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

Figures & data

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

Abbreviations: Akt, v-akt murine thymoma viral oncogene homologue; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Erk, extracellular signal-related kinase; Mek, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol-3-kinase; PLC-γ, phospholipase-C gamma; PKC, protein kinase C; Ras, rat sarcoma viral oncogene homologue; Raf, Raf proto-oncogene, serine/threonine kinase; STAT, signal transducers and activators of transcription; TGF-α, transforming growth factor alpha.

Table 1 Selected Phase II and III trials of cetuximab in LA HNSCC

Trial	Phase	Sample size	Study population	Treatment regimen	Primary endpoint	Results
Definitive RT or CRT
Bonner et al^Citation36,Citation37	III	424 (213 in Arm A, 211 in Arm B)	Stage III–IV Untreated Oropharynx, larynx, hypopharynx	Arm A: RT alone Arm B: RT + cetuximab	LRC	• LRC: Arm A, 24.4 months; Arm B, 14.9 months (HR, 0.68; P=0.005) • Median OS: Arm A, 49.0 months; Arm B, 29.3 months (HR, 0.74; 95% CI, 0.57–0.97; P=0.03) • 5-year OS: Arm A, 36.4%; Arm B, 45.6% (HR, 0.73; 95% CI, 0.56–0.95; P=0.018) • Distant control: no significant differences • Toxicity: apart from rash and infusion reactions, no difference in rate of grade ≥3 toxicities
RTOG 0522^Citation39	III	891 (444 in Arm A, 447 in Arm B)	Stage III–IV Untreated Oropharynx, larynx, hypopharynx	Arm A: cetuximab + treatment in Arm B Arm B: bolus cisplatin ×2 cycles + RT	PFS	• PFS: HR (Arm A/B), 1.08; 95% CI, 0.88–1.32; P=0.76 • OS: HR (Arm A/B), 0.95; 95% CI, 0.74–1.21; P=0.32 • LRF: HR (Arm A/B), 1.30; 95% CI, 0.99–1.70; P=0.97 • Toxicity: higher rates in Arm A for grade 3–4 mucositis (Arm A, 43%; Arm B, 33%; P=0.002), skin reaction (20% vs 1%; P<0.001), fatigue (14% vs 9%; P=0.03), anorexia (16% vs 11%; P=0.04), hypokalemia (10% vs 5%; P=0.005)
Adjuvant CRT
RTOG 0234^Citation102	II	203 (97 in Arm A, 106 in Arm B)	High-risk resected HNSCC 94% stage IV 47% oral cavity	Arm A: RT + cisplatin and cetuximab Arm B: RT + docetaxel and cetuximab	DFS	• 2-year DFS: Arm A, 57% (95% CI, 47–67); Arm B, 66% (95% CI, 56–75) • 2-year OS: Arm A, 69% (95% CI, 60–79); Arm B, 79% (95% CI, 71–87) • 2-year distant metastases: Arm A, 26% (95% CI, 17–35); Arm B, 13% (95% CI, 7–20) • Toxicity: similar in both arms
Adjuvant RT
Mesia et al^Citation103	II	91 (45 in Arm A, 46 in Arm B)	Stage III, IVA–B Untreated Oropharynx	Arm A: RT + cetuximab Arm B: RT + cetuximab, then 12 weeks of cetuximab maintenance	LRC	• LRC at 1 year: Arm A, 59%; Arm B, 47% (P=0.25) • LRC at 2 years: 44% for both arms • Toxicity: comparable between arms
Induction chemotherapy, then concurrent CRT
TREMPLIN^Citation40	II	116 (60 in Arm A, 56 in Arm B)	Stage III, IVA–B Untreated Larynx, hypopharynx	IC with TPF Responders (≥50% response) randomized to Arm A: RT + cisplatin (bolus ×3 cycles) Arm B: RT + cetuximab	LP	• LP: Arm A, 95% (95% CI, 86–98); Arm B, 93% (95% CI, 83–97) • OS at 18 months: Arm A, 92% (95% CI, 82–96); Arm B, 89% (95% CI, 79–95) • LFP: Arm A, 87% (95% CI, 76–93); Arm B, 82% (95% CI, 70–90) • Despite a higher rate of local failures in Arm B, more salvage laryngectomies were performed and resulted in similar ultimate locoregional failure rates (13.3% in Arm A, 10.7% in Arm B) • Toxicity: no difference in grade 3 or 4 mucositis; more grade 3 or 4 in-field dermatitis seen in Arm B (57%) vs Arm A (26%)
ECOG 1308^Citation104,Citation105	II	80 (59 in Arm A, 21 in Arm B)	Stage III, IVA–B Untreated Oropharynx, HPV positive	IC with paclitaxel + cisplatin + cetuximab If clinical CR → Arm A: low-dose IMRT + cetuximab or If PR/SD → Arm B: standard IMRT + cetuximab	2-year PFS	• Complete RR to IC: 63.8% (central review), 71.3% (investigator reported), with 59/80 patients receiving low-dose IMRT + cetuximab in Arm A • Overall RR: 86% (14% unevaluable) • Rate of posttreatment neck dissection: 13.4% (low-dose IMRT) vs 22.2% (standard IMRT); P=0.46
Induction chemotherapy, then risk-based local therapy
Massarelli et al^Citation106	II	136	Stage IVA-B Untreated Oropharynx, oral cavity, larynx, hypopharynx, nasopharynx	Arm A: paclitaxel + carboplatin + cetuximab Arm B: TPF + cetuximab; each followed by risk-based local therapy, defined by HPV status and stage, and stratification by smoking status	2-year PFS	• Overall RR to IC: Arm A, 78%; Arm B, 82% • Overall RR after local therapy: Arm A, 94%; Arm B, 85% • 2-year PFS: Arm A, 89%; Arm B, 80%

