CLINICAL REVIEW

David W. Eisele, MD, Section Editor

Molecular targeting in combination with platinum-based chemoradiotherapy in head and neck cancer treatment Nikolaus M€ockelmann, MD,1* Malte Kriegs, PhD,2 Balazs B. L€orincz, MD,1 Chia-Jung Busch, MD,1 Rainald Knecht, MD, PhD1 1

Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg–Eppendorf, Hamburg, Germany, 2Laboratory of Radiobiology and Experimental Radiooncology, University Medical Center Hamburg–Eppendorf, Hamburg, Germany.

Accepted 6 March 2015 Published online 7 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/hed.24031

ABSTRACT: Background. Significant evidence exists supporting the use of platinum-based chemoradiotherapy (CRT) as a primary curative approach in locoregionally advanced head and neck cancer (HNSCC). Despite these aggressive protocols, 70% of patients die within 5 years because of locoregional recurrence or distant metastasis. To increase the response and survival of patients with HNSCC, CRT has been combined with molecular agents targeting distinct kinases. Methods. This study was performed using a systematic literature review. Results. The effect of targeted therapy on patient survival in the context of CRT remains controversial, with toxicities tending to be more severe but still acceptable.

Conclusion. Supplementing CRT with target therapeutics might only improve survival in some patients with locally advanced HNSCC. Therefore, future studies must address the underlying biological mechanisms that can have an impact on treatment response. Such knowledge is essential in order to facilitate the effective and personalized treatment of patients with locally advanced HNSCC by combining CRT and targeted therapy. C 2015 Wiley Periodicals, Inc. Head Neck 38: E2173–E2181, 2016 V

INTRODUCTION

(mAbs) or small molecule inhibitors have been added to the standard regimens. As head and neck tumors frequently show overexpression of the epidermal growth factor receptor (EGFR), which is associated with a worse prognosis,4 many studies have combined CRT with antiEGFR strategies. In addition to this, other receptor tyrosine kinases (RTKs), such as the EGFR-related human epidermal receptor 2 (HER2) or the vascular endothelial growth factor receptor (VEGFR),5 have also been targeted in clinical studies. This review discusses the results of various clinical studies combining platinum-based CRT and targeted therapies with regard to tumor response and the survival outcome of patients with locally advanced HNSCC in a curative treatment setting. We also illustrate the underlying molecular mechanisms of various targeting strategies and evaluate their potential in the context of multimodality tumor treatment.

Most patients with head and neck squamous cell carcinoma (HNSCC) are diagnosed in a locoregionally advanced stage (stage III–IVB), at which point a single treatment modality is generally ineffective. Therefore, these patients are treated with combined therapeutic regimens consisting of at least 2 modalities of either surgery, radiation, or chemotherapy. The standard therapy is platinum-based chemotherapy administered either sequentially or concurrently to radiotherapy (RT). Alternatively, the surgical resection of the primary tumor and regional lymph nodes can be performed followed by risk-adapted adjuvant RT or platinum-based chemoradiotherapy (CRT).1 Despite this aggressive treatment, tumor recurrence rates are high and the 5-year survival rate for these patients is still limited to 30%.2 As neither cisplatin (CDDP) nor ionizing radiation are tumor specific and therefore often lead to severe acute and late toxicities, CDDP and ionizing radiation doses cannot be further increased in standard treatment.3 In order to improve the efficiency of CRT for patients with head and neck squamous cell carcinoma (HNSCC), targeted therapeutics using either monoclonal antibodies

*Corresponding author: N. M€ockelmann, Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg–Eppendorf, Martinistr. 52, 20246 Hamburg, Germany. E-mail: [email protected]

KEY WORDS: head and neck squamous cell carcinoma, platinumbased chemoradiotherapy, targeted therapy, monoclonal antibody, tyrosine kinase inhibitor

MATERIALS AND METHODS For this review, studies on concurrent primary as well as adjuvant platinum-based CRT in combination with molecular targeted therapy were screened. A systematic review of the literature was performed using the PubMed database as well as information from meeting abstracts (ASCO, ESTRO, ASTRO, and ESMO) and references in review articles. In addition, previously published phase III and II trials, relevant phase I studies, and other ongoing trials listed on clinicaltrials.gov were included. HEAD & NECK—DOI 10.1002/HED

