Cancer of the Head and Neck: Targeted Molecular Therapy of Head and Neck Cancer

Katharine A. Price

Rafael Santana-Davila

Laura Q. M. Chow

Cesar A. Perez

Garrett Green

Loren K. Mell

Ezra E. W. Cohen

INTRODUCTION

Significant progress has been made in understanding the molecular biology of squamous cell carcinoma of the head and neck (SCCHN) including large-scale comprehensive sequencing, mutational analysis, and transcriptome arrays. From these analyses, it has become clear that several actionable alterations occur in SCCHN and that distinct biologic subtypes exist that depend on different biologic processes. The two broadest subtypes of SCCHN can be divided generally by etiology into tobacco related and human papillomavirus (HPV) related. It is clear that these subtypes not only represent entities that behave differently clinically but are quite disparate in their molecular phenotype and presumably in their sensitivity to specific targeted agents. This chapter will review the development of the most commonly tested targeted agents in SCCHN with an emphasis on drugs that have at least reached clinical trials. The only approved molecularly targeted agent in SCCHN currently is cetuximab, but as the number of agents grows and our ability to use predictive biomarkers improves, it is likely that many more will become part of standards of care in the near future.

Epidermal Growth Factor Receptor

The epidermal growth factor receptor (EGFR) is a transmembrane cell surface receptor that is a member of the ErbB family of receptor tyrosine kinases. The EGFR is activated by ligand binding that results in receptor homodimerization and stimulation of intracellular protein tyrosine kinase activity and activation of downstream signaling pathways including PI3K/AKT and RAS/MAPK/ERK. Dysregulation of the EGFR by increased expression or mutations can lead to altered growth signals and tumorigenesis.

The discovery that the EGFR is highly expressed in SCCHN marked the beginning of the era of targeted therapy for the treatment of SCCHN. The EGFR is expressed in the majority of patients with SCCHN and is associated with poor prognosis.¹^,²^,³^,⁴^,⁵^,⁶^,⁷ In a landmark paper by Grandis et al.,² it was demonstrated that mRNA from both the ligand TGF-α and the EGFR were significantly elevated in both tumor specimens and histologically normal mucosa specimens from patients with SCCHN compared with tissue from normal control patients. Ang and colleagues retrospectively tested tissue from 155 patients with SCCHN enrolled in a phase III trial for EGFR overexpression and correlated the results with multiple variables including T and N stage and survival endpoints. There was no association between high EGFR expression and T or N stage or the rate of distant metastases. However, both overall survival and disease-free survival rates of patients with high EGFR-expressing SCCHN were significantly lower (p = 0.0006 and p = 0.0016, respectively), and the local-regional relapse rate was significantly higher (p = 0.0031) compared with those of patients with low EGFR-expressing SCCHN.⁴

The strong preclinical evidence for the role of EGFR signaling in the genesis and progression of SCCHN led to the development of drugs targeting the EGFR that have met with mixed success in the clinical arena. Both monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) have been studied in clinical trials, but to date, only the EGFR monoclonal antibodies have achieved routine use in clinical practice.

EGFR Monoclonal Antibody: Cetuximab

Cetuximab (Erbitux, Bristol-Meyers Squibb, Princeton, NJ) is a chimeric monoclonal antibody that was first approved by the FDA in 2006 for use in patients with locally advanced cancer of the head and neck in combination with radiation therapy, thus making it the first approved targeted therapy for SCCHN. The standard dosing for cetuximab is an initial loading dose of 400 mg/m² followed by weekly doses of 250 mg/m². The long half-life of cetuximab does allow for every other week dosing with similar efficacy.⁸ The classic side effect of cetuximab is an acneiform rash, present in 76% to 88% of patients, with 1% to 17% having a severe rash.⁹ Other skin toxicities are commonly seen including skin dryness and fissuring, paronychia, and secondary bacterial skin infections. Infusion reactions are also common with cetuximab and can be serious (even fatal) in ˜3% of patients overall. However, the rate of infusion reactions can vary by geographic region, with consistently higher rates (up to 25%) reported in the southeastern United States.¹⁰^,¹¹^,¹²^,¹³ Cardiopulmonary arrest and sudden death have been reported in 2% of patients receiving cetuximab concurrent with radiation therapy and 3% of patients receiving cetuximab in combination with cytotoxic chemotherapy. Close monitoring of serum electrolytes, including magnesium, is strongly recommended.⁹

Cetuximab has been approved for use in SCCHN as part of definitive treatment in combination with radiation therapy, for R/M-SCCHN in combination with platinum-based cytotoxic chemotherapy, and as a single-agent for R/M-SCCHN after progression on platinum-based therapy. The subsequent pages will describe the key clinical trials that led to these approved indications.

