Table III.

Select Clinical Trials of EGFR Therapeutics

Lead Author (Year Published)	Phase	Study	Patient and Disease Demographics				Outcomes
			Number	Stage	Tumor Characteristics	EGFR expression (% of total patients)
Bonner et al. (2006)	III	High-dose XRT with and without cetuximab	424	III or IV	Nonmetastatic, measurable SCC	79	-Addition of cetuximab improved median duration of local-regional control (24.4 months cetuximab with XRT vs. 14.9 months XRT alone)
					Oropharynx (56%), hypopharynx (17%), larynx (27%)
Bonner et al. (2010)	III	High-dose XRT with and without cetuximab	424	III or IV	Nonmetastatic, measurable SCC	79	-Five-year OS 5-year overall survival 45.6% on cetuximab and XRT versus 36.4% with radiotherapy alone -Median OS 49.0 on cetuximab and XRT 49.0 months (95% CI 32.8–69.5) versus 29. 3 months (20.6–41.4) on XRT alone -Presence of cetuximab-induced rash was associated with improved survival
		Update on Bonner et al. (2006) study			Oropharynx (56%), hypopharynx (17%), larynx (27%)
Vermorken et al. (2007)	II	Treatment with cetuximab and subsequent combination of cetuximab and platinum therapy in the setting of disease progression	103	III or IV	Recurrent or metastatic SCC	97	-103 patients started on single agent cetuximab; 53 progressed and began combination therapy -Median OS 178 days in the single-agent phase -During the single-agent phase, disease was controlled (any response or stabilized disease) in 46% of patients and time to progression 70 days -During the dual-agent phase, disease was controlled in 26% of patients and time to progression 50 days
					Pharynx (38%), larynx (20%), paranasal sinuses (3%); other (39%)
		Open-label, no control arm			Progression after a 2-6 cycles of platinum-based therapy
Vermorken et al. (2008)	III	Platinum-based therapy and fluorouracil with and without cetuximab	442	NR	Metastatic or local-regionally recurrent SCC	92	-Addition of cetuximab lead to an increased median OS from 7.4 months to 10.1 months -Addition of cetuximab increased the progression-free survival time from 3.3 months to 5.6 months
					Oral cavity (20%), oropharynx (34%), hypopharynx (14%), larynx (25%), other (7%)
Ang et al. (2014)	III	Cisplatin-based C-XRT with and without cetuximab	891	III or IV	Oropharynx (70%), hypopharynx (7%), larynx (23%)	NR	-Cetuximab did not improve 3-year OS (72.9% without cetuximab vs. 75.8% with cetuximab; P = .32) -Addition of cetuximab led to increased radiation treatment interruptions and increased severe grade mucositis, rash, fatigue, anorexia, and hypokalemia -Patients with HPV+ tumor had improved survival with 3-year OS 85.6% vs. with HPV- tumors 60.1% (p < 0.001)
Weidhass et al. (2016)	III	Cisplatin-based C-XRT with and without cetuximab	413	III or IV	Oropharynx (72%), hypopharynx/larynx (28%) 17% KRAS-variant (70/413)	NR	-Cetuximab improved one- and two-year OS with in patients with KRAS-variant (HR, 0.19; 95% CI, 0.04-0.86; p = 0.03)
		Patients subcategorized by KRAS mutation
Mesia et al. (2015)	II	Cisplatin-based C-XRT compared to a dose-reduced cisplatin-based C-XRT with panitumumab	150	III or IV	Locally advanced SCC	NR	-Panitumumab did not improve two-year local-regional control (68% without vs. 61% with panitumumab) -Addition of panitumumab was associated with increased rates of grade 3-4 mucosal inflammation, dysphagia, and radiation-related skin toxicity
CONCERT-1					Oral cavity (9%), oropharynx (53%), hypopharynx (19%), larynx (18%)