Abbreviations: LA, locally advanced; HNSCC, head and neck squamous cell carcinoma; RT, radiation therapy; CRT, chemoradiation therapy; LRC, locoregional control; HR, hazard ratio; OS, overall survival; CI, confidence interval; PFS, progression-free survival; LRF, locoregional failure; DFS, disease-free survival; IC, induction chemotherapy; TPF, docetaxel/cisplatin/5-fluorouracil; LP, larynx preservation; LFP, larynx function preservation; HPV, human papillomavirus; CR, complete response; IMRT, intensity-modulated radiation therapy; RR, response rate; PR, partial response; SD, stable disease.

Table 3 Selected Phase II and III data on ErbB family inhibitors in LA and R/M HNSCC

Agent	Study	Sample size	Study population	Treatment regimen	Primary endpoint(s)	Median (or %) PFS	Median (or %) OS	RR
Monoclonal antibodies
Panitumumab	Randomized, Phase III^Citation44	657	R/M	Panitumumab/CT vs CT alone	OS	5.8 vs 4.6 months (HR, 0.780; 95% CI, 0.659–0.922; P=0.004)	11.1 vs 9.0 months (HR, 0.873; 95% CI, 0.729–1.046; P=0.14)	36% vs 25%
	Randomized, Phase II^Citation46	103	R/M	Panitumumab/CT vs CT alone	PFS	6.9 vs 5.5 months (HR, 0.63; 95% CI, 0.40–1.00)	12.9 vs 13.8 months (HR, 1.10; 95% CI, 0.71–1.72)	44% vs 37%
	Randomized, Phase II^Citation47	151	LA	Panitumumab/RT vs CRT	2-year LR control rate	HR, 1.73; 95% CI, 1.07–2.81; P=0.03	HR, 1.59; 95% CI, 0.91–2.79; P=0.10	NR
	Randomized, Phase III^Citation48	320	LA	Panitumumab/RT vs cisplatin/RT	2-year PFS rate	2-year 76% vs 73% (HR, 0.95; 95% CI, 0.6–1.5; P=0.83)	2-year 88% vs 85% (HR, 0.89; 95% CI, 0.54–1.48; P=0.66)	NR
Zalutumumab	Randomized, Phase III^Citation51	286	R/M	Zalutumumab/BSC vs BSC alone	OS	9.9 vs 8.4 weeks (HR, 0.63; 95% CI, 0.47–0.84; P=0.001)	6.7 vs 5.2 months (HR, 0.77; 95% CI, 0.57–1.05; unadjusted P=0.06)	NR
Nimotuzumab	Nonrandomized, Phase I/II^Citation115	24	LA	Nimotuzumab/RT	Safety	NR	Nimotuzumab 200 and 400 mg: 44.30 months	NR
	Randomized trial^Citation55	106	LA	Nimotuzumab/RT vs placebo/RT	RR	NR	Overall: 12.5 vs 9.47 months In-site subgroup analysis: 14.0 vs 8.83 months (P=0.02)	59.5% vs 34.2% (P=0.04)