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RESULTS Epidermal growth factor receptor inhibition in platinumbased chemoradiotherapy Approximately 90% of all HNSCC show an overexpression of EGFR,6 which correlates with poorer survival.4 The EGFR belongs to the HER family of RTK and regulates pathways important for cell proliferation and survival, such as the Akt-activated and mitogenactivated protein kinase pathway.7,8 The EGFR can be inhibited using a variety of strategies, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs). Many preclinical and clinical trials have tested different EGFR inhibitors, some of which have already been approved for clinical practice in HNSCC9 in combination with radiation10 or chemotherapy.11

Monoclonal antibodies of the epidermal growth factor receptor Cetuximab (C225, Erbitux, Bristol–Myers Squibb, New York, NY) was the first targeted therapeutic agent approved by the U.S. Food & Drug Administration for the treatment of HNSCC. Cetuximab is a chimeric immunoglobulin G1 (IgG1) mAb, which binds with high affinity to the extracellular domain of EGFR and, thus, inhibits the binding of ligands, such as transforming growth factor-alpha or epidermal growth factor.12 As a result of the EGFR blockade, cetuximab inhibits the proliferation of EGFR-expressing cells and reduces tumor growth.13 In addition to HNSCC, cetuximab is also used in the therapy of colorectal cancer14 and is currently being tested in many preclinical and clinical trials for use in other tumor entities. Cetuximab has been approved for 2 different indications in HNSCC thus far: in addition to the primary RT of locally advanced HNSCC in a curative setting,10 and for recurrent and/or metastatic HNSCC in first-line treatment in combination with CDDP and 5-fluorouracil, as applied in the EXTREME trial.11 Further, a number of studies have investigated the addition of cetuximab to the primary CRT of locally advanced HNSCC; most of these, however, have been in nonrandomized phase II settings. In addition, a randomized phase III trial was initiated by the Radiation Therapy Oncology Group (RTOG 0522). In this 2-armed setting in patients with stage III to IV HNSCC, platinum-based CRT therapy regimes with or without cetuximab were compared for progression-free survival (PFS). The 2-year data were presented in 2011 at the annual American Society of Clinical Oncology (ASCO) meeting.15 In this study, patients with HNSCC of the oropharynx, larynx, and hypopharynx were treated with either 70 to 72 Gy and 2 concurrent cycles of CDDP (100 mg/m2) every 3 weeks (control group) or using the same therapy protocol with the addition of cetuximab (loading dose 16–7 weekly doses). The survival of 895 patients was evaluated with a median follow-up of 2.4 years. A large number of patients received the intended number of CDDP cycles (>90% received 2 cycles) and cetuximab doses (74% received the loading dose 16 or more doses). No significant difference in the primary endpoint was Cetuximab.

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observed between the 2 regimes: the PFS (hazard ratio [HR] 5 1.05; 95% confidence interval [CI] 5 0.84–1.29; p 5 .66) was 63% in the cetuximab arm versus 64% in the control arm after 2 years. Overall survival (OS) rates also failed to statistically differ (HR 5 0.87; 95% 95% CI 5 0.66–1.15; p 5 .17), with 83% in the cetuximab arm compared to 80% in the control arm. Further, no difference in the patterns of failure was observed. The addition of cetuximab was associated with a significantly higher rate of grade 3 to 4 mucositis (45% in the cetuximab arm vs 35% in the control arm; p 5 .003) and skin reactions similar to the acne-like skin rash described earlier for anti-EGFR treatment studies (40% in the cetuximab arm vs 17% in the control arm; p < .0001).16 A total of 4 phase II trials have previously investigated the effects of cetuximab together with platinum-based CRT on treatment response, survival, and toxicity in single-armed settings.17–20 One of these studies was ended early after 2 treatment-related deaths, which were considered to be severe adverse events.19 The other studies reported no treatment-related deaths, but did describe, as expected, high rates of skin rash (15%,17 18%,18 28%,20 and 57%19). This skin toxicity was observed in a similar frequency as in the RTOG 0522 trial, although less often than in the trial of Bonner et al10 (87% of patients), which added cetuximab to RT. In terms of grade 3 mucositis, the rates were higher (45%,15 54%,20 59%,17 and 65%18) than described in the group receiving CRT alone in RTOG 0522 (35%). In conclusion, the addition of cetuximab is associated with a higher rate of early and reversible side effects, such as mucositis and skin rash. Despite the greater toxicity, some studies have demonstrated promising response rates through the addition of cetuximab. The phase II trial by Pfister et al19 illustrates an overall response rate (ORR) of 94%, an OS of 76%, a PFS of 56%, and a locoregional control rate of 71% at 3 years. Although another U.S. phase II trial performed by the Eastern Cooperative Oncology Group 330320 showed lower response rates of 48% in patients treated with additional cetuximab, it was also able to demonstrate a higher rate of stable disease of 31%. Data on survival and disease control stemming from this study are not yet available. Two other European studies showed response rates of 77%17 and 91%18 with cetuximab, but with lower OS rates (64%17 and 40%18) than observed in the U.S. studies by Pfister et al19 (76%) and Ang et al15 (80%). This could be due to the fact that the U.S. studies included a higher proportion of patients with oropharyngeal squamous cell carcinomas (SCCs; 60%19 and 70%15) and fewer hypopharyngeal SCC tumors (hypopharyngeal SCC 5 5%19 and 7%15) compared with the European studies by Merlano et al18 (oropharyngeal SCC 5 30%; hypopharyngeal SCC 5 28%) and Kuhnt et al17 (oropharyngeal SCC 5 49%; hypopharyngeal SCC 5 30%). Compared with Europe, a higher percentage of oropharyngeal SCC in North America are induced by human papillomavirus (HPV) infection21–23 and show better survival when treated with radiation 1/- chemotherapy in contrast to patients with tobacco-related or alcohol-related cancer.24,25 Therefore, the greater presence of HPV-triggered oropharyngeal SCC might explain the differences in survival outcome described in the trials. In the RTOG 0522

