the number of new cases of HNSCC and anticipated deaths from HNSCC in the United States are approximately 55,000 and 12,000, respectively.2 Tobacco and alcohol use remain the strongest risk factors for HNSCC, act synergistically, and are implicated in the majority of diagnoses.3,4 Viral etiologies have also been implicated; specifically, Epstein–Barr virus is present in a significant proportion of nasopharyngeal cancers, whereas high-risk human papillomavirus (HPV) is now the primary cause of oropharyngeal cancers (OPCs).57

More than half the patients with HNSCC present with potentially curable, locally advanced (LA) disease, or disease that has spread to nearby tissue or lymph nodes, but has not metastasized.8 Historically, surgery was the mainstay of treatment for HNSCC; however, the advent of functional organ preservation in the last few decades has shifted the treatment paradigm to include definitive chemoradiation (CRT). While early-stage disease is routinely treated with surgery or radiation (RT) alone, LA disease typically requires site-specific multimodal therapy.9 Although survival rates improved over the last few decades, 30%–60% of patients still develop local recurrences, and approximately 20% develop distant metastases.8 For patients with recurrent or metastatic (R/M) HNSCC, therapeutic options remain limited, and prognosis is dismal. The most active cytotoxic regimens are platinum-based and are associated with response rates (RRs) of up to 30% and median overall survival (OS) of 6–9 months.10,11

Unfavorable survival outcomes coupled with the toxicity of current treatments underscore the importance of incorporating targeted therapies within the treatment paradigm. Epidermal growth factor receptor (EGFR) is the most well-studied member of the ErbB family and is overexpressed in more than 90% of HNSCC.1215 Furthermore, there is a correlation between increased EGFR levels and higher stage disease, increased lymph node metastasis, shorter relapse-free survival, and decreased OS.12,1418 Not surprisingly, targeting the ErbB family is an area of avid research. This paper focuses on the role of the ErbB family in the pathogenesis of HNSCC, and the clinical data evaluating ErbB family inhibition for the management of HNSCC.

Methods

To identify relevant clinical trials of ErbB family inhibitors in HNSCC, PubMed and ClinicalTrials.gov databases were searched using the key search terms or aliases “ErbB” and “HNSCC”. In addition, abstracts presented at the European Cancer Congress, European Society of Medical Oncology, and American Society of Clinical Oncology meetings were evaluated.

The ErbB family in HNSCC

The ErbB family consists of four transmembrane receptors, EGFR/ErbB1/human epidermal growth factor receptor (HER)-1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4.19,20 ErbB signaling activation begins with binding of natural ligands (typically epidermal growth factor [EGF] and transforming growth factor [TGF]-α) to EGFR, ErbB3, or ErbB4. ErbB2 has no known soluble ligands, but is the preferred heterodimerization partner for EGFR. Ligand binding leads to receptor homo- or heterodimerization with other ErbB family receptors (eg, ErbB2).19,20 Upon dimerization, intracellular tyrosine residues undergo autophosphorylation, triggering a cascade of downstream effects. Four primary signaling pathways have been implicated in downstream EGFR signaling: 1) phosphatidylinositol-3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt), 2) Ras/Raf/mitogen-activated protein kinase (MAPK), 3) phospholipase-C (PLC)-γ/protein kinase C (PKC), and 4) signal transducers and activators of transcription (STAT) pathways.21 These pathways culminate in the transcription of genes involved in cellular proliferation, invasion, metastasis, cell survival, and angiogenesis (Figure 1).1922

Figure 1
ErbB family of receptors and their associated signaling pathways and downstream effects.