Cetuximab with Radiation Therapy for Locally Advanced SCCHN

In 2006, Bonner et al.¹⁴ published a landmark trial in the New England Journal of Medicine that showed the benefit of cetuximab when added to definitive radiation therapy for the treatment of locally advanced SCCHN (LA-SCCHN). In this phase III, multinational, randomized study, 213 patients with LA-SCCHN were treated with radiation therapy and 211 patients were treated with radiation therapy plus weekly cetuximab (initial dose 400 mg/m² followed by 250 mg/m² weekly for the duration of radiation therapy). Baseline patient characteristics were well balanced. The majority of patients in both arms had cancer of the oropharynx followed by cancer of the larynx and hypopharynx; patients with cancer of the oral cavity were not included. Approximately 30% of the primary cancers in each arm were T4. Treatment toxicities were similar in both arms with the exception of increased grade 3 or 4 rash and infusion reactions in the patients receiving cetuximab. With a median follow-up of 54 months, the addition of cetuximab to definitive radiation therapy significantly improved survival outcomes. In patients treated with cetuximab and radiation therapy, the median duration of locoregional control was 24.4 months compared with 14.9 months in patients treated with radiation therapy alone (HR for locoregional progression or death, 0.68, p = 0.005). The median 3-year overall survival for patients treated with cetuximab plus radiation therapy was 49.0 months compared with 29.3 months in patients treated with radiation therapy alone (HR for death, 0.74, p = 0.03). The addition of cetuximab to radiation therapy significantly prolonged 3-year progression-free survival from 12.4 to 17.1 months (HR 0.70, p = 0.006). Long-term follow-up results of this landmark trial reported persistent survival benefit at 5 years in patients who received cetuximab and suggested a benefit in those patients who developed a rash greater than or equal to grade 2.¹⁵ The Bonner trial established concurrent cetuximab and radiation therapy as a curative treatment option for LA-SCCHN, although the standard of care for most patients remains concurrent radiation therapy and cisplatin. The fact that the control arm in the Bonner trial was radiation therapy alone, which is no longer considered standard of care for patients with LA-SCCHN with a good performance status, makes it difficult to interpret the results in light of other, more established treatment options. The TREMPLIN study for larynx preservation randomized 116 patients who responded to induction chemotherapy to either chemoradiation with highdose cisplatin or radiation therapy with cetuximab, but could not prove one regimen to be superior to the other.¹⁶ To date, there are no completed phase III trials that definitively show that cetuximab with radiation therapy is superior to chemoradiation therapy for LA-SCCHN.

Based on the premises that cetuximab added to chemotherapy enhances the response rate and improves survival in patients with R/M-SCCHN and that cetuximab is a radiation sensitizer, the randomized, phase III trial by the Radiation Therapy Oncology Group (RTOG) 0522 was conducted to assess the incremental benefit of adding cetuximab in the curative treatment setting to a backbone of accelerated radiation therapy (72 Gy in 42 fractions over 6 weeks) and two cycles of high-dose cisplatin (100 mg/m²).¹⁷ From November 2005 through May 2009, 941 patients with stage III or IV SCCHN were enrolled and 891 analyzed. Most of the patients were men (88%) with cancer of the oropharynx (70%; 73% p16 positive). Although the results were much anticipated, the addition of cetuximab failed to improve any outcome measures but did increase overall treatment toxicity. Patients with p16-positive cancer of the oropharynx had improved overall survival compared with p16-negative patients (85.6% vs. 60.1%, p < 0.001), as expected. EGFR expression did not determine survival outcomes. The combination of concurrent radiation therapy, cisplatin, and cetuximab as curative-intent therapy should not be routinely used unless specific subsets of patients who may benefit can be identified.¹⁷

Cetuximab for Recurrent/Metastatic SCCHN

Multiple studies have investigated the use of cetuximab for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) both as a single agent and in conjunction with cytotoxic chemotherapy. In 2005, two phase II trials that examined the role of cetuximab in patients with platinum-refractory R/M-SCCHN were published in the Journal of Clinical Oncology.¹⁸^,¹⁹ One trial by Herbst and colleagues treated 132 patients with squamous cell carcinoma of the oral cavity, pharynx, and larynx with a platinum doublet (cisplatin/paclitaxel or cisplatin/5-fluorouracil) to assess for responsiveness to platinum therapy. The 30 patients who responded to the initial chemotherapy were continued on the same regimen. The remaining patients with either stable disease (n = 51) or disease progression (n = 25) were subsequently treated with cisplatin (75 to 100 mg/m² once every 3 weeks) plus cetuximab at standard doses. A protocol amendment was performed after trial initiation to allow treatment of patients with progressive disease within 90 days of initial response to the platinum regimen with cisplatin and cetuximab (n = 54). Cetuximab did have activity in patients with proven platinum-refractory disease. In the group of patients with immediate progression or stable disease on platinum therapy, 20% and 18%, respectively, of patients subsequently responded to platinum and cetuximab. In contrast, only 6% of the patients who initially responded to platinum therapy but progressed within 90 days achieved a response upon treatment with cisplatin and cetuximab. Median durations of response for patients with immediate progression on platinum therapy, with progression within 90 days of platinum therapy, and with stable disease were 4.2, 4.1, and 7.4 months, respectively, with corresponding median overall survivals of 6.1, 4.3, and 11.7 months in patients who received cisplatin with cetuximab.¹⁸ Although the response rate to cisplatin/cetuximab in patients with initial progressive disease and those with stable disease were similar, the median response rate and overall survival were much better in the patients with stable disease, likely speaking to a more favorable underlying biology in this group of patients. Nonetheless, this trial was proof of principle that platinum resistance could be overcome with the addition of cetuximab in a subset of patients with R/M-SCCHN, albeit shortlived. The second trial by Baselga et al.¹⁹ enrolled patients with R/M-SCCHN with documented disease progression on a regimen of cisplatin or carboplatin. Ninety-six patients who met eligibility criteria were treated with platinum therapy at the same doses on which they progressed along with cetuximab at standard doses. The response rate was 10%, and the disease control rate (all responses plus stable disease) was 53%. Median time to progression was 85 days, and median overall survival was 183 days.

