Anti-EGFR monoclonal antibodies
Panitumumab (Vectibix
®, Amgen; Thousand Oaks, CA, USA) is a fully human anti-EGFR mAb. In a phase I study, the combination of panitumumab with carboplatin, paclitaxel, and intensity-modulated radiotherapy was evaluated in patients with locally advanced SCCHN (
N = 19) [
39]. All patients achieved at least a partial response (PR), and the most common AEs (≥10% of patients) were oral pain, xerostomia, acneiform rash, and anemia. The phase II PRISM study evaluated second-line panitumumab monotherapy following prior chemotherapy for metastatic/recurrent SCCHN (
N = 52) [
40]. The interim safety analysis demonstrated that the most common AEs (≥10% of patients) were skin disorders, fatigue, hypomagnesemia, and nausea. Grade ≥ 3 skin-related AEs were observed in 12% of patients. In SPECTRUM, cisplatin/5-FU plus panitumumab was compared with cisplatin/5-FU alone in patients with metastatic/recurrent SCCHN (
N = 657) [
41]. The addition of panitumumab to chemotherapy did not significantly improve median OS versus chemotherapy alone (11.1 vs. 9.0 months; HR, 0.87; 95% CI, 0.73–1.05;
P = 0.14), but did improve median PFS (5.8 vs. 4.6 months; HR, 0.78; 95% CI, 0.66–0.92;
P = 0.004). The RR was 36% for panitumumab plus chemotherapy versus 25% for chemotherapy alone. The three most common grade ≥3 AEs (≥10% of patients) were neutropenia (32% for panitumumab and chemotherapy vs. 33% for chemotherapy alone), skin toxicity (17% vs. 1%), and anemia (12% vs. 14%). Infusion-related reactions of any grade occurred in <1% of patients in each group [
41].
Several ongoing phase II studies are currently evaluating panitumumab in locally advanced SCCHN (combination with radiotherapy vs. chemoradiotherapy, NCT00547157; combination with chemoradiotherapy, NCT00500760; combination with postoperative chemoradiotherapy, NCT00798655) or metastatic/recurrent SCCHN (as first-line treatment in combination with cisplatin and docetaxel, NCT00454779). An ongoing phase III trial is evaluating panitumumab plus radiotherapy versus cisplatin plus radiotherapy for locally advanced SCCHN (NCT00820248).
Nimotuzumab (YM Biosciences; Ontario, Canada) is a humanized anti-EGFR mAb that has been granted approval in SCCHN in several countries outside the United States. It exhibits a reduced binding affinity for the EGFR compared with the murine mAb [
42], but has demonstrated a unique clinical profile, with an absence of the severe skin toxicities that are observed with cetuximab and panitumumab. A pharmacodynamic study assessing the combination of nimotuzumab and radiotherapy in patients with unresectable locoregional SCCHN showed that nimotuzumab was well tolerated, with no evidence of skin rash. Nine of 10 patients achieved an objective response based on RECIST criteria [
43].