In HNSCC, increased ErbB expression has been linked to poor outcomes, including decreased OS, locoregional relapse, and treatment failure.16,23,24 Biomarker analysis from a prospective Phase III trial demonstrated that high EGFR expression was associated with significantly shorter OS (P=0.0006) and disease-free survival (DFS; P=0.0016), and higher locoregional relapse rates (P=0.0031).16

ErbB2 gene expression and ErbB3 protein expression have been linked to reduced treatment response and poor outcomes in laryngopharyngeal cancer.23,24 In a study that investigated molecular correlates of locoregional failure following CRT, overexpression of ErbB2 or MDM2 proto-oncogene, E3 ubiquitin protein ligase (MDM2) was identified as an independent predictor of decreased locoregional DFS.23 Microarray analysis of samples from primary, metastatic, and recurrent HNSCC demonstrated that ErbB3 overexpression was more common in metastases than in primary lesions (P=0.003), was associated with shorter survival compared with negative ErbB3 levels (median survival, 22 vs 40 months; P=0.027), and was an independent prognostic predictor of OS (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.01–2.23; P=0.040]).24 In patients with oral squamous cell carcinoma (SCC), combined expression of EGFR, ErbB2, and ErbB3 was more predictive of reduced survival, with ErbB2 demonstrating the strongest correlation.17

ErbB family signaling and RT sensitization

ErbB signaling may modulate response to RT.25,26 EGFR overexpression has been linked to poor RT responses in glioblastoma multiforme25 and SCC cell lines,27,28 and ErbB2 and ErbB3 expression have been associated with gefitinib resistance in HNSCC cell lines.26

Several mechanisms may underlie the association between ErbB family members and responses to RT.2729 In human SCC cell lines, ionizing RT stimulates kinase activity via ErbB receptors, resulting in downstream activation of intracellular proliferative pathways.2729 In addition, cytoprotective pathways triggered via EGFR may increase cell survival in response to RT.30 In human SCC cell lines, ionizing RT triggers ligand-independent caveolin-driven nuclear translocation of EGFR and formation of a complex with DNA-dependent protein kinase, thereby preventing DNA repair after RT exposure.31 In addition, RT may allow tumor cells to circumvent EGF-mediated growth inhibition. RT exposure promotes entry of SCC cells into S- and G2/M phases after stimulation with EGF and ionizing RT, significantly increasing SCC proliferation in an EGFR-dependent manner;27 this suggests that EGFR may play a role in post-RT tumor repopulation.27,32 Finally, EGFR overexpression has been implicated in fostering cancer stem cell survival, including expression of certain cancer stem cell genes and tumorsphere formation in HNSCC cell lines.33

Clinical data on ErbB family inhibitors in HNSCC

There are two classes of available agents with anti-EGFR activity: monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs). mAbs act at the receptor’s extracellular domain, whereas TKIs act on the cytosolic adenosine triphosphate–binding domain of EGFR to inhibit autophosphorylation.34 Cetuximab is the first and only targeted therapy approved by the US Food and Drug Administration (FDA) for the treatment of HNSCC.35 This agent has the most robust clinical data among ErbB family inhibitors and is routinely used in clinical practice. Other targeted agents are currently being investigated in HNSCC. Herein, we discuss Phase II and III data available for ErbB family inhibitors, including completed (Tables 113) and ongoing trials (Table 4).

Table 1
Selected Phase II and III trials of cetuximab in LA HNSCC
Table 2
Selected Phase II and III trials of cetuximab in R/M HNSCC
Table 3
Selected Phase II and III data on ErbB family inhibitors in LA and R/M HNSCC
Table 4
Selected ongoing clinical trials of ErbB family inhibitors in Phase II or III development for HNSCC

Approved and investigational anti-EGFR mAbs

Cetuximab

Cetuximab is an IgG1 chimeric (human–murine) mAb that competitively binds with high affinity to EGFR. Cetuximab has two FDA-approved indications: treatment of LA HNSCC (combined with RT) and R/M HNSCC (combined with platinum/5-fluorouracil or as monotherapy for platinum-refractory disease).3537