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trial, a statistically nonsignificant correlation was observed between improved PFS and p16 positivity (being p16 as a surrogate marker for HPV infection) in oropharyngeal SCC after treatment with CRT without cetuximab. These findings differ from those of Rosenthal et al26, where cetuximab was found to be most effective in p16-positive patients with oropharyngeal SCC when added to RT. In summary, the data from the cited trials demonstrate that the addition of cetuximab to a platinum-based CRT in patients with locally advanced HNSCC leads to survival rates comparable to that of CRT alone. However, the administration of cetuximab is associated with increased side effects. The failure of cetuximab to clearly increase CRT efficiency might be due to the relatively low cetuximab doses administered compared to those in the EXTREME trial, for example, which was able to demonstrate a positive effect of cetuximab on survival (6–8 doses vs 29 doses). Furthermore, cetuximab might be effective in some patients, whereas others do not necessarily benefit from cetuximab treatment. One possible factor influencing therapy response might be infection with HPV, as suggested in the trial by Rosenthal et al.26 In this way, failing to address p16/HPV status, as in the RTOG 0522 trial, impedes the interpretation of those data. As mentioned before, better PFS seems to correlate with p16-positive status in oropharyngeal SCC treated with CRT alone. The question of whether cetuximab is more effective in combination with RT or with a platinum-based CRT in HPV-positive patients will be investigated by the RTOG 1016 trial. Panitumumab. Panitumumab (Vectibix, Amgen, Thousand Oaks, CA) is a fully humanized mAb against EGFR and was tested in a randomized phase II trial (CONCERT-1)27 on patients with locally advanced HNSCC. Preliminary results for 2-year survival were presented at the ASCO meeting in 2012. In this study, 150 patients were randomized in a 2:3 ratio to receive CRT and CRT 1 panitumumab treatment. Patients in the CRT arm received 3 cycles of CDDP 100 mg/m2 during RT in standard fractionation. The panitumumab arm included 3 cycles of reduced dose CDDP (75 mg/m2) and the addition of panitumumab (9.0 mg/kg) during RT. The primary endpoint was locoregional control rate after 2 years, with secondary endpoints including PFS, OS, and safety. Forty-two percent of the patients tested positive for HPV, as determined by p16 immunohistochemistry. Locoregional control rates at 2 years were found to be 61% (range, 50% – 71%) for panitumumabtreated patients compared to 68% (range, 54% – 78%) in the group treated solely with CRT. Similar trends were observed in PFS rates, with 40% in the panitumumab arm and 35% in the CRT arm (HR 5 1.15; 95% CI 5 0.68– 1.96; p 5 .61). OS after 2 years was reported to be 64% in patients in the panitumumab arm and 76% in the CRT arm (HR 5 1.63; 95% CI 5 0.88–3.02; p 5 .12). The rate of adverse events (AEs) grade 3 was higher in the panitumumab group for mucositis (55% vs 24%) and rash (11% vs 0%). In addition, there was also an increased rate of RT delays in the panitumumab group (16% vs 3%) as well as a lower cumulative CDDP dose