In a phase I/II trial, nimotuzumab plus radiotherapy was evaluated in 24 patients with locally advanced SCCHN [
44]. The RR was 50% with doses of 50–100 mg (low dose) nimotuzumab, and 81% with 200–400 mg (high dose) nimotuzumab. Median OS for low-dose nimotuzumab was 8.6 months, compared with 44.3 months for high-dose nimotuzumab (
P = 0.03 for high- vs. low dose). Three-year OS rates were 16.7 and 66.7% for the low- and high doses, respectively. The most common AEs with high-dose nimotuzumab were fever, hypotension, and tremors. No cases of skin rash were observed [
44]. A separate phase IIb study investigated nimotuzumab plus chemoradiotherapy versus chemoradiotherapy alone (group 1), or nimotuzumab plus radiotherapy versus radiotherapy alone (group 2), as first-line therapy in 92 patients with advanced unresectable SCCHN [
45]. The RR (100% vs. 70%;
P = 0.02), median PFS (not reached vs. 12.66 months;
P = 0.013), and median OS (not reached vs. 22.0 months;
P = 0.004) were all significantly improved with nimotuzumab plus chemoradiotherapy versus chemoradiotherapy alone. With nimotuzumab plus radiotherapy, the RR was 76% versus 40% for radiotherapy alone (
P = 0.023), while median PFS was 10.1 versus 6.9 months (
P = 0.24), and median OS was 14.37 versus 12.79 months (
P = 0.71), respectively. The nimotuzumab-related AEs in group 1 were asthenia, dizziness, microscopic hematuria, vomiting, and loose stools; fever, chills, pruritus, rash, headache, hypertension, and fluctuation in blood pressure were reported as nimotuzumab-related AEs in group 2. There were four cases of skin reactions in patients receiving nimotuzumab [
45]. At 48 months, the addition of nimotuzumab to chemoradiotherapy significantly increased median OS compared with chemoradiotherapy alone (47% vs. 21%; HR, 0.35;
P = 0.01), but not when combined with radiotherapy versus radiotherapy alone (34% vs. 13%;
P = not specified) [
46].
In a double-blind trial, patients with unresectable locoregional SCCHN (
N = 106) were assigned randomly to receive first-line therapy with nimotuzumab plus radiotherapy versus placebo plus radiotherapy [
47]. Complete RRs were 59.5% for patients receiving nimotuzumab and radiotherapy versus 34.2% of patients receiving radiotherapy alone (
P = 0.038), and median OS was 12.5 months and 9.5 months (
P = 0.0491), respectively. In a subgroup analysis of patients with EGFR-positive tumors, significant survival benefit was seen with nimotuzumab plus radiotherapy versus radiotherapy alone (16.5 vs. 7.2 months;
P = 0.0038). The three most common AEs considered to be related to nimotuzumab treatment were asthenia, fever, and headache. No cases of skin rash were observed. A small pilot study involving 17 patients with locally advanced SCCHN was conducted to evaluate the combination of nimotuzumab and concurrent chemotherapy [
48]. The RR was 76% and no grade 3–4 AEs were reported. An ongoing phase II study is being conducted to investigate the combination of nimotuzumab plus cisplatin and radiotherapy for locally advanced SCCHN (NCT00702481), and a phase III study is assessing postoperative concurrent chemoradiotherapy with or without nimotuzumab for locally advanced SCCHN (NCT00957086).
Zalutumumab (Genmab; Copenhagen, Denmark) is a fully human, high-affinity anti-EGFR mAb [
49], which has received fast track designation from the Food and Drug Administration for advanced, metastatic, and/or unresectable SCCHN that has progressed following standard platinum-based chemotherapy. In a phase I/II study in 28 patients with metastatic/recurrent SCCHN, zalutumumab was associated with a RR of 7.1% [
50]. The most frequently reported AEs were infusion-related reactions, rash/acne, and dyspnea. In a phase III pivotal trial, zalutumumab plus best supportive care (BSC) was compared with BSC plus optional methotrexate (control group) in 286 patients with metastatic/recurrent SCCHN after failure of platinum-based chemotherapy [
51]. The dose of zalutumumab was titrated according to the development of skin rash in individual patients. Median OS was not significantly different between groups (6.7 vs. 5.2 months in the zalutumumab versus control group, respectively; HR, 0.77; 95% CI, 0.57–1.05;
P = 0.0648), but PFS was significantly prolonged (9.9 vs. 8.4 weeks; HR, 0.63; 95% CI, 0.47–0.84;
P = 0.0012). The three most common AEs (≥10% of patients) were rash (92% for zalutumumab and BSC versus 0% for control), anemia (25% vs. 19%), and pyrexia (22% vs. 13%). Grade 3–4 AEs that were more common in the zalutumumab group than in the control group included rash, hypomagnesemia, pneumonia, and headache. Results are awaited from a phase I/II trial of zalutumumab plus cisplatin-based chemoradiotherapy as first-line therapy for locally advanced SCCHN (NCT00401401). A phase III study to determine whether the addition of zalutumumab to primary curative radiotherapy increases locoregional control in SCCHN is currently recruiting patients (DAHANCA 19, NCT00496652).