Cetuximab for LA HNSCC

Bonner et al36,37 conducted a pivotal multinational, randomized, Phase III trial evaluating the addition of cetuximab to definitive RT for patients with stage III–IV, nonmetastatic HNSCC. Approximately 60% of patients had oropharyngeal primaries. Overall, cetuximab-RT had an acceptable toxicity profile, with the exception of acneiform rash and infusion-related events, which were more common with cetuximab. Median duration of locoregional control (primary endpoint) was better with cetuximab-RT vs RT alone (24.4 vs 14.9 months; P=0.005). Median OS was also improved with cetuximab-RT vs RT alone (49.0 vs 29.3 months; P=0.03).36 After 5 years of follow-up, OS rate was 45.6% for cetuximab-RT vs 36.4% with RT alone (P=0.018). With cetuximab-RT, OS was significantly improved in patients who experienced grade ≥2 acneiform rash compared with patients who had no or grade 1 rash (HR, 0.49; 95% CI, 0.34–0.72; P=0.002).37 Subset analyses demonstrated that the benefit of cetuximab was restricted to patients aged <65 years, or those with a good Karnofsky performance status (ie, 90–100).37 Importantly, no head-to-head comparisons have evaluated cetuximab vs a platinum-based regimen concurrent with RT. The Radiation Therapy Oncology Group (RTOG) recently completed accrual of a randomized Phase III trial to address this comparison in HPV-positive oropharyngeal SCC (RTOG 1016; Table 4). Therefore, cisplatin-based CRT is still widely accepted as standard treatment for patients with LA HNSCC, based on a meta-analysis of 17,346 patients that demonstrated an absolute 5-year survival benefit of 6.5% with concomitant CRT compared with RT alone.38

The addition of cetuximab to definitive cisplatin-based CRT does not further improve survival. RTOG 0522 evaluated 891 patients with stage III–IV nonmetastatic HNSCC who were randomized to receive CRT (cisplatin 100 mg/m2 on days 1 and 22; RT 70–72 Gy) or the same regimen with weekly cetuximab.39 At the third interim analysis, the conditional power was <10%, which triggered early reporting. The addition of cetuximab resulted in more frequent RT interruptions (26.9% vs 15.1% for CRT alone); mean cisplatin delivery was similar. Patients with p16-positive OPC had better 3-year probability of progression-free survival (PFS; 72.8% vs 49.2%; P<0.001) and OS (85.6% vs 60.1%; P<0.001) than patients with p16-negative OPC; EGFR expression did not distinguish outcome. Cetuximab had significantly higher rates of acute grade ≥3 mucositis, skin reactions, fatigue, anorexia, and hypokalemia; after 90 days, adverse event (AE) rates were similar.

Integration of cetuximab into a larynx preservation paradigm was evaluated in TREMPLIN, a randomized Phase II trial of 116 patients with stage III–IV laryngeal or hypopharyngeal SCC suitable for total laryngectomy.40 After three cycles of induction chemotherapy (cisplatin/docetaxel/5-fluorouracil), further treatment was based on response to chemotherapy. Patients with <50% response received salvage surgery; patients with ≥50% response were randomized to definitive RT (70 Gy) with either high-dose cisplatin or concurrent cetuximab (400 mg/m2 loading dose, then 250 mg/m2 weekly). Treatment compliance was higher with cetuximab (71% completed all weekly doses) vs cisplatin (42% received all three doses). There was no difference in acute grade ≥3 mucositis (43% in each arm), but grade ≥3 in-field dermatitis was more common with cetuximab (57% vs 26%). In an intent-to-treat analysis, there was no difference in larynx preservation at 3 months (primary endpoint; 95% with cisplatin vs 93% with cetuximab), larynx function preservation (87% vs 82%), and OS at 18 months (92% vs 89%). Locoregional failure rate (median follow-up, 36 months) was 13.3% with cisplatin and 21.4% with cetuximab. However, due to the increased locoregional failure rate with cetuximab, more salvage laryngectomies were performed in the cetuximab arm, ultimately resulting in similar locoregional failure rates (13.3% vs 10.7%). There was no difference in 2-year laryngoesophageal dysfunction–free survival rate, a composite endpoint included after the study was designed (79% vs 72%).40

Additional studies of cetuximab integrated into standard platinum-based CRT or with RT alone in the induction or adjuvant settings are summarized in Table 1; ongoing trials with RT are listed in Table 4.