The single-agent response to cetuximab in patients with R/M-SCCHN after failure of platinum-based chemotherapy
was shown to be 13% in an open-label, multicenter phase II trial by Vermorken et al.²⁰ The study design allowed patients who progressed on cetuximab alone to subsequently receive salvage therapy with platinum and cetuximab. In the initial phase, 103 patients with platinum-refractory disease were treated with cetuximab at standard doses with a response rate of 13%, disease control rate of 46%, and median time to progression 70 days. Of the 53 patients who progressed on cetuximab and went on to receive salvage therapy, there were no responders. This trial highlights the very modest benefit of single-agent cetuximab and underscores the need for a reliable biomarker for patients who will respond to cetuximab, so as to avoid unnecessary toxicity and treatment cost in those patients unlikely to derive a benefit from this therapeutic approach. Given the similar response rates of the trials by Baselga and Vermorken in platinum-refractory disease (10% and 13%, respectively), there does not appear to be any benefit of retreating patients with platinum-refractory R/M-SCCHN with a platinum agent, as a similar response could likely be achieved with cetuximab alone with less toxicity.

In 2006, Burtness and colleagues reported in the Journal of Clinical Oncology that the addition of cetuximab to cisplatin in patients with R/M-SCCHN improved overall response rate but not progression-free or overall survival. In this phase III, randomized, placebo-controlled trial, 117 patients with R/M-SCCHN were randomized to receive cisplatin 100 mg/m² IV once every 4 weeks with cetuximab (Arm A) or placebo (Arm B). The study was negative for its primary endpoint of progressionfree survival (4.2 months with cetuximab, 2.7 months with placebo; p = 0.09). Median overall survival was 9.2 months with cetuximab and 8.0 months with placebo (p = 0.21). The objective response rate was significantly improved with the addition of cetuximab from 10% with placebo to 26% (p = 0.03).²¹

The EXTREME trial by Vermorken et al.²² in 2008 that added cetuximab to a regimen of platinum and 5-fluorouracil was the first trial to demonstrate an improvement in overall survival in patients with recurrent/metastatic cancer since the introduction of cisplatin in the 1980s.²³ The study was a first-line therapy trial for patients with R/M-SCCHN and randomized 220 of 442 eligible patients to platinum (cisplatin 100 mg/m² IV or carboplatin [AUC 5] on day 1) and 5-fluorouracil (1,000 mg/m²/day days 1 to 4) with or without cetuximab at standard doses for a maximum of six cycles. In patients with a response of stable disease or better, cetuximab was continued until disease progression or unacceptable toxicities. The addition of cetuximab to cytotoxic chemotherapy improved the median overall survival from 7.4 to 10.1 months (HR 0.80, p = 0.04). Both progression-free survival and response rate were also significantly improved in the cetuximab arm. Sepsis was significantly more common in the patients who received cetuximab (p = 0.02), but no cetuximab-associated deaths were reported. A separate quality of life (QOL) analysis reported that the addition of cetuximab to chemotherapy did not adversely affect patient QOL.²⁴ Although the EXTREME trial to date represents the regimen with the longest median overall survival in patients with recurrent/metastatic cancer, it is not known whether first-line platinum-based chemotherapy followed by second-line cetuximab could achieve the same survival benefit. Given the overall survival benefit and lack of measurable effect on QOL, it is a very appropriate regimen to consider for patients with R/M-SCCHN who have a good performance status for whom aggressive therapy is appropriate.

Although most of the studies of cetuximab in combination with chemotherapy in patients with R/M-SCCHN have included platinum-containing regimens, one promising phase II trial studied the combination of weekly cetuximab at standard doses with paclitaxel (80 mg/m² weekly) as first-line treatment for patients with R/M-SCCHN.²⁵ Treatment was well tolerated, and the overall response rate was 54% (95% confidence interval [CI] 39% to 69%), with 10 (22%) complete responses and a disease control rate of 80%. Median progression-free and overall survival times were 4.2 (95% CI 2.9 to 5.5 months) and 8.1 months (95% CI 6.6 to 9.6 months), respectively.²⁵ This regimen represents a good therapeutic option, particularly for patients who develop recurrent/metastatic disease shortly after completing definitive chemoradiation therapy with a platinum agent, or for those patients whose performance status precludes the use of platinum chemotherapy.

Lack of Predictive Biomarkers for Benefit of EGFR Monoclonal Antibodies

Despite the fact that the majority of SCCHN overexpress EGFR, only a fraction of patients will have a major response to treatment with EGFR inhibitors.²⁰ To date, there is no reliable biomarker that can predict response or primary resistance to EGFR inhibition in SCCHN. Multiple secondary analyses of the EXTREME trial have been conducted to try to identify a predictive biomarker for response to cetuximab, including analyses of EGFR copy number, tumor EGFR expression, and p16/HPV status. Licitra et al.²⁶^,²⁷ performed sequential analyses of the tissue of patients treated on the EXTREME trial to explore whether EGFR copy number or EGFR expression were candidate predictive biomarkers for efficacy of cetuximab in the first-line recurrent/metastatic setting in combination with platinum-based chemotherapy. In 2011, the investigators used dual-color fluorescent in situ hybridization (FISH) techniques to determine the absolute and relative EGFR copy number in 312 of 442 (71%) patient samples. Only 11% of tumors were found to have a high level of amplification of the EGFR gene; most tumor samples were modestly amplified. There was no association of EGFR copy number with overall survival, progression-free survival, or best overall response. The authors concluded that EGFR copy number was not a candidate predictive biomarker for response to cetuximab in combination with first-line platinum/5-fluorouracil chemotherapy in patients with R/M-SCCHN.²⁶ In 2013, the same investigators published a similar analysis exploring whether tumor EGFR expression level was predictive of cetuximab benefit. Tissue was available from 93% of patients treated on the EXTREME study, and tumor EGFR expression level was scored (scale 1 to 300). The benefit of adding cetuximab to chemotherapy was seen across all score ranges, indicating that tumor EGFR expression was not a valid predictive biomarker.²⁷