Tyrosine kinase inhibitors (TKIs) targeting EGFR
Gefitinib (Iressa
®, AstraZeneca; Wilmington, DE), an oral, small-molecule, reversible EGFR TKI, was the first TKI to reach phase III investigation in SCCHN, but is no longer being pursued for this indication due to recent negative study results [
4]. In a phase II trial assessing second-line gefitinib 500 mg/day in patients with metastatic/recurrent SCCHN (
N = 52), the RR was 10.6%, median OS was 8.1 months, and 1-year OS rate was 29.2% [
52]. The most common AEs were diarrhea, skin toxicity, and anorexia. A subsequent phase II trial was conducted to evaluate gefitinib 250 mg/day in patients with recurrent and/or metastatic SCCHN (
N = 71), with the aim of reducing the incidence of toxicities [
53]. One patient achieved a PR. Median OS was 5.5 months and PFS was 1.8 months, while the 1-year OS rate was estimated at 19%. Skin toxicity was reported for 64% of patients.
When gefitinib 250 mg/day was combined with radiotherapy in a phase I/II study involving 16 patients with locally advanced inoperable SCCHN, the RR was 37.5% [
54]. Neoadjuvant gefitinib in combination with docetaxel, carboplatin, and 5-FU, followed by concurrent docetaxel, radiation therapy, and gefitinib was evaluated in patients with locally advanced SCCHN (
N = 62) [
55]. Following completion of neoadjuvant therapy, the RR was 46%, and following completion of adjuvant therapy, the RR was 80%. The estimated 3-year survival rate was 54%. The most common grade 3–4 AEs reported during the neoadjuvant treatment phase were neutropenia, oral mucositis, and diarrhea, while during the adjuvant phase, these were oral mucositis/esophagitis/dysphagia, anorexia, and fatigue.
Two phase III studies have assessed gefitinib in patients with metastatic/recurrent SCCHN. In patients who had received numerous prior treatments, gefitinib 250 mg/day plus docetaxel was compared with docetaxel alone (
N = 270) [
56]. The study was terminated early, with a reported median OS of 6.8 months for gefitinib plus docetaxel versus 6.0 months for docetaxel alone (
P = 0.74); median PFS was 3.3 versus 2.2 months (
P = 0.18). In a separate trial, gefitinib 250 mg/day, gefitinib 500 mg/day, and methotrexate were compared in 486 patients [
57]. Neither dose of gefitinib significantly increased median OS compared with methotrexate (gefitinib 250 mg/day, 5.6 months vs. methotrexate, 6.0 months; HR, 1.22; 95% CI, 0.95–1.57;
P = 0.12; and gefitinib 500 mg/day, 6.7 months vs. methotrexate, 6.0 months; HR, 1.12; 95% CI, 0.87–1.43;
P = 0.39). The RR was 2.7% for gefitinib 250 mg/day, 7.6% for gefitinib 500 mg/day, and 3.9% for methotrexate, with no significant differences between either dose of gefitinib and methotrexate. The three most common AEs (≥10% of patients) with gefitinib 250 mg/day, gefitinib 500 mg/day, and methotrexate were rash (29.1, 39.2, and 4.4%), diarrhea (25.9, 39.2, and 11.9%), and stomatitis (9.5, 13.9, and 34.6%).
Erlotinib (Tarceva
®, Genentech; South San Francisco, CA) is another oral, small-molecule, reversible EGFR TKI that has demonstrated efficacy in patients with SCCHN. In a phase I/II study involving 37 patients with locally advanced SCCHN, erlotinib administered in combination with cisplatin and radiotherapy was associated with a RR of 74% (all complete responses [CRs]) and 3-year PFS and OS rates of 61 and 72%, respectively [
58]. The most common nonhematologic AEs were nausea/vomiting, dysphagia, and stomatitis. In another phase II study, patients with locally advanced SCCHN (
N = 128) were assigned randomly to receive cisplatin plus radiotherapy or cisplatin plus radiotherapy and erlotinib [
59]. An interim analysis of the first 100 patients demonstrated a RR for both treatment arms of 71% (all CR), and the most common serious AEs were nausea, vomiting, and dehydration.