Cetuximab for R/M HNSCC

The proof-of-principle trial of cetuximab as first-line treatment for R/M HNSCC was published in 2005.41 This Eastern Cooperative Oncology Group randomized, multi-institutional, placebo-controlled, Phase III trial of 117 evaluable patients evaluated cisplatin (100 mg/m2 every 4 weeks) with cetuximab (400 mg/m2 loading dose, then 250 mg/m2 weekly) or placebo. Significant improvement in RR was observed with cetuximab (26% vs 10%; P=0.03). While cetuximab had better median PFS (4.2 vs 2.7 months) and OS (9.2 vs 8.0 months), these findings were not statistically significant. The trial, however, was not adequately powered for survival.

Based on these findings, the EXTREME trial confirmed the benefit of adding cetuximab to chemotherapy as first-line treatment for R/M HNSCC.42 Four hundred forty-two patients were randomized to cisplatin (100 mg/m2) or carboplatin (5 mg/mL/min) on day 1, followed by 5-fluorouracil 1,000 mg/m2 daily for 4 days, every 3 weeks for a maximum of six cycles, or the same chemotherapy plus cetuximab (400 mg/m2 loading dose, then 250 mg/m2 weekly). Patients in the cetuximab arm with response or stable disease received maintenance cetuximab until disease progression or unacceptable toxicity. Crossover was not allowed. Median OS was 7.4 months with chemotherapy alone vs 10.1 months with cetuximab (P=0.04). Addition of cetuximab also prolonged median PFS (from 3.3 to 5.6 months; P<0.001) and RR (from 20% to 36%; P<0.001). These clinical benefits were not associated with adverse quality of life. Of 219 patients receiving cetuximab, 9% had grade 3 skin reactions and 3% had grade ≥3 infusion reactions; there were no cetuximab-related deaths. A subset analysis suggested greater benefit for patients aged <65 years and those who had better performance status or received cisplatin. Additional trials have evaluated cetuximab in the first-line setting and for platinum-refractory R/M HNSCC (Table 2).

Panitumumab

Panitumumab is a fully human IgG2 mAb with high affinity for EGFR.43 Unlike cetuximab, panitumumab’s human structure results in minimal infusion-related reactions. Results of the SPECTRUM trial were recently published.44 This was a randomized, multinational, Phase III trial of 657 patients with R/M HNSCC who received cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1,000 mg/m2 daily on days 1–4) every 3 weeks with or without panitumumab (9 mg/kg on day 1) until disease progression or for a maximum of six cycles. Patients without disease progression could continue receiving panitumumab maintenance after the initial six cycles of chemotherapy. Crossover was not allowed. There was no significant difference in median OS (primary endpoint; 11.1 vs 9.0 months; P=0.14). Panitumumab did prolong median PFS by 1.2 months (5.8 vs 4.6 months; P=0.004). Several grade ≥3 toxicities were more frequent with panitumumab, including skin or eye toxicity, diarrhea, hypomagnesemia, and cardiac arrhythmias. There were also more treatment-related deaths with panitumumab (14 [4%] patients) vs chemotherapy (8 [2%] patients). A predefined subanalysis evaluating the prognostic implication of HPV status was performed; however, direct comparisons with other trials may be confounded by the low p16 cutoff threshold (10%) that was utilized. Furthermore, approximately half of p16-positive tumors involved nonoropharyngeal primaries, for which the relative importance of HPV status remains to be defined.45 The randomized Phase II PARTNER trial preliminarily demonstrated improved PFS and RR with docetaxel/cisplatin plus panitumumab vs docetaxel/cisplatin alone as first-line treatment for R/M HNSCC, but with an increased frequency of grade 3/4 AEs (73% vs 56%).46 For LA HNSCC, the randomized Phase II CONCERT-2 trial of 151 patients receiving panitumumab/RT vs CRT demonstrated trends favoring CRT for 2-year locoregional control (primary endpoint; 51% with panitumumab/RT vs 61% with CRT), PFS (P=0.03), and OS (P=0.10); rates of grade ≥3 AEs were similar (85% vs 81%).47 More recently, results from the National Cancer Institute of Canada Clinical Trials Group HN.6 Phase III trial of panitumumab/RT (accelerated fractionation) vs cisplatin/RT (standard fractionation) in LA HNSCC were presented, which failed to establish noninferiority for the primary endpoint of 2-year PFS (76% vs 73%; HR, 0.95; 95% CI, 0.6–1.5; P=0.83) and showed a similar grade >3 nonhematologic AE rate (91% vs 88%; P=0.25).48 In a separately presented quality of life analysis, significant differences favoring the panitumumab arm were seen during the last week of RT; however, there was no durable quality of life benefit relative to cisplatin/RT.49 A Phase II study of panitumumab/chemotherapy vs chemotherapy alone in R/M HNSCC (NCT00756444) was recently completed and data are forthcoming. Several trials of panitumumab for R/M and LA HNSCC are ongoing (Table 4).