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(223.1 mg/m2 vs 296.9 mg/m2). HPV status had no influence on treatment outcome. The 2 groups were statistically indistinguishable in terms of locoregional control, PFS, and OS rates, with a trend toward better locoregional control and PFS through the addition of panitumumab, but with a reduced OS and higher treatment-related toxicity. Another phase II trial, presented by Ferris et al28 at the ASCO meeting in 2014, investigated the addition of panitumumab to adjuvant CRT for HNSCC of the oral cavity (73%), larynx (20%), hypopharynx (5%), or oropharynx (2%) with high-risk features in the histopathology after primary resection (margins .05). Furthermore, a phase I study36 and 2 phase II studies37,38 reported high response rates (76%, 80.7%, and 78.6%, respectively) in cohorts treated with CRT plus nimotuzumab, although with limited validity because of nonrandomized designs. In summary, the addition of nimotuzumab to CRT might improve treatment response and survival more effectively than the addition of cetuximab. However, conclusions must been drawn with caution because of various limitations in study design. Zalutumumab. Zalutumumab (HUMAX-EGFR, Genmab, Utrecht, The Netherlands) is a fully human IgG1 mAb against EGFR, which binds to the EGFR domain III.39 Zalutumumab was tested in combination with platinumbased CRT in a phase III trial (DAHANCA 19) by the Danish Head and Neck Cancer group (DAHANCA),40 with initial results being presented at the European Cancer Congress 2013 in Amsterdam. The study enrolled 619 patients with HNSCC of the oropharynx (69%), hypopharynx (12%), larynx (15%), and oral cavity (4%). Stratification was performed according to tumor site, stage (89% stage III/IV), HPV/p16 status (75% of oropharyngeal SCC were positive), and concurrent CDDP treatment (70% of patients). In the case of stage III to IV cancer, the protocol for the control arm included intensitymodulated radiotherapy with 66 to 68 Gy and weekly CDDP at 40 mg/m2. Patients in the zalutumumab (experimental) group received identical CRT combined with zalutumumab (8 mg/kg) in the week before the start of RT, as well as once a week continuously during RT. As in several other DAHANCA trials, nimorazole was used to target hypoxic tumor areas,41 being administered in both patient groups 90 minutes before each radiation. After 3 years, no differences had been observed with regard to the primary endpoint of locoregional control, which was found to be 78% in the zalutumumab arm and 79% in the control arm (HR 5 0.8; 95% CI 5 0.6–1.2). When these results were analyzed according to p16 status, locoregional control was greater for all patients in the p16-positive population (83% vs 73% in the p16-negative subgroup of patients). However, p16-status had no impact on the effect of zalutumumab on locoregional control: locoregional control was 83% in p16-positive patients (HR 5 1.0; 95% CI 5 0.6–1.8) and 73% in p16-negative patients treated with or without zalutumumab (HR 5 0.8; 95% CI 5 0.5–1.4). Similarly, disease-specific survival (HR 5 1.0; 95% CI 5 0.7–1.7) and OS (HR 5 0.9; 95% CI 5 0.6–1.3) were comparable in the 2 arms. Treatmentassociated skin rash occurred at high rates in patients treated with zalutumumab (94% for all grades and 29% grade 3–4). Thirteen percent of the patients had to stop zalutumumab treatment because of folliculitis. In summary, the addition of zalutumumab to primary CRT plus nimorazole showed no benefit over CRT plus nimorazole alone with regard to locoregional control, disease-specific survival, and OS 3 years after treatment. Treatment-

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related toxicity, such as skin rash, was increased but still acceptable.