	Phase IIb^Citation56	92	LA	Nimotuzumab/CRT vs placebo/CRT	Biomarker correlation with outcomes	NR	>30 vs 22 months (P<0.003)	NR
	Randomized trial^Citation57	56	LA	Nimotuzumab/CRT vs CRT	RR, safety	NR	NR	96% vs 72% (P=0.02)
Sym004	Nonrandomized, Phase II^Citation62	26	R/M	Sym004	PFS	82 days	NR	NR
TKIs
Erlotinib	Randomized, Phase II^Citation71	204	LA	Erlotinib/CRT vs CRT	Complete RR	HR, 0.9 (P=0.71)	NR	Complete RR: 52% vs 40% (P=0.08)
	Nonrandomized, Phase II^Citation72	115	R/M	Erlotinib	Efficacy	9.6 weeks	6.0 months	4.3%
	Nonrandomized, Phase II^Citation73	44	R/M	Erlotinib/CT	Efficacy, toxicity	3.3 months	7.9 months	21%
	Nonrandomized, Phase II^Citation74	50	R/M	Erlotinib/CT	Efficacy, toxicity	6.01 months	11 months	67%
Lapatinib	Randomized, Phase II^Citation77	107	LA	Lapatinib vs placebo	Apoptotic index	NR	NR	17% vs 0%
	Randomized, Phase II^Citation116	67	LA	Lapatinib/CRT followed by lapatinib vs placebo/CRT followed by placebo	Complete RR	35.3 vs 12.1 months (HR, 0.74; 95% CI, 0.38–1.45; P=0.18)	30.9 months vs not reached (HR, 0.90; 95% CI, 0.44–1.84; P=0.38)	Complete RR: 53% vs 36% (P=0.09)
	Nonrandomized, Phase II^Citation78	45	R/M	Lapatinib	RR, PFS	52 days	288 and 155 days in EGFR inhibitor–naïve and EGFR inhibitor–pretreated patients, respectively	0%
	Randomized, Phase III^Citation80	688	LA	Adjuvant lapatinib/CRT vs adjuvant placebo/CRT	DFS	DFS: 53.6 months vs not reached (HR, 1.10; 95% CI, 0.85–1.43; P=0.45)	NR	NR
Afatinib	Randomized, Phase II^Citation85	121	R/M	Afatinib vs cetuximab	Tumor shrinkage before crossover	Stage I: 13.0 vs 15.0 weeks (HR, 0.93; 95% CI, 0.62–1.38; P=0.71)	Stage I: 35.9 vs 47.1 weeks	Stage I: 8.1% vs 9.7% (P=0.78)
	Randomized, Phase III^Citation83	483	R/M	Afatinib vs methotrexate	PFS	2.6 vs 1.7 months (HR, 0.80; 95% CI, 0.65–0.98; P=0.030)	6.8 vs 6.0 months (HR, 0.96; 95% CI: 0.77–1.19; P=0.70)	10% vs 6% (P=0.10)
Dacomitinib	Nonrandomized, Phase II^Citation87	69	R/M	Dacomitinib	RR	12.1 weeks	34.6 weeks	12.7%
Vandetanib	Randomized, Phase II^Citation90	29	R/M	Vandetanib/CT vs CT	Partial RR	9 vs 3.21 weeks	NR	13% vs 7%