Erlotinib monotherapy was evaluated in a phase II trial involving 155 patients with metastatic/recurrent SCCHN [
60]. The RR was 4.3%, median OS was 6.0 months, and median PFS was 9.6 weeks. The most common drug-related AEs were rash, diarrhea, and dry skin. A separate phase I/II study was conducted to evaluate erlotinib plus cisplatin in patients with metastatic/recurrent SCCHN (
N = 51) [
61]. Of 43 evaluable patients, nine demonstrated a tumor response, the median PFS was 3.3 months, and the median OS was 7.9 months. The three most frequently reported AEs were rash, hypomagnesemia, and anemia.
In ongoing phase II studies, erlotinib in combination with cisplatin-based chemotherapy is being evaluated in chemonaive metastatic/recurrent SCCHN (NCT01064479, NCT00076310); as first-line therapy in combination with cetuximab, carboplatin, and paclitaxel for metastatic/recurrent SCCHN (NCT01316757); as first-line therapy in combination with chemoradiotherapy for locally advanced SCCHN (NCT00720304; NCT00442455); and as first-line therapy in combination with radiotherapy for locally advanced SCCHN (NCT01192815). Phase III studies of erlotinib in combination with first-line platinum-based chemotherapy for metastatic/recurrent SCCHN (NCT00448240) and as maintenance therapy in fully resected SCCHN (NCT00412217) were terminated due to low enrollment.
Lapatinib (Tykerb
®, GlaxoSmithKline; Research Triangle Park, NC, USA) is an oral, small-molecule, reversible inhibitor of both EGFR and ErbB2/HER2 [
62]. In a phase I dose-escalation study involving 31 patients with locally advanced SCCHN, lapatinib was administered in combination with cisplatin and radiotherapy [
63]. The RR was 81% for all doses combined (500, 1,000, and 1,500 mg/day) and 65% at the recommended phase II dose of 1,500 mg/day. The most common AEs (≥10% of patients) at 1,500 mg/day were radiation mucositis, radiation dermatitis, nausea, and vomiting. In a subsequent phase II trial, lapatinib was again combined with cisplatin and radiotherapy, followed by maintenance lapatinib or placebo, after completion of chemoradiotherapy in patients with locally advanced SCCHN (
N = 67) [
64]. The complete RR was 53% with lapatinib versus 36% with placebo, and HRs for PFS and OS were 0.71 (95% CI, 0.34–1.52) and 0.70 (95% CI, 0.31–1.63), respectively. No grade 3–4 AEs were observed during maintenance therapy, other than grade 3 localized edema (lapatinib, 3%) and weight loss (placebo, 3%).
In a separate phase II study of lapatinib monotherapy in patients with metastatic/recurrent SCCHN (
N = 42), no objective responses were observed [
65]. In ongoing phase II studies, lapatinib plus capecitabine is being evaluated in metastatic/recurrent SCCHN (NCT01044433), and lapatinib plus radiotherapy is being evaluated in patients with locally advanced SCCHN who cannot tolerate chemotherapy (NCT00490061). In addition, a phase III study is being conducted to investigate lapatinib versus placebo administered postoperatively in combination with chemoradiotherapy followed by maintenance lapatinib/placebo in high-risk patients (NCT00424255).
A key limitation of currently available EGFR-targeted therapies, including mAbs and TKIs, is de novo or acquired resistance, mediated through mechanisms including the mutant type III variant of
EGFR [
66,
67], mutations in the tyrosine kinase domain of
EGFR [
67], and tumor cell surface expression of other members of the ErbB receptor family [
68]. In an effort to address this issue, TKIs that block more than one member of the ErbB family and/or bind irreversibly to their targets are being investigated for the treatment of SCCHN.