In 2014, a retrospective analysis of the EXTREME trial was conducted to see if there was a differential response to cetuximab and first-line platinum chemotherapy by p16 and HPV status.²⁸ Paired tissue samples were used to assess p16INK4A expression and HPV status in extracted DNA samples using oligonucleotide hybridization assays. A total of 416 (of 442) patients had available tissue. Only 10% of tissue was positive for p16 and 5% for HPV; these patients had improved survival compared with patients who were p16 or HPV negative. HPV or p16 status did not appear to influence
response to therapy; cetuximab combined with chemotherapy improved outcomes in both groups.²⁸ In contrast, p16 subset analysis of the SPECTRUM trial (chemotherapy with or without panitumumab in patients with R/M-SCCHN, see section “Other EGFR Monoclonal Antibodies”) suggested a possible increased benefit of EGFR inhibition in patients with p16-negative tumors. In 443 (67%) patients, p16 status was assessed and 99 samples (22%) were p16 positive. Median overall survival in patients with p16-negative tumors was longer in the panitumumab group than in the control group (11.7 months [95% CI 9.7 to 13.7] vs. 8.6 months [6.9 to 11.1]; HR 0.73 [95% CI 0.58 to 0.93]; p = 0.0115), but this difference was not shown for p16-positive patients (11.0 months [7.3 to 12.9] vs. 12.6 months [7.7 to 17.4]; 1.00 [0.62 to 1.61]; p = 0.998).²⁹ Further studies are needed to validate or refute these findings.

Cetuximab as a Component of Induction or Adjuvant Therapy

Induction chemotherapy followed by definitive chemoradiation is an acceptable treatment paradigm for LA-SCCHN. The accepted standard induction therapy regimen is cisplatin (75 to 100 mg/m² day 1), docetaxel (75 mg/m² day 1), and 5-fluorouracil (1,000 mg/m² days 1 to 4) once every 21 days for three cycles followed by definitive chemoradiation.³⁰^,³¹ Cetuximab as part of induction chemotherapy was initially studied in a phase I trial and found to be safe and tolerable.³² Two phase II studies added cetuximab to carboplatin and paclitaxel in both the induction and definitive chemoradiation component of treatment. The regimen was felt to be safe and effective.³³^,³⁴ However, the Brown study compared their results to prior studies that had been conducted at their institution using the same regimens without cetuximab, and the survival results appeared the same.³⁵^,³⁶ The future of induction therapy with or without cetuximab remains to be determined.³⁷

The role of cetuximab as part of adjuvant therapy for resected SCCHN is still under investigation. The randomized phase II trial conducted by the RTOG 0234 randomized patients with resected stage III or IV SCCHN with one or more risk factors including extracapsular extension, positive surgical margins, or two or more involved lymph nodes to radiation therapy with either weekly cetuximab and cisplatin (30 mg/m²) or weekly cetuximab and docetaxel (15 mg/m²). Cetuximab was safely incorporated into both treatment regimens. The cetuximab/docetaxel arm was better tolerated and had improved disease-free and overall survival compared with cetuximab/cisplatin and historical controls. The regimen of cetuximab/docetaxel is currently undergoing further study as part of an adjuvant phase II/III RTOG trial for resected stage III or IV SCCHN with high-risk features (RTOG 1216). Cetuximab alone in combination with radiation therapy is currently being investigated in patients with intermediate risk, resected SCCHN (RTOG 0920); future results may provide an additional indication for the use of cetuximab.

Other EGFR Monoclonal Antibodies

Several other monoclonal antibodies directed against the EGFR have been developed and tested in patients with SCCHN, although none to the same extent as cetuximab, and the advantage of these EGFR monoclonal antibodies over cetuximab remains to be defined. Panitumumab (Vectibix, Amgen Inc., Thousand Oaks, CA) is a human IgG2 monoclonal antibody targeting EGFR domain III that was shown to be safe in combination with intensity-modulated radiation therapy (IMRT) and chemotherapy in a phase I trial of stage III and IV SCCHN,³⁸ but met with limited success in patients with R/M-SCCHN. The SPECTRUM trial was an open-label, phase III, multicenter, international trial that randomized 657 patients with R/M-SCCHN to up to six 3-week cycles of cisplatin (100 mg/m² on day 1) and 5-fluorouracil (1,000 mg/m² on days 1 to 4) with or without panitumumab (9 mg/kg on day 1). Patients in the panitumumab arm were given the option of continuing panitumumab as maintenance therapy. The study failed to meet its primary endpoint of overall survival, but the addition of panitumumab did improve progression-free survival to 5.8 months (95% CI 5.6 to 6.6) in the panitumumab group from 4.6 months (4.1 to 5.4) in the control group ( HR 0.780, 95% CI 0.659 to 0.922; p = 0.0036). Grade 3 or 4 toxicities were higher in the panitumumab arm, notably skin and eye toxicity, diarrhea, hypomagnesaemia, hypokalemia, and dehydration. Fourteen patients (4%) on the panitumumab arm died during treatment, five of which (2%) were attributed to the drug; eight patients (2%) died in the control arm. Planned subset analysis suggested a possible preferential benefit of panitumumab for patients with p16-negative SCCHN (see section on “Lack of Predictive Biomarkers for Benefit of EGFR Monoclonal Antibodies”). The role that panitumumab may play in the clinical management of patients with R/M-SCCHN remains to be further defined.

