Is there a role for epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor wild-type non-small cell lung cancer?

Table 2 Relevant second- and third-line phase III trials

Trial	Comparison	Populationcharacteristics	Efficacy in allpatients	Efficacy insubgroupenriched for EGFR wt	Mutationalanalysis	Efficacy bymutationalstatus
BR.21[1,21]	E (n = 488) vs P (n = 243)	Second line (51%) or third line (49%); nonADC, 50%; non-Asian, 87%	OS for E, 6.7 mo; OS for P, 4.7 mo; HR 0.70; P < 0.001	NonADC HR, 0.8; non-Asian HR, 0.8	n = 204 (27.9%); EGFR activating mutation, 34	EGFR mutated: OS HR, 0.55; EGFR wt OS HR, 0.74; interaction P = 0.47
ISEL[20,23]	G (n = 959) vs P (n = 480)	Second line (49%) or third line (51%); nonADC 52%; non-Asian, 90%	OS for G, 5.6 mo; OS for P, 5.1 mo; HR, 0.89; P = 0.089	NonADC HR < 1.01; non-Asian HR = 0.92	n = 215 (14.9%); activating EGFR mutation, 26	NR
INTEREST[24,25]	G (n = 723) vs D (n = 710)	Second line (84%) or third line (16%); nonADC, 44%; non-Asian, 78%	OS for G, 7.6 mo; OS for D, 8 mo; HR, 1.02 (met non inferiority criteria)	NonADC HR < 11; non-Asian HR = 11	n = 297 (20.7%); activating EGFR mutation, 44	EGFR mutated: OS HR, 0.83; EGFR wt: OS HR, 1.02; interaction P = 0.59
TITAN[26]	E (n = 203) vs D/Pem (n = 221)	Second line; non-Asian, 86%; nonADC, 55%	OS for E, 5.3 mo; OS for D/Pem, 5.5 mo; HR = 0.96; P = 0.73	Squamous OS HR = 0.86; non-Asian OS HR = 0.94	n = 167 (39.3%); activating EGFR mutation, 18	EGFR mutated: OS HR = 1.19; EGFR wt: OS HR = 0.85
HORG[27]	E (n = 166) vs Pem (n = 166)	Second line (57%) or third line (43%); nonADC, 77.5%; non-Asian, 100%	PFS for E, 3.6 mo; PFS for Pem 2.9 mo; P = 0.136; OS for E, 8.2 mo; OS for Pem, 10.1 mo; P = 0.986	Squamous OS HR = 1.97	n = 123 (37%); activating EGFR mutations, 11	NR

¹HR estimated from forest plot in publication. ADC: Adenocarcinoma; C: Cisplatin; Cb: Carboplatin; D: Docetaxel; E: Erlotinib; EGFR: Epidermal growth factor receptor; G: Gefitinib; Gem: Gemcitabine; HR: Hazard ratio; NR: Not reported; OS: Median overall survival; P: Placebo; Pem: Pemetrexed; PFS: Median progression free survival; T: Paclitaxel; wt: Wild type.