Tyrosine kinase inhibitors of the epidermal growth factor receptor In addition to mAb, TKI can also be used to inhibit the EGFR. These small molecule inhibitors bind to the intracellular kinase domain and block receptor phosphorylation.42 Erlotinib. Erlotinib (Tarceva; Genentech, South San Francisco, CA) is a reversible EGFR-TKI that can be administered orally. To date, 2 randomized trials and 1 nonrandomized phase I/II trial have analyzed the effects of erlotinib in primary platinum-based CRT. The phase II trial published by Martins et al43 in 2013 used CDDP plus RT with or without erlotinib in 204 patients with locally advanced HNSCC, with oropharyngeal SCC in 64% in the control group and in 70% in the experimental erlotinib group. Sixty percent of all oropharyngeal SCC cases were p16 positive. The median follow-up time was 26 months. The response rates were described to be lower than in the subsequently mentioned trials, with a complete response rate of 52% in the erlotinib arm versus 40% in the control arm (p 5 .08), despite the administration scheme being identical and no major differences in terms of patient characteristics. No significant difference in PFS was observed (HR 5 0.9; p 5 .71) between the 2 groups, with 54% in the erlotinib arm and 46% in the control arm. As for treatment-related toxicity, a greater number of patients developed rash in the erlotinib arm compared to those in the control arm (68% vs 10%, respectively; p < .001), although the 2 arms were similar in terms of other grade 3 to 4 toxicities. Interestingly, patients in the erlotinib group with skin rash showed a better PFS than those without rash. These data are in line with those of Bonner et al44 showing similar effects in patients treated with cetuximab in addition to RT compared to RT alone. In another phase II study,45 128 patients were assigned randomly to CRT with or without concurrent erlotinib. An interim analysis of the first 100 patients was presented in 2010 at the ASCO meeting. Response rates were higher than in the trial mentioned above, with a complete response rate of 71% in both groups. The most common severe adverse events were nausea, vomiting, and dehydration. A single treatment-related death occurred in the control arm. To date, efficacy data have not been presented. In a phase I/II study46 involving 31 patients with locally advanced HNSCC (32% of them with oropharyngeal SCC), the addition of erlotinib together with CRT resulted in a complete response rate of 74% (95% CI 5 56.8% to 86.3%). The 3-year PFS and OS were 61% and 72%, respectively. The most common nonhematologic AEs were grade 3 to 4 dermatitis (52%), nausea (48%), and vomiting (39%). Acne-like skin rash occurred in 74.2% of patients. Gefitinib. Gefitinib (IRESSA; AstraZeneca, London, UK) is an orally active EGFR-TKI approved for the treatment of advanced non-small cell lung cancer.47 Two phase II

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trials and 1 phase I trial have thus far been conducted on the effects of gefitinib together with platinum-based CRT in HNSCC. The phase I trial48 demonstrated that gefitinib was tolerated well, with a single case of grade 4 diarrhea and grade 4 neutropenic fever as dose-limiting toxicities. Fifty-three percent of patients (8 of 15) experienced grade 1 to 2 acne-like skin rashes. Gregoire et al49 tested gefitinib in a randomized, double-blinded, placebo-controlled phase II study with local disease control rate at 2 years as the primary endpoint. Their analysis demonstrated that gefitinib (250 mg/ daily or 500 mg/daily) failed to improve local disease control rate compared to placebo when given either concurrently with CRT (32.7% gefitinib vs 33.6% placebo; p 5 .607) or as a maintenance therapy (28.8% gefitinib vs 37.4% placebo; p 5 .894). Secondary endpoints, such as ORR, CRR, PFS, and OS, were comparable to the 2-year local disease control rate results, with no significant difference being determined between gefitinib plus CRT versus placebo plus CRT treatments. Concerning toxicity profile, the most common AEs observed in both arms of the study were vomiting and nausea. The addition of the gefitinib component did not result in an increase in CRT-related toxicities, such as mucositis (16.4% gefitinib vs 12.9% placebo) or dysphagia (30.9% gefitinib vs 37.1% placebo). In general, the toxicity profiles of gefitinib and placebo were similar, with the exception of skin rash and diarrhea, which occurred more often in the gefitinib arm at doses of 500 mg. At this dose level, the rate of skin rash was 52.7% (vs 19.8% in the placebo arm), whereas the rate of diarrhea was 47.3% (vs 11.2% in the placebo arm). Preliminary results of another phase II trial from India were presented at the annual ASCO meeting in 2014.50 In this study, participants received gefitinib 250 mg/daily combined with CDDP 30 mg/m2 weekly, given concurrently with normofractionated RT of up to 70 Gy. Eightysix patients were followed for up to 6 months after completion of CRT. Therapy response was significantly better in the experimental group, with an ORR of 88.37% (p < .05) compared to the control arm with an ORR of 69.76%. Complementary to previous studies, the rates of skin rash and mucositis in this analysis were also increased in the study group compared to the control group, with rates of 51.16% (study group) versus 39.53% (control group) as well as at 97.67% (study group) versus 90.69% (control group) for rash and mucositis, respectively. As with the addition of any mAb to CRT, neither erlotinib nor gefitinib as TKI-type agents resulted in increased control or survival rates in locally advanced HNSCC, even if survival was not the primary endpoint in some of the mentioned trials. Therefore, additional data are needed to obtain further insight into the possible advantages of the use of TKIs in primary CRT, without neglecting their higher toxicity profiles.