Zalutumumab (formerly HuMax-EGFr; Genmab, Princeton, NJ), a human IgG1 monoclonal antibody targeting the EGFR domain III, has shown single-agent activity in patients with R/M-SCCHN³⁹^,⁴⁰ and prolonged progression-free survival compared with best supportive care.³⁹ The largest trial of zalutumumab was published in 2011 by Machiels and colleagues and randomized 191 patients with R/M-SCCHN and progressive disease on platinum therapy in a 2:1 fashion to zalutumumab or best supportive care with the option to receive methotrexate (maximum dose 50 mg/m² weekly). In order to exploit the observation that the characteristic rash associated with EGFR inhibitors can be an indication of treatment response, the dose of zalutumumab was individually titrated (after standard loading doses of 8 mg/kg followed by two weekly doses of 4 mg/kg) to a maximum dose of 16 mg/kg every 2 weeks to try and achieve a grade 2 rash. Based on survival analysis of 82 patients with a grade 2 to 3 rash and 78 patients with a grade 0 to 1 rash, maximum rash grade was not predictive of overall survival (8.0 months for grade 2 to 3, 95% CI 6.7 to 9.8, vs. 6.8 months for grade 0 to 1, 95% CI 6.1 to 1.7; HR for death 0.72, 95% CI 0.51 to 1.02; p = 0.068). Single-agent activity of zalutumumab was 6.3% compared with 1.1% in the best supportive care/methotrexate arm. As with panitumumab, progression-free survival but not overall survival was improved by zalutumumab. Median overall survival was 6.7 months (95% CI 5.8 to 7.0) in the zalutumumab group and 5.2 months (4.1 to 6.4) in the control group (hazard ratio [HR] for death, stratified by WHO performance status, was 0.77, 97.06% CI 0.57 to 1.05; p = 0.0648). Progressionfree survival was longer in the zalutumumab group (9.9 weeks) than in the control group (8.4 weeks; HR for progression or death, stratified by WHO performance status, was 0.63, 95% CI 0.47 to 0.84; p = 0.0012). A second, smaller, open-label, phase II study investigated the efficacy and safety of zalutumumab in patients with platinum-refractory R/M-SCCHN.⁴⁰
Ninety patients were enrolled; notably 23% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. Objective response rate for zalutumumab was 5.7%, and disease control rate (objective responses + stable disease) was 39.8%. Median overall survival was 5.3 months (95% CI [4.1, 7.1]), and median progression-free survival was 2.1 months (95% CI [2.0, 2.6]). Performance status, as would be expected, impacted survival outcomes: patients with an ECOG performance status of 0 to 1 survived a median of 6.3 months compared with 2.5 months for those patients with a performance status of 2.⁴⁰ Side effects of zalutumumab in both studies were consistent with those reported for other EGFR monoclonal antibodies.³⁹^,⁴⁰ Zalutumumab appears to have single-agent activity comparable to cetuximab. Although it statistically prolonged progression-free survival compared with best supportive care/methotrexate, the magnitude of the benefit is small and the clinical relevance of this benefit is questionable. Perhaps the clinical utility for zalutumumab will lie in the treatment of patients with a poor performance status who are not candidates for more aggressive treatment regimens.

Nimotuzumab (formerly h-R3; Oncoscience AG, Germany, and YM Biosciences Inc., ON, Canada) is a humanized anti-EGFR IgG1 monoclonal antibody that is approved for treating SCCHN in multiple countries in Asia, Africa, and South America.⁴¹ Most of the trials of nimotuzumab have used it along with radiation therapy or chemoradiation therapy for LA-SCCHN.⁴²^,⁴³^,⁴⁴ A phase I trial using nimotuzumab in combination with radiation therapy in patients with SCCHN unsuitable for standard chemoradiation therapy confirmed activity of nimotuzumab by demonstrating decreased phosphorylation of the EGFR and was tolerated in this patient population.⁴² An open-label, phase II study in India demonstrated improvement in long-term survival in patients who received nimotuzumab in combination with radiation therapy or chemoradiation therapy. The trial randomized 92 treatment-naive patients (1:1) with advanced SCCHN into chemoradiation (CRT +/− nimotuzumab) or radiation (RT +/− nimotuzumab) group by investigator’s discretion. Overall response was 100% with CRT + nimotuzumab, 70% with CRT, 76% with RT + nimotuzumab, and 37% with RT alone. Five-year overall survival was 57% with CRT + nimotuzumab, 26% with CRT (p = 0.03), 39% with RT + nimotuzumab, and 26% with RT alone (p > 0.05). Studies from Cuba also suggested a survival benefit for nimotuzumab when given along with radiation or chemoradiation therapy⁴⁴^,⁴⁵ with associated improvement in disease-related symptoms and QOL.⁴⁴ Notably, nimotuzumab does not cause significant skin toxicity, making it an attractive option compared with other EGFR monoclonal antibodies.

EGFR Tyrosine Kinase Inhibitors

Specific EGFR Tyrosine Kinase Inhibitors: Gefitinib and Erlotinib

Gefitinib (Iressa; AstraZeneca, Wilmington, DE) and Erlotinib (Tarceva; Genentech, Inc., South San Francisco, CA) are highly specific, reversible EGFR TKIs that have been studied in patients with SCCHN as part of definitive treatment and in patients with R/M-SCCHN, but neither drug has become part of standard practice.