Abbreviations: LA, locally advanced; R/M, recurrent or metastatic; HNSCC, head and neck squamous cell carcinoma; PFS, progression-free survival; OS, overall survival; RR, response rate; CT, chemotherapy; HR, hazard ratio; CI, confidence interval; CRT, chemoradiation; LR, locoregional; NR, not reported; BSC, best supportive care; RT, radiation therapy; TKI, tyrosine kinase inhibitor; EGFR, epidermal growth factor receptor; DFS, disease-free survival.

Table 4 Selected ongoing clinical trials of ErbB family inhibitors in Phase II or III development for HNSCC

Agent	Study	Study population	Study regimen(s)	Primary endpoint(s)	Target accrual (status)
mAbs
Cetuximab	Randomized, Phase III (NCT00956007 [formerly NCT01311063] [RTOG 0920])	LA	Cetuximab/RT vs RT	OS	700 (recruiting)
	Randomized, Phase III (NCT01302834 [RTOG 1016])	LA	Cetuximab/RT vs CRT	OS	706 (ongoing; not recruiting)
Panitumumab	Randomized, Phase III (NCT00820248 [NCIC CTG HN.6])^Citation117	LA	Panitumumab/RT vs CRT	PFS	320 (ongoing; not recruiting)
	Nonrandomized, Phase II (NCT00446446 [PRISM])	R/M	Panitumumab monotherapy	RR	52 (ongoing; not recruiting)
	Nonrandomized, Phase II (NCT00798655)	LA	Panitumumab/CRT	Disease progression, change in tumor size	46 (ongoing; not recruiting)
Zalutumumab	Randomized, Phase III (NCT00496652 [DAHANCA 19])	LA	Zalutumumab/CRT vs CRT	LR control rate	600 (ongoing; not recruiting)
Nimotuzumab	Randomized, Phase III (NCT00957086)	LA	Adjuvant nimotuzumab/CRT vs adjuvant CRT	DFS	710 (recruiting)
	Randomized, Phase III (NCT01074021)	LA	Nimotuzumab/CRT vs placebo/CRT (in nasopharyngeal cancer)	LR control rate, safety	480 (ongoing; not recruiting)
	Randomized, Phase III (NCT02012062)	LA	Neoadjuvant CT and nimotuzumab/concurrent CRT vs neoadjuvant CT and concurrent CRT (in nasopharyngeal cancer)	Safety	320 (recruiting)
	Randomized, Phase II (NCT01516996)	LA	Nimotuzumab/neoadjuvant and concurrent CRT vs neoadjuvant and concurrent CRT	RR	80 (recruiting)
MEHD7945A	Randomized, Phase II (NCT01577173)	R/M	MEHD7945A vs cetuximab	PFS	122 (ongoing; not recruiting)
TKIs
Erlotinib	Nonrandomized, Phase II (NCT00720304)	LA	Erlotinib/CRT	PFS, TTP	37 (ongoing; not recruiting)
	Randomized, Phase II (NCT01064479)	R/M	Erlotinib/CT followed by erlotinib maintenance vs placebo/CT followed by placebo maintenance	PFS	120 (recruiting)
Afatinib	Randomized, Phase III (NCT01345669 [LUX-Head & Neck 2])	LA	Adjuvant afatinib vs placebo after CRT	DFS	669 (recruiting)
	Randomized, Phase III (NCT01427478 [GORTEC 2010-02])	LA	Afatinib maintenance after CRT vs placebo maintenance after CRT	DFS	315 (recruiting)
	Randomized, Phase III (NCT01856478 [LUX-Head & Neck 3])	R/M	Afatinib vs methotrexate	PFS	300 (recruiting)
	Randomized, Phase III (NCT02131155 [LUX-Head & Neck 4])	LA	Adjuvant afatinib vs placebo after CRT	DFS	150 (recruiting)
	Randomized, Phase II (NCT01415674 [PREDICTOR])	LA	Neoadjuvant afatinib vs placebo	Biomarkers	60 (ongoing; not recruiting)
Lapatinib	Randomized, Phase II (NCT01711658 [TRYHARD])	LA	Lapatinib/CRT vs CRT	PFS	176 (recruiting)