Epidermal growth factor receptor– and human epidermal growth factor receptor-2 inhibition in platinum-based chemoradiotherapy The EGFR belongs to the ErbB family of tyrosine kinase receptors, also known as the HER family. After HEAD & NECK—DOI 10.1002/HED

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ligand binding, these proteins can form monodimers or heterodimers with other HER receptors, such as HER2, HER3, or HER4. The frequent heterodimerization of EGFR with HER2 induces a strong proliferative signal,7,8,51 in turn creating a potential goal for combined target inhibition. Therefore, dual inhibition of ErbB2/ HER2 was tested. Lapatinib. Lapatinib (TYKERB/TYVERB, GlaxoSmithKline, Brentford, UK) is an oral, reversible, dual TKI of EGFR and HER2. In a placebo-controlled, randomized phase II study, patients with locally advanced HNSCC were treated with lapatinib 1500 mg daily, combined with CDDP 100 mg/m2 on days 1, 22, and 43, and concurrent RT of up to 70 Gy, followed by a maintenance therapy with lapatinib. The control group received placebo together with CRT as well as in the maintenance phase, similar to the lapatinib arm. The primary endpoint was complete response rate 6 months after completion of CRT. Initial results were presented at the ASCO meeting in 201052 and were later published in 2013 along with the 6-month, 12-month, and 18-month survival data.53 Sixtyseven patients were included and randomly assigned to one of the treatment arms. Most patients had oropharyngeal SCC (64%), with a p16 positivity of 15% in the total cohort. Therefore, results from this trial likely represent primarily p16-negative patients with locally advanced HNSCC. The complete response rate at 6 months was 53% in the lapatinib arm versus 36% in the placebo group in the intent-to-treat population (95% CI 5 27.8 to 42.6; p 5 .093). The PFS rate at 18 months was 55% in the lapatinib group compared to 41% in the placebo group, resulting in a treatment outcome difference of 14% (95% CI 5 211 to 38). The OS rate at 18 months was 68% in patients treated with lapatinib and 57% in the control group (treatment outcome difference 11%; 95% CI 5 213 to 35). The difference between the arms was greatest for patients with p16-negative disease, with a median PFS of >20.4 months in the study group compared to 10.9 months in the control group. However, p16 analysis was only available for 64% of the patients, and was not preplanned into the trial design. Grade 3 to 4 treatment-related overall toxicities were comparable between the treatment arms, and CRT dose intensities were not adversely affected by the addition of lapatinib. However, there was an increase in grade 3 diarrhea (6% vs 0%) and skin rash (9% vs 3%) in the lapatinib arm. In conclusion, the 6-month, 12-month, and 18-month data show a statistically nonsignificant superiority of combined lapatinib treatment restricted to the p16-negative HNSCC fraction. The absence of the favorable effect expected for p16-positivity could be due to the small number of such tumors in this study. Furthermore, lapatinib was tolerated well when administered concurrently with CRT as well as a maintenance treatment. Currently, an ongoing RTOG phase II trial (TRYHARD/NCT01711658) is investigating the effects of lapatinib given together with CRT for HPV-negative tumors on 2-year PFS. Because of the favorable toxicity profile of lapatinib in maintenance therapy, as presented by Harrington et al,53 a phase III trial has been set up to determine the difference in disease-free survival (DFS) when E2178

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using lapatinib in addition to adjuvant platinum-based CRT in high-risk patients after surgical tumor resection. The preliminary results were presented at the ASCO Annual Meeting in 2014, but failed to show any survival benefit in the lapatinib group compared to the placebo group.54

Vascular endothelial growth factor receptor inhibition in platinum-based chemoradiotherapy Angiogenesis plays a crucial role in local tumor growth and in the formation of distant metastases. It is regulated by ligand activation of different isoforms of the VEGFR. VEGFR is overexpressed on activated endothelial cells and regulates their proliferation and differentiation. Human cancer cells express high levels of VEGFR, which correlate with the extent of neovascularization within the tumor.55 In HNSCC, elevated serum levels of vascular endothelial growth factor A have been associated with worse prognosis.56 Therefore, VEGFR is a potential target for cancer therapy and its inhibitors have been investigated for the treatment of HNSCC. Bevacizumab. Bevacizumab (Avastin, Genentech), a humanized anti-VEGF mAb, is an inhibitor of angiogenesis and has already been approved for the treatment of several types of metastatic cancer. For HNSCC, a nonrandomized phase II trial investigated the effect of bevacizumab together with primary CRT with CDDP on 2year PFS.57 Patients were treated with intensitymodulated radiotherapy with a total dose of 70 Gy and concurrent CDDP (50 mg/m2) on days 1, 2, 22, 23, 43, and 44 combined with bevacizumab (15 mg/kg) on days 1, 22, and 43. Forty-two patients with locally advanced oropharyngeal SCC (n 5 39; 93%) and SCCs of the larynx (n 5 3; 7%) were included. The median follow-up time was approximately 31.8 months. Grade 3 to 4 toxicities observed during treatment included functional mucositis (86%), lymphopenia (100%), leukopenia (57%), and neutropenia (43%). In addition, an increase in myelosuppression was observed, supporting the results of a phase I trial with bevacizumab and CRT in which 2 of 10 treated patients suffered from grade 4 lymphopenia.58 The efficacy data revealed a 2-year PFS rate of 75.9% (95% CI 5 63.9% to 90.1%) and a 2-year OS rate of 88% (95% CI 5 78.6% to 98.4%), rates which are quite high and encouraging compared to those for other primary CRT regimens. In conclusion, the addition of bevacizumab to platinum-based CRT has shown promising antitumor activity with an acceptable increase in treatment-related toxicity.