Gefitinib (Iressa; AstraZeneca, Wilmington, DE) is a highly selective oral EGFR TKI with a single-agent response rate of 7% to 11% in phase II trials of R/M-SCCHN⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹; escalating the dose of gefitinib to achieve a rash greater than or equal to grade 2 did not alter the response rate.⁴⁹ A single phase II trial of gefitinib for the treatment of platinum-refractory nasopharynx cancer showed no activity.⁵⁰ A single phase I trial showed promising results with the combination of gefitinib and celecoxib, but this combination was not pursued in subsequent clinical trials. Two phase III trials have investigated the activity of gefitinib in patients with R/M-SCCHN.⁵¹^,⁵² The first trial published in 2009 randomized 486 patients to gefitinib (250 mg/day), gefitinib (500 mg/day), or methotrexate (40 mg/m² IV weekly). There were no significant differences in response rate or overall survival across all arms, and the gefitinib arms had increased rates of tumor bleeding events compared with methotrexate (8.9%, gefitinib 250 mg/day; 11.4%, gefitinib 500 mg/day; 1.9%, methotrexate).⁵¹ Given promising preclinical and phase I data of the combination of docetaxel and EGFR TKIs,⁵³^,⁵⁴ a phase III trial through the ECOG was conducted investigating the efficacy of docetaxel and gefitinib in patients with previously treated R/M-SCCHN. A total of 270 patients were randomized to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/day (arm B) until disease progression. Patients in the placebo arm were allowed to receive gefitinib at the time of disease progression. The study was closed early due to lack of benefit. Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (HR, 0.93; 95% CI, 0.72 to 1.21; p = 0.60).⁵²

Multiple phase I and II trials demonstrated the feasibility of adding gefitinib to definitive radiation therapy⁵⁵ or chemoradiation therapy⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹ for patients with stage III and IV SCCHN without clear benefit and with potential increased toxicity.⁵⁷^,⁶⁰ Three phase II trials utilized gefitinib concurrent with definitive chemoradiation therapy for LA-SCCHN followed by maintenance gefitinib with mixed responses.⁶¹^,⁶²^,⁶³ No benefit was seen when gefitinib was used in combination with hyperfractionated radiation, cisplatin, or 5-fluorouracil, followed by gefitinib maintenance,⁶¹ or when gefitinib was combined with standard cisplatin and radiation followed by maintenance gefitinib.⁶² A possible benefit, compared with historical controls, was seen when gefitinib was added to a regimen of split-course concurrent chemoradiation therapy with fluorouracil, hydroxyurea, and twice daily radiation therapy followed by maintenance gefitinib for 2 years.⁶³ Given the overall lack of benefit of gefitinib in patients with LA-SCCHN receiving radiation therapy or chemoradiation therapy and in patients R/M-SCCHN, treatment with this agent is not considered an acceptable standard practice.

Erlotinib has been studied in R/M-SCCHN as a single agent, in combination with cytotoxic chemotherapy, and in combination with other targeted agents. Although an early study of erlotinib as neoadjuvant therapy in an untreated patient population showed encouraging results with a single-agent response rate of 29%,⁶⁴ the activity of erlotinib in patients with R/M-SCCHN is modest and consistent with that seen with gefitinib. The best evidence for single-agent activity of erlotinib comes from a multicenter phase II study published in 2004 in the Journal of Clinical Oncology of 115 patients with R/M-SCCHN treated with erlotinib that showed an overall response rate of 4.3% (95% CI, 1.4% to 9.9%) and disease stabilization in 38.3% of patients for a median duration of 16.1 weeks.⁶⁵ Erlotinib in combination with chemotherapy for patients with R/M-SCCHN did not appear to have any additional benefit over other regimens. The combination
of erlotinib and docetaxel was not tolerated,⁶⁶ and a phase I/II trial reported a 21% response rate for the combination of erlotinib and cisplatin, consistent with established regimens in this patient population.⁶⁷ Erlotinib maintenance therapy after treatment with platinum and gemcitabine for recurrent nasopharynx cancer was not effective.⁶⁸ The combination of erlotinib and temsirolimus was poorly tolerated and led to early closure of the study. Erlotinib and bevacizumab were investigated in a phase I/II trial and showed a 14% response rate in the phase II portion, including four patients with a complete response. Median time of overall survival and progression-free survival were 7.1 months (95% CI 5.7 to 9.0) and 4.1 months (2.8 to 4.4), respectively.⁶⁹ Unfortunately, there were three patients with significant bleeding events, which likely limit the routine use of this combination.

Multiple phase I and II trials demonstrated the feasibility of erlotinib in combination with chemoradiation therapy for LA-SCCHN as definitive treatment⁷⁰^,⁷¹^,⁷² and in the adjuvant setting.⁷³ The largest study by Martens and colleagues randomized 204 patients with LA-SCCHN to standard radiation therapy with concurrent high-dose cisplatin with or without erlotinib 150 mg daily. Although erlotinib did not significantly increase the treatment toxicity, it failed to improve efficacy endpoints of complete response rate or progression-free survival.⁷⁰ Two studies used both erlotinib and bevacizumab in combination with chemoradiation therapy,⁷⁴^,⁷⁵ with one study reporting an increased risk of osteoradionecrosis.⁷⁴ Two phase I studies also showed the feasibility of using erlotinib in combination with reirradiation for recurrent SCCHN, one in combination with celecoxib.⁷⁶^,⁷⁷ Two phase III trials using erlotinib were attempted but closed early due to poor accrual—one in combination with first-line chemotherapy for R/M-SCCHN and a second as maintenance monotherapy for resected disease (NCT00448240 and NCT00412217). As with gefitinib, the overall modest activity of erlotinib did not lead to approval of its use in treating patients with cancer of the head and neck.