Abbreviations: HNSCC, head and neck squamous cell carcinoma; mAb, monoclonal antibody; LA, locally advanced; RT, radiation therapy; OS, overall survival; CRT, chemoradiation therapy; PFS, progression-free survival; R/M, recurrent or metastatic; CT, chemotherapy; RR, response rate; LR, locoregional; DFS, disease-free survival; TKI, tyrosine kinase inhibitor; TTP, time to progression.

Table 2 Selected Phase II and III trials of cetuximab in R/M HNSCC

Phase	Sample size	Treatment regimen	Primary endpoint(s)	RR	Median PFS (months)	Median OS (months)
First-line
Randomized III^Citation41	117	Arm A: cetuximab + cisplatin	PFS	A: 26%	A: 4.2	A: 9.2
		Arm B: cisplatin + placebo (crossover to Arm A allowed after October 2000 for patients with PD)		B: 10% (P=0.03)	B: 2.7	B: 8.0
Randomized III^Citation42	442	Arm A: cetuximab + cisplatin/5-FU	OS	A: 36%	A: 5.6	A: 10.1
		Arm B: cisplatin/5-FU alone		B: 20% (OR, 2.33; 95% CI, 1.50–3.60; P<0.001)	B: 3.3 (HR, 0.54; 95% CI, 0.43–0.67; P<0.001)	B: 7.4 (HR, 0.80; 95% CI, 0.64–0.99; P=0.04)
Nonrandomized II^Citation107	54	Cetuximab + cisplatin + docetaxel	RR	54%	7.1	15.3
Nonrandomized II^Citation108	46	Cetuximab + paclitaxel	RR	54%	4.2	8.1
Platinum-resistant
Nonrandomized II^Citation109	96	Cetuximab + platinum-based chemotherapy	RR	10%	NR	183 days
Nonrandomized II^Citation110	84	Cetuximab + docetaxel	RR	11%	3.1	6.7
Nonrandomized II^Citation111	66	Cetuximab + cisplatin + pemetrexed	PFS	29.3%	4.4	9.7
Nonrandomized II^Citation112	130	Platinum + 5-FU or taxane ×2 cycles If SD or PD → then: platinum + cetuximab	RR	SD: 18% PD1: 20% PD2a: 6%	SD: 4.9 PD1: 3 PD2a: 2	SD: 11.7 PD1: 6.1 PD2a: 4.3
Randomized II^Citation113	61	Arm A: cetuximab 500 mg/m^2 every 2 weeks	RR	A: 11%	A: 2.2	A: 7.4
		Arm B: cetuximab 750 mg/m^2 every 2 weeks (closed early due to lack of efficacy)		B: 8%	B: 2.0	B: 9.4
Nonrandomized II^Citation114	103	Cetuximab monotherapy	RR	13%	NR	178 days

Notes:

a PD2 corresponds to patients who failed platinum-based therapy within 90 days of receipt of treatment.

Abbreviations: R/M, recurrent or metastatic; HNSCC, head and neck squamous cell carcinoma; RR, response rate; PFS, progression-free survival; OS, overall survival; PD, progressive disease; 5-FU, 5-fluorouracil; OR, odds ratio; CI, confidence interval; HR, hazard ratio; SD, stable disease; NR, not reported.

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