DISCUSSION Platinum-based CRT is a standard curative treatment option for locally advanced HNSCC in patients who are well enough to cope with its substantial treatment-related toxicity. As the 5-year survival rate of these patients is still low, the implementation of target therapeutics in addition to CRT is favored and has already been tested in several trials, as reviewed here (Tables 1 and 2). The majority of these studies failed to show a statistically significant benefit in survival (DFS, PFS, and OS) resulting

CDDP 1 RT 1 bevacizumab

CDDP 1 RT vs CDDP 1 RT 1 cetuximab CDDP 1 RT 1 cetuximab CDDP 1 5-FU 1 RT 1 cetuximab CDDP 1 RT 1 cetuximab CDDP 1 RT 1 cetuximab CDDP 1 RT vs CDDP 1 RT 1 panitumumab S 1 CDDP 1 RT 1 panitumumab CDDP 1 RT vs CDDP 1 RT 1 nimotuzumab CDDP 1 RT vs CDDP 1 RT 1 nimotuzumab CDDP 1 RT vs CDDP 1 RT 1 zalutumumab

Treatment

N/A

N/A 77% 91% 94% 48% N/A N/A 70% vs 100%* 70% vs 96% N/A

ORR

N/A

N/A N/A N/A N/A N/A 68% vs 61% (2 y) N/A N/A N/A 79% vs 78% (3 y)

Locoregional control

88% (2 y)

83% vs 80% (2 y) 64% (2 y) 40% (3.75 y) 76% (3 y) N/A 76% vs 64% (2 y) 76% (2 y) 26% vs 57% (5 y)* N/A N/A

OS

76% (2 y)

64% vs 63% (2 y) N/A 38% (3.75 y) 56% (3 y) N/A 35% vs 40% (2 y) 73% (2 y) 14.95% vs 54.24*† N/A N/A

PFS

Survival data

N/A

N/A 45% (2 y) N/A N/A N/A N/A N/A N/A N/A N/A

DFS

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40% vs 52% 71% vs 71% 74% 46% vs 34% 70% vs 88%* 36% vs 53%

CDDP 1 RT 1 placebo vs CDDP 1 RT 1 lapatinib

CRR

CDDP 1 RT vs CDDP 1 RT 1 erlotinib CDDP 1 RT vs CDDP 1 RT 1 erlotinib CDDP 1 RT 1 erlotinib CDDP 1 RT 1 placebo vs CDDP 1 RT 1 gefitinib CDDP 1 RT vs CDDP 1 RT 1 gefitinib

Treatment

N/A

N/A N/A N/A 34% vs 33% (1 y) N/A

Locoregional control

57% vs 68% (1.5 y)

N/A N/A 72% (3 y) 59% vs 57% (2 y) N/A

OS

PFS

41% vs 55% (1.5 y)

46% vs 54% N/A 61% (3 y) 39% vs 44% (2 y) N/A

Survival data

N/A

N/A N/A N/A N/A N/A

DFS

Abbreviations: CRR, complete response rate; OS, overall survival; PFS, progression-free survival; DFS, disease-free survival; EGFR, epidermal growth factor receptor; CDDP, cisplatin; RT, radiotherapy; N/A, not available; HER2, human epidermal growth factor receptor 2. *Statistically significant.

EGFR Martins43 Hayes45 Herchenhorn46 Gregoire49 Singh50 EGFR 1 HER2 Harrington53,54

Trial

TABLE 2. Overview of response rates and survival data of tyrosine kinase inhibitor 1 chemoradiotherapy treatment.