Zalutumumab

Zalutumumab is a fully human IgG1 mAb that targets EGFR domain III and inhibits binding of EGF and TGF-α to EGFR.50 Zalutumumab also prevents conformational changes in EGFR that are necessary for its activation.50 An open-label, randomized, Phase III trial investigated zalutumumab plus best supportive care (BSC) vs BSC alone in 286 patients with R/M HNSCC after failure of platinum-based chemotherapy.51 Zalutumumab prolonged median PFS compared with BSC alone (9.9 vs 8.4 weeks; P=0.0012). However, the trial failed to meet its primary endpoint of improved median OS (6.7 vs 5.2 months; P=0.06). The most frequent grade ≥3 AEs with zalutumumab were rash, anemia, and pneumonia.51 Although Genmab (Princeton, NJ, USA) suspended clinical development of zalutumumab in 2011,50 there is an ongoing Phase III trial evaluating zalutumumab combined with definitive CRT for pharyngeal and laryngeal primaries (NCT00496652 [DAHANCA 19]). Preliminary results reported no increase in locoregional control, disease-specific survival, or OS with the addition of zalutumumab to CRT.52

Nimotuzumab

Nimotuzumab is a fully humanized IgG1 mAb that binds domain III of EGFR.53 Unlike zalutumumab, nimotuzumab prevents ligand binding, but not conformational receptor changes.54 A Phase II, randomized, placebo-controlled, double-blinded trial compared nimotuzumab-RT with placebo-RT in 106 patients with LA HNSCC who were medically unfit for standard CRT.55 The primary endpoint of complete RR was met (59.5% for nimotuzumab-RT vs 34.2% for RT; P=0.04). The intent-to-treat analysis demonstrated a nonsignificant trend toward improved median OS with nimotuzumab-RT (12.5 vs 9.47 months). However, in a research site–specific subanalysis of 88 patients, nimotuzumab-RT was associated with significant OS benefit (median 14.0 vs 8.83 months; P=0.02). Finally, an analysis of median OS by EGFR status showed that it was significantly longer for patients with EGFR-positive tumors who were receiving nimotuzumab vs placebo (16.5 vs 7.2 months; P=0.004). There was no survival advantage for patients with EGFR-negative tumors. No grade ≥3 AEs or skin toxicity were observed.55 Another study linking nimotuzumab-elicited outcomes with EGFR expression was a randomized, multicenter, Phase IIb study that divided 92 patients with LA HNSCC into two treatment groups (CRT vs RT for those with poor performance status), further stratified by whether they received nimotuzumab or placebo.56 Patients receiving nimotuzumab-CRT had a significantly higher median OS than those receiving placebo-CRT (>30 months vs 22 months; P<0.003). There was a significant correlation between EGFR expression and improved OS in the nimotuzumab-CRT arm (P=0.02), which remained significant at 24 months (P=0.01).56 Recently, preliminary results of a Phase II trial of 56 patients with LA HNSCC who were randomized to CRT with or without nimotuzumab demonstrated significantly higher RR with nimotuzumab vs CRT alone (96% vs 72%; P=0.02).57 Furthermore, there was no potentiation of treatment-related toxicity, suggesting nimotuzumab could be safely added to standard CRT.