Dual and Pan-ErbB Tyrosine Kinase Inhibitors

Single-agent TKIs that target multiple ErbB family receptors are known as dual or pan-ErbB TKIs. Several of these agents—lapatinib, afatinib, and dacomitinib—are being studied in patients with SCCHN in both the locally advanced and metastatic settings. Lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC) is a reversible TKI that targets both EGFR and HER2. A phase II study that gave 107 treatment-naive patients with SCCHN lapatinib or placebo prior to chemoradiation therapy reported a response rate of 17% with a decrease in tumor proliferation rate as measured by Ki-67 immunostaining.⁷⁸ When lapatinib was tested as monotherapy in patients with R/M-SCCHN, however, no significant antitumor activity was noted in either patients without prior EGFR exposure (arm A) or with prior EGFR exposure (arm B).⁷⁹ In an intent-to-treat analysis, no complete or partial responses were observed, and stable disease was the best response observed in 41% of arm A (median duration, 50 days, range, 34 to 159) and 17% of arm B subjects (median, 163 days, range, 135 to 195). Median progression-free survival was 52 days in both arms. Median overall survival was 288 (95% CI, 62 to 374) and 155 (95% CI, 75 to 242) days for arms A and B, respectively. Collectively, these studies suggest that any benefit for lapatinib in SCCHN may be as part of initial therapy. A phase I study established the dose of lapatinib with chemoradiation therapy for patients with SCCHN to be 1,500 mg/day.⁸⁰ A recently published placebo-controlled phase II trial of lapatinib given concurrent with chemoradiation and then as maintenance therapy showed a numerical improvement in the 6-month complete response rate—the primary endpoint of the study—from 36% with placebo to 53% with lapatinib (p = 0.093).⁸¹ The secondary endpoints of progression-free and overall survival at 18 months were also improved from 41% to 55% (PFS) and 57% to 68% (OS) for placebo and lapatinib, respectively. Interestingly, p16-negative patients appeared to have a marked improvement in progression-free survival with lapatinib versus placebo (>20.4 months vs. 10.9 months).⁸¹ The results of several phase II and III studies incorporating lapatinib into initial therapy for LA-SCCHN are pending, and will hopefully help to define the role of this agent in the future treatment strategies for patients with LA-SCCHN.

Afatinib (Giotrif; Boehringer Ingelheim, Ingelheim, Germany) and dacomitinib (PF-00299804; Pfizer Inc, New York, NY) are irreversible TKIs that target EGFR, HER2, and HER4⁸²^,⁸³ and likely HER3 given the requirement for HER3 to heterodimerize with other ErbB family receptors. A randomized, crossover, phase II study compared single-agent afatinib to cetuximab. Patients treated with afatinib had increased adverse events leading to treatment discontinuations and dose reductions, but the agents were equivalent across all efficacy endpoints. In the 68 patients who crossed over to the other therapy upon disease progression, disease control rate was 33.3% for afatinib and 18.8% for cetuximab, suggesting a lack of crossresistance in some patients with sequential treatment with different EGFR inhibitors.⁸⁴ Presently, a randomized, phase III trial (LUX Head & Neck 1) is investigating the efficacy of single-agent afatinib versus methotrexate in patients with platinum-resistant R/M-SCCHN.⁸⁵ Other phase II and III trials are under way to determine the potential benefit of afatinib as part of neoadjuvant, adjuvant, and maintenance therapy.

Dacomitinib has been studied in one open-label, multicenter, single-arm phase II trial in patients with R/M-SCCHN.⁸⁶ Sixty-nine patients were enrolled and received dacomitinib 45 mg orally daily. Partial response rate to dacomitinib was 12.7%, and 57.1% of patients had stable disease (14.3% lasting ≥24 weeks). The median progression-free survival was 12.1 weeks and the median overall survival was 34.6 weeks. The most common grade 3 or higher treatment-related adverse events were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Approximately 40% of patients required either a dose reduction or a treatment interruption secondary to drug toxicity.⁸⁶ Preclinical data support the use of dacomitinib along with radiation therapy for the treatment of SCCHN⁸⁷ and in cetuximab-resistant SCCHN,⁸⁸ but no clinical trial data are yet available.

Mechanisms of Resistance to EGFR Inhibition

Collectively, all of the evidence for EGFR inhibition, despite the overexpression of EGFR in most SCCHN, shows a relatively modest benefit in terms of treatment response and survival. The presence of primary or acquired resistance to EGFR-targeted therapy is likely a factor in mitigating the success of these agents. Recent preclinical and clinical investigations have demonstrated several possible mechanisms leading to resistance to EGFR inhibition including activation of other ErbB family receptors (e.g., HER2 and HER3) and activation
of other signaling pathways such as vascular endothelial growth factor (VEGF), the hepatocyte growth factor (HGF)/c-MET pathway, and the Notch pathway.⁸⁹^,⁹⁰^,⁹¹^,⁹²^,⁹³^,⁹⁴^,⁹⁵^,⁹⁶ Preclinical data of the role of the insulin-like growth factor receptor (IGFR) pathway have been mixed.⁹⁷^,⁹⁸^,⁹⁹ Activation of downstream signaling pathways has also been implicated in resistance to EGFR inhibition including the PI3K/AKT pathway, RAS/MAPK/ERK pathway, mammalian target of rapamycin (mTOR) pathway, and the signal transducer and activator or transcription 3 (STAT3) pathway.¹⁰⁰^,¹⁰¹^,¹⁰² Other mechanisms of resistance have been described as well including the potential benefit of the combination of EGFR and cyclooxygenase-2 (COX-2) inhibition, epigenetic events such as hypermethylation of death-associated protein kinase (DAPK), and nuclear EGFR expression.¹⁰³^,¹⁰⁴^,¹⁰⁵