Abbreviations: ORR, overall response rate; OS, overall survival; PFS, progression-free survival; DFS, disease-free survival; EGFR, epidermal growth factor receptor; RTOG, Radiation Therapy Oncology Group; CDDP, cisplatin; RT, radiotherapy; N/A, not available; 5-FU, 5- fluorouracil; ECOG, Eastern Cooperative Oncology Group; S, surgery; VEGFR, vascular endothelial growth factor receptor. *Statistically significant. † Median PFS in months.

EGFR Ang (RTOG 0522)15 Kuhnt17 Merlano18 Pfister19 Langer (ECOG 3303)20 Giralt (CONCERT-1)27 Ferris28 Reddy32 Bhatnagar35 Eriksen (DAHANCA 19)40 VEGFR Fury57

Trial

TABLE 1. Overview of response rates and survival data of monoclonal antibody 1 chemoradiotherapy treatment.

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from the addition of molecular targeting agents. However, certain trends toward improved survival could be observed. Additionally, response rates were found to be increased in some studies, serving as an argument for some benefit resulting from targeted therapeutics. However, this advantage might be restricted to merely a specific subgroup of patients. Unfortunately, subgroup analysis was not possible in most of the studies because of the low numbers of patients included in the phase II trials. Most trials observed a larger number of skin rashes, mucositis, and other reversible side effects in the study arms, which must be taken into consideration in the application of targeted therapeutics. The failure of targeted therapy to improve CRT in the majority of patients underscores the importance of individualized strategies. Data from Bonner et al44 have already shown that acute skin toxicities are characteristic of patients who benefit from cetuximab in the context of RT. Similar observations have been presented by Martins et al,43 who identified patients developing a rash as a group that seems to benefit from erlotinib treatment in the context of CRT. Additionally, preclinical data clearly demonstrate that targeting tumor cells by inhibiting specific RTK does require the overexpression of these RTKs.59,60 Therefore, biomarkers that can predict the response and sensitivity of individual tumors to a specific therapy have to be developed so that patients who do not express these specific biomarkers might be treated using alternative approaches. In addition to the individualized use of established targeted therapeutics, a broad spectrum of molecular therapeutics should be tested in the context of CRT in HNSCC. So far, most studies have focused on the EGFR family and the related RTKs, whereas alternative pathways and substances might be just as promising. Such possibilities include mammalian target of rapamycin inhibitors or histone deacetylase inhibitors, which have thus far only been tested in phase I studies and in ongoing trials61 (NCT01064921, NCT01695122). Several other drugs are currently under preclinical investigation in the hopes of their improving CRT outcomes. We have been able to demonstrate that the small molecule inhibitor sorafenib (Nexavar; Bayer, Leverkusen, Germany) leads to radiosensitization in HPV-negative HNSCC cell lines62 and also sensitizes these cells toward CDDP (unpublished data from the authors of the present review article). As these effects seem to be mediated mainly by the inhibition of DNA double-strand break repair, an important factor influencing cell survival after ionizing radiation and CDDP, sorafenib seems to be a promising targeted therapeutic agent for combination with CRT worthy of being investigated in further preclinical studies. Although improvement in survival was observed with RT alone,10 in the RTOG 052215 and in the DAHANCA 1940 studies, the failure of added anti-EGFR therapy to improve CRT indicates that the combination of treatment modalities, their timing, and dosing of the drugs still need to be evaluated in detail. It seems to be fundamentally questionable whether EGFR targeting, whose antiproliferative effect is delivered by blocking replication as well as transcription,8,9 is capable of enhancing the effects of CDDP, whose cytotoxic effects depend on the very same transcription and replication63 processes. For this reason, the sequential application E2180

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of EGFR or related inhibitors might be a more promising approach, enhancing cell death both by inhibiting cell survival mechanisms, such as DNA repair,64–66 after ionizing radiation or CDDP treatment, as well as by allowing proliferation and transcription to induce apoptosis by CDDP. Furthermore, it is not clear yet whether the activity of EGFR-dependent pathways, such as the Akt and mitogenactivated protein kinase pathway, can fully account for CDDP resistance or sensitivity, and, consequently, whether the inhibition of these pathways by EGFR blocking increases or instead decreases the sensitivity of HNSCC cells to CDDP treatment.63 In conclusion, current approaches combining target therapeutics with platinum-based CRT in locally advanced HNSCC have thus far shown only limited improvement in patient survival. However, specific targeted therapy might improve the survival in specific subgroups of patients. Therefore, the underlying biological mechanisms leading to improved treatment response must be further elucidated in order to facilitate the effective and personalized treatment of patients with locally advanced HNSCC.

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