A Phase II study of nimotuzumab/chemotherapy vs chemotherapy alone in LA HNSCC (NCT01425736) was recently completed and data are forthcoming. Several ongoing Phase II and III trials evaluating nimotuzumab for treatment of LA HNSCC are summarized in Table 4.

MEHD7945A and Sym004

MEHD7945A, a first-in-class human IgG1 mAb targeting EGFR and ErbB3/HER3,5860 will be evaluated vs cetuximab in a Phase II trial in R/M HNSCC (NCT01577173). Sym004, a novel anti-EGFR therapy containing 2 mAbs targeting nonoverlapping epitopes in domain III,61 was evaluated in a Phase II study of 26 heavily pretreated patients with R/M HNSCC who developed resistance to anti-EGFR mAb-based therapy.62 Preliminary findings revealed tumor shrinkage in 8 patients, while 14 had stable disease; median PFS was 82 days. Skin rash was reported by 96% of patients, including 42% with grade ≥3.

Investigational ErbB family TKIs

While several oral, small-molecule, ErbB family TKIs are being evaluated, none have been approved for HNSCC at the time of publication.

Gefitinib

Gefitinib is a reversible EGFR TKI.63 Based on results from Phase III trials demonstrating that gefitinib has limited activity compared with chemotherapy for R/M HNSCC,64,65 there are no known plans for further development of gefitinib in HNSCC.

Erlotinib

Erlotinib is another reversible EGFR TKI.66,67 In LA HNSCC, erlotinib has demonstrated modest activity as neoadjuvant monotherapy,68 combined with definitive CRT,69 and with definitive bevacizumab-CRT.70 Another Phase II trial, however, demonstrated no improvement in complete RR or PFS when adding erlotinib to definitive CRT for LA HNSCC.71

For R/M HNSCC, Phase II data with erlotinib suggest antitumor activity with acceptable tolerability. Erlotinib monotherapy in 115 patients with R/M HNSCC, regardless of HER1/EGFR status, demonstrated an RR of 4.3% (all partial responses).72 There were no differences in PFS or OS in subgroup analyses; however, patients with grade ≥2 rash had significantly higher OS (P=0.045). Skin rash and diarrhea were the most frequently reported drug-related toxicities. A Phase I/II trial of 45 patients receiving cisplatin and erlotinib for R/M HNSCC demonstrated an RR of 21%, median PFS of 3.3 months, and median OS of 7.9 months.73 There was minimal grade ≥3 toxicity. A Phase II study of 50 patients receiving erlotinib in combination with cisplatin/docetaxel for R/M HNSCC demonstrated an RR of 67% and disease control rate (DCR) of 95%.74 Median OS and PFS at 19 months of follow-up were 11 and 6 months, respectively. Ongoing Phase II trials evaluating erlotinib with CRT for LA HNSCC and with chemotherapy followed by maintenance in R/M HNSCC are summarized in Table 4.

Lapatinib

Lapatinib is a reversible EGFR and ErbB2/HER2 TKI.75,76 A randomized, placebo-controlled, Phase II trial of lapatinib monotherapy followed by definitive CRT demonstrated clinical activity (RR, 17% vs 0% with placebo) in 107 patients with treatment-naïve LA HNSCC.77 In the R/M HNSCC setting, however, a Phase II trial of 45 patients receiving lapatinib monotherapy demonstrated good tolerability but no responses.78 Evaluation of lapatinib in Phase II trials with induction chemotherapy was discouraged after Phase I results demonstrated unacceptable toxicities (predominantly renal failure) when combined with standard induction regimens for LA laryngeal and hypopharyngeal SCC.79 A recently completed placebo-controlled Phase III trial of adjuvant lapatinib plus CRT followed by 1 year of lapatinib maintenance in patients with resected, high-risk HNSCC did not improve DFS.80 Ongoing Phase II trials are evaluating lapatinib with definitive CRT followed by 1 year of lapatinib maintenance for LA HNSCC (NCT00387127) and definitive RT for LA HNSCC in patients who cannot tolerate concurrent CRT (NCT00490061).