Afatinib (BIBW 2992, Boehringer Ingelheim; Ingelheim, Germany) is an oral, small-molecule, irreversible ErbB family inhibitor that targets EGFR, ErbB2, and ErbB4 [
69,
70]. Preliminary results from stage 1 of a 2-stage phase II study of afatinib versus cetuximab in 124 patients with platinum-refractory metastatic/recurrent SCCHN showed PRs in 22 and 13% of patients, respectively [
71]. Median PFS was 16 versus 10 weeks for afatinib versus cetuximab, respectively. Primary afatinib-related AEs were diarrhea and skin-related AEs, while skin-related AEs were the primary cetuximab-related AEs. A phase III trial of afatinib versus methotrexate in patients with platinum-refractory metastatic/recurrent SCCHN (NCT01345682) is planned, and a phase III trial of afatinib versus placebo as adjuvant therapy after chemoradiotherapy in patients with unresected locoregional SCCHN (NCT01345669) is recruiting participants.
PF-00299804 (PF-299, Pfizer; New York, NY, USA) is an oral, small-molecule, irreversible, pan-HER inhibitor that targets EGFR, ErbB2, and ErbB4 [
72]. Results from the first stage of a 2-stage phase II study investigating PF-00299804 as first-line treatment in metastatic/recurrent SCCHN showed PRs in 6 of 56 (11%) evaluable patients, and median PFS of 2.8 months. The most common grade 3 AEs (≥3% of patients) were diarrhea, fatigue, dermatitis acneiform, and hand–foot skin reaction [
73]. The criteria for proceeding to stage 2 of the trial were fulfilled and patient accrual is ongoing.
In addition to treatment strategies targeting more than one ErbB receptor family member and/or binding irreversibly, approaches that combine agents with different mechanisms of action, i.e., targeting other pathways involved in SCCHN, may also have potential to delay or overcome resistance to EGFR-targeted therapy in SCCHN [
67]. Preclinical data support the evaluation of the mammalian target of rapamycin (mTOR) pathway, which is involved in EGFR downstream signaling, as a potential therapeutic strategy for SCCHN [
74,
75]. A number of clinical trials are currently investigating such treatment combinations. Two phase II studies are evaluating erlotinib plus temsirolimus (NCT01009203) or everolimus (NCT00942734) in platinum-refractory SCCHN. Cetuximab plus temsirolimus is being evaluated in a phase II study in patients with metastatic/recurrent SCCHN not responding to prior cetuximab-based therapy (NCT01256385). Other phase I/II studies are evaluating cetuximab plus platinum and everolimus (NCT01283334), or temsirolimus (NCT01015664), in metastatic/recurrent SCCHN. Cetuximab with cisplatin/paclitaxel plus everolimus or placebo is also being investigated in a phase II study in locally advanced SCCHN (NCT01133678).
High levels of vascular endothelial growth factor (VEGF) expression and some subtypes of VEGF receptors (VEGFRs) [
76,
77] that are associated with tumor angiogenesis, lymphangiogenesis, and an increased risk of mortality have been observed in SCCHN tumors [
76‐
78]. Results from a phase I/II study of erlotinib plus the anti-VEGFR mAb bevacizumab in patients with metastatic/recurrent SCCHN (
N = 48) demonstrated an RR of 15%, a median PFS of 4.1 months, and a median OS of 7.1 months [
79]. The most common AEs (≥10% of patients) were rash, diarrhea, and fatigue. Ongoing phase II studies are evaluating erlotinib plus bevacizumab (NCT00392665) or cetuximab plus bevacizumab (NCT00409565, NCT00407810) in patients with metastatic/recurrent SCCHN, and cetuximab with bevacizumab plus chemoradiotherapy (NCT00703976, NCT00968435) for locally advanced SCCHN. Sorafenib, an inhibitor of multiple protein kinases, including those associated with VEGFRs, is also being evaluated in a phase II study for SCCHN in combination with cetuximab (NCT00815295).