Fayette et al. (2016)	II	Duligotuzumab compared to cetuximab following progressing on/after cisplatin-based chemotherapy	121	III or IV	Recurrent or metastatic SCC	NR	-OS was statistically similar between duligotuzumab (7.2 months) compared to cetuximab (8.7 months; HR 1.15, 90% CI 0.81-1.63) -Expression level of neuregulin 1 (NRG1, ligand to HER3) nor ERBB3 expression (encodes HER3) did not influence response lai
MEHGAN study					Oral cavity (29%), oropharynx (30%), hypopharynx (10%), larynx (16%), unspecified (10%), unknown (6%)
Martins et al. (2013)	II	Cisplatin and XRT with and without erlotinib Randomized	204	III or IV	Locally advanced SCC	4/90 samples assessed had EGFR amplification	-Addition of erlotinib did not increase toxicity -The TKI erlotinib did not confer additional tumor response or survival
					Oral cavity (7%), oropharynx (67%), hypopharynx (6%), larynx (18%), nasopharynx (1%), other (1%)
Argiris et al. (2013)	III	Docetaxel with or without gefitinib	270	NR	Recurrent or metastatic SCC	NR	-The TKI gefitinib did not lead to improved survival or outcomes
		Randomized			Oral cavity (22%), oropharynx (33%), larynx (26%), multiple (5%), other (14%)
Kim et al. (2015)	II	Dacomitinib monotherapy	48	NR	Local-regionally recurrent or metastatic SCC	NR	-20.8% (10) of patients with partial response and 65% (31) of patients with stable disease -OS 6.6 months and PFS 3.9 months -in the cohort, the patients with PI3K pathway mutations
					Progression on or intolerance to platinum therapy
					Oral cavity (37%), oropharynx (23%), hypopharynx(17%), larynx (19%), maxillary sinus (4%)
Machiels et al. (2015)	III	Afatinib or methotrexate as a second-line therapy following prior platinum-based therapy and disease progression	483	NR	Recurrent or metastatic SCC	NR	-PFS improved with afatinib (median 2.6 months) compared to methotrexate (median 1.7 months), hazard ratio 0.80 (95% CI 0.65-0.98, p=0.03) -Of note, 59% of patients were previously treated with EGFR-targeted therapy
					Progression after or on platinum-based therapy
					Oral cavity (28%), oropharynx (32%), hypopharynx (19%), larynx (21%)
Harrington et al. (2015)	III	Adjuvant C-XRT with lapatinib or placebo followed by 1 year of lapatinib or placebo	688	II, III, IVA	Surgical margin <5mm or ECE	70 (IHC 3+)	-Addition of lapatinib did not improve overall survival (HR 0.96, 95% CI 0.73 to 1.25) nor disease free survival (HR 1.10, 0.85 to 1.43) -Lapatinib was associated with increased grade 3-4 adverse events (75%) compared to placebo (67%, p=0.019)
					Oral cavity (41%), oropharynx (19%), hypopharynx(13%), larynx (23%), multiple sites (4%)
Soulières et al. (2017)	II	Buparlisib, oral pan-PI3K inhibitor, or placebo with paclitaxel as second-line therapy after progression with platinum-based treatment	158	NR	Recurrent or metastatic SCC	NR	-Median PFS was improved with second-line buparlisib and paclitaxel (4.6 months) compared to placebo and paclitaxel (3.5 months; HR 0.65 [95% CI 0.45–0.95) -Of note, 46% of patients were previously treated with EGFR-targeted therapy
					Progression after or on platinum-based therapy
BERIL-1					Oral cavity (29%), oropharynx (28%), hypopharynx (18%), larynx (16%), nasopharynx (3%), other/unknown (6%)

C-XRT, chemoradiotherapy. ECE, extracapsular extension. HR, hazard ratio. NR, not recorded. OS, overall survival. PFS, progression-free survival. SCC, squamous cell carcinoma. XRT, radiotherapy.