Afatinib

Afatinib is an irreversible ErbB family inhibitor (targets include EGFR, ErbB2/HER2, and ErbB4/HER4).81,82 Five Phase III studies are evaluating afatinib for LA HNSCC as adjuvant therapy and for R/M HNSCC as monotherapy or in combination with chemotherapy (Tables 3 and and4).4). In the LUX-Head & Neck 1 trial of afatinib vs methotrexate in R/M HNSCC after failure of platinum-based therapy, afatinib was associated with a significant improvement in the primary endpoint of PFS compared with methotrexate (2.6 vs 1.7 months; P=0.030); OS was not improved (P=0.70).83 The objective RR was 10% with afatinib (vs 6% with methotrexate), and DCR was 49% (vs 39%). PFS benefit was associated with positive patient-reported outcomes, with afatinib-treated patients reporting less pain, improved swallowing, and delayed deterioration of global health status. In subgroup analyses, patients with p16-negative non-OPC and local recurrence (rather than metastasis) without prior EGFR-targeted mAb therapy seemed to derive the most benefit from afatinib. The most common grade 3/4 treatment-related AEs were rash/acne (10%) and diarrhea (9%). A more recently presented biomarker analysis found a propensity for greater PFS benefit with afatinib vs methotrexate in the settings of p16-negative (2.7 vs 1.6 months; HR, 0.70; P=0.029), PTEN-high (2.9 vs 1.4 months; HR, 0.36; P=0.014), HER3-low (2.9 vs 2.0 months; HR, 0.47; P=0.014), and EGFR-amplified (2.8 vs 2.2 months; HR, 0.64; P=0.162) disease.84 Final results of a randomized, open-label, Phase II study that compared afatinib to cetuximab in 124 patients with platinum-refractory R/M HNSCC were recently published.85 In stage I, patients were randomized to daily afatinib or weekly cetuximab until disease progression or unacceptable toxicity, at which time crossover was permitted (stage II). Stage I results demonstrated comparable antitumor activity (tumor shrinkage, RR) and median PFS (13.0 weeks with afatinib vs 15.0 weeks with cetuximab; P=0.71). Approximately half (56%) the patients crossed over to the other treatment arm (stage II); disease progression was the primary reason. DCR by independent central review was 33% for afatinib (vs 19% with cetuximab), and median PFS was 9.3 weeks (vs 5.7 weeks) during stage II. Grade ≥3 toxicities were more frequent in patients treated with afatinib (47% vs 16%). The authors concluded that patients may benefit from sequential therapy, especially treatment with afatinib after cetuximab failure.85 Other Phase II trials of afatinib include one in a neoadjuvant setting (NCT01538381 [EORTC NOCI-HNCG]), another to evaluate potential biomarkers (NCT01415674 [PREDICTOR]), and another in HPV-negative LA HNSCC as a component of induction chemotherapy (NCT01732640).

Dacomitinib

Dacomitinib is an irreversible TKI that targets EGFR, ErbB2/HER2, and ErbB4/HER4.86 A Phase II study of dacomitinib monotherapy in 69 patients with R/M HNSCC demonstrated an RR of 12.7%; median PFS and OS were 12.1 and 34.6 weeks, respectively.87 Diarrhea, acneiform dermatitis, and fatigue were the most frequent grade ≥3 AEs. An ongoing placebo-controlled, Phase I/II study seeks to identify biomarker modulations associated with dacomitinib treatment when given preoperatively for resectable oral cavity HNSCC (NCT01116843).