Several novel agents are now being studied in phase II and III trials to try and overcome EGFR resistance in the clinical setting. There are many new drugs that have been designed to target more than one receptor in an effort to increase clinical efficacy. Several of these agents including lapatinib, afatinib, and dacomitinib have already been discussed (see section “Dual and Pan-ErbB Tyrosine Kinase Inhibitors”). Vandetanib (Caprelsa; AstraZeneca Pharmaceuticals LP, Wilmington, DE) is an oral TKI that targets both EGFR and VEGF receptor 2. Vandetanib in combination with docetaxel in platinum-refractory patients with SCCHN was not found to be effective,¹⁰⁶ but it is currently being studied in combination with chemoradiation therapy for patients with LA-SCCHN (NCT00720083). The monoclonal antibody MEHD7945A (Genentech, Inc., South San Francisco, CA) targets both EGFR and HER3 and showed promising results in a phase I trial where 20% of patients with R/M-SCCHN achieved a partial response (abstract only). It is currently being compared to cetuximab in a randomized phase II trial in patients with R/M-SCCHN (NCT01577173).

Novel therapeutic combinations using an EGFR inhibitor in combination with other targeted therapies have been investigated or are under active investigation. Dual inhibition of the EGFR and vascular endothelial growth factor receptor (VEGFR) has shown responses in patients with R/M-SCCHN.⁶⁹^,⁹⁴ The combination has also been used along with CRT for patients with LA-SCCHN,⁷⁴ albeit with potential increased toxicity.⁷⁴^,⁷⁵ Multiple ongoing phase II trials are investigating the use of EGFR and VEGF inhibition in patients with R/M- and LA-SCCHN (NCT00392665, NCT00968435, NCT00703976). Dual inhibition of the EGFR and mTOR pathways is ongoing in patients with R/M-SCCHN (NCT01256385, NCT0128334, NCT00942734), despite initial phase I/II data showing poor patient tolerability and a short progression-free survival.¹⁰⁷ The TKI dasatinib (Sprycel; Bristol-Myers Squibb, Princeton, NJ), despite having multiple targets including BCR-ABL, stem cell factor receptor (c-KIT), platelet-derived growth factor receptor (PDGFR), and Src family kinases, showed no responses when used as monotherapy for patients with R/M-SCCHN¹⁰⁸ but is being investigated concurrent with and after failure of cetuximab-based radiation therapy (NCT00882583, NCT01488318). Sorafenib (Nexavar; Bayer, Leverkusen, Germany) and sunitinib (Sutent; Pfizer Inc., New York, NY) both target multiple protein kinases but have shown poor activity and significant side effects when studied in patients with R/M-SCCHN¹⁰⁹^,¹¹⁰^,¹¹¹; tivantinib (formerly ARQ 197) is a c-MET inhibitor currently under active investigation in combination with EGFR inhibitors (see “c-MET” section below for more details). Phase I data for the use of the COX-2 inhibitor celecoxib (Celebrex; Pfizer, Inc., New York, NY) along with an EGFR inhibitor demonstrated a 22% response rate in patients with R/M-SCCHN and showed promising activity along with reirradiation for recurrent SCCHN,⁷⁷^,¹¹² but there are no current ongoing trials of this combination.

c-MET

The HGF/c-MET pathway has been shown to be involved in the pathogenesis and progression of SCCHN.¹¹³^,¹¹⁴^,¹¹⁵^,¹¹⁶^,¹¹⁷^,¹¹⁸^,¹¹⁹^,¹²⁰^,¹²¹^,¹²²^,¹²³^,¹²⁴ The HGF is a peptide growth factor that is secreted by mesenchymal cells and acts primarily on epithelial cells where it binds to the c-MET receptor and, through activation of multiple downstream pathways, regulates cell growth, motility, and invasion. Serum HGF and HGF concentration in tumor tissue has been shown to be significantly elevated in patients with SCCHN and is associated with tumor progression and recurrence.¹¹³^,¹¹⁵ Silencing Met receptor tyrosine kinase signaling through Met knockdown in established SCCHN cell lines impaired activation of downstream MAPK signaling, reduced tumor growth by increased cell apoptosis, decreased regional lymph node metastases, and increased survival of nude mice with orthotopic xenografts.¹²⁵ Increased expression of c-MET has been associated with poor response to radiation therapy in patients with SCCHN.¹²⁶ c-MET expression in some studies has been associated with lymph node metastasis, advanced tumor stage, risk of recurrence, and decreased survival.¹¹⁹^,¹²⁴^,¹²⁷ More recent studies using archival tissue of patients treated for SCCHN identified increase c-MET expression by immunohistochemistry (57% to 58%) but found no significant correlation of c-MET expression on treatment response or survival.¹²⁸^,¹²⁹

Recent data suggest that the HGF/c-MET pathway may play a more critical role in HPV-negative head and neck cancers.¹³⁰ The role of HGF and c-MET expression and c-MET gene copy number in HPV-negative and HPV-positive tonsil cancers was recently investigated. HGF overexpression was found to be an independent prognostic factor for decreased survival in HPV-negative but not HPV-positive tumors. Neither c-MET overexpression nor c-MET copy number was associated with survival outcomes in either cohort.¹³⁰ Baschnagel and colleagues examined archival tissue for 107 patients with SCCHN treated with chemoradiation and correlated c-MET expression with p16 status and clinical endpoints. High c-MET expression predicted for worse disease-free survival in p16-negative but not p16-positive patients.¹³¹

Only gold members can continue reading. Log In or Register to continue