Vandetanib

Vandetanib is a multitargeted TKI, including EGFR and vascular endothelial growth factor receptor 2.88,89 Preliminary results of vandetanib plus docetaxel (n=15) vs docetaxel alone (n=14) for R/M HNSCC demonstrated a partial RR of 13% with vandetanib plus docetaxel vs 7% with docetaxel alone, and a median PFS of 9 vs 3.2 weeks; serious AEs were comparable between arms.90 A Phase II trial of vandetanib with adjuvant CRT in high-risk, stage III–IV HNSCC was terminated early due to withdrawal of study drug; as only 34 of 170 planned patients were accrued, no analysis was performed (NCT00720083).

Perspectives

EGFR overexpression and its key role in HNSCC carcinogenesis make EGFR inhibition a promising molecular treatment strategy. Two classes of ErbB inhibitors are available: mAbs and small-molecule TKIs. To date, cetuximab remains the only FDA-approved ErbB family inhibitor for HNSCC. For LA disease, cetuximab is approved in combination with definitive RT; however, studies are ongoing to provide direct comparisons with platinum-based regimens. In R/M disease, cetuximab is approved both in combination with platinum-containing regimens and as monotherapy for platinum-refractory disease. The limited effect of other EGFR inhibitors in HNSCC could be explained by the different mechanisms of action of mAbs and TKIs. Notably, cetuximab has been shown to elicit an antibody-dependent cellular cytotoxicity response that is dependent on EGFR expression levels in HNSCC.91,92 Overexpression of EGFR and other ErbB family receptors, ErbB ligands, and downstream pathway components in HNSCC may promote positive feedback of the pathway.93 In cell lines, kinase-inactive EGFR can dimerize with ErbB2 and activate signaling downstream of EGFR, suggesting that the presence of EGFR is important for promoting cell survival, even in the absence of EGFR kinase activity.94 Kinase-inactive EGFR has also been shown to physically interact with several cancer-related proteins, including Axl and ephrin type-A receptor 2.95 Furthermore, EGFR has been shown to have kinase-independent roles in maintaining intracellular glucose levels and initiating autophagy, both of which contribute to increased cell survival.96,97 This evidence for functions of EGFR beyond its tyrosine kinase role may partially explain the lack of substantial efficacy of EGFR TKIs in EGFR-overexpressing cancers like HNSCC.

Because EGFR mutations are rarely detected in HNSCC,93 there is also a need to identify biomarkers to predict those patients most likely to benefit from EGFR-targeted agents, and lack of patient selection may partially explain the minimal responses observed thus far with the majority of EGFR inhibitors tested in HNSCC. Rash has been suggested to be a biomarker for EGFR inhibitor response and has been associated with improved outcomes in several tumor types, including HNSCC.98 In two HNSCC trials, statistically significant improvements in OS have been observed in patients who developed grade ≥2 skin rash following either erlotinib or cetuximab treatment compared with patients who developed no or grade 1 skin rash.37,72 Similarly, in a trial evaluating gefitinib in patients with R/M HNSCC, grade of skin toxicity positively correlated with DCR, PFS, and OS.99 Although the mechanism by which EGFR inhibitors cause dermatological toxicity is not fully understood, there is evidence to suggest that immune cell infiltration and inhibition of EGFR homodimer signaling may be associated with these skin toxicities.100,101

Conclusion

Although ErbB family members represent valid therapeutic targets in HNSCC, the modest RR seen with ErbB family inhibitors illustrates the need for continued research to identify potential resistance mechanisms and biomarkers for response. A detailed understanding of the role this family plays in the pathogenesis of HNSCC is critical so that we may further exploit this promising treatment strategy in our effort to maximize patient survival.

Acknowledgments

The authors received no direct compensation related to the development of the manuscript. Writing, editorial support, and formatting assistance were provided by Melissa Brunckhorst, PhD, of MedErgy, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. (BIPI). BIPI was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.

Footnotes

Author contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in either drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

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