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 1 First-line and maintenance phase III trials

Trial	Comparison	Populationcharacteristics	Efficacy in allpatients	Efficacy insubgroup enriched for EGFR wt	Mutationalanalysis	Efficacy bymutational status
INTACT 1[11]	C + Gem + G (n = 730) vs C + Gem + P (n = 363)	First line; nonADC, 53.9%; non-Asian, 94.7%	PFS for C + Gem + G, 5.5 mo; PFS for C + Gem + P, 6 mo; P = 0.763; OS for C + Gem + G, 9.9 mo; OS for C + Gem + P, 10.9 mo; P = 0.45	NR	NR	NR
INTACT 2[13]	Cb + T + G (n = 692) vs Cb + T + P (n = 345)	First line; nonADC, 44.9%; non-Asian, 95.8%	PFS for Cb + T + G, 5.3 mo; PFS for Cb + T + P, 5 mo; P = 0.056; OS for Cb + T + G, 9.8 mo; OS for Cb + T + P, 9.9 mo; P = 0.638	NR	NR	NR
TALENT[12]	C + Gem + E (n = 580) vs C + Gem + P (n = 579)	First line; nonADC, 61.6%; non-Asian 93.6%	PFS for C + Gem + E, 5.9 mo; PFS for C + Gem + P, 6.1 mo; HR = 0.98; P = 0.74; OS for C + Gem + E, 10.7 mo; OS for C + Gem + P, 11 mo; HR = 1.06; P = 0.486	NR	NR	NR
TRIBUTE[14]	Cb + T + E (n = 539) vs Cb + T + P (n = 540)	First line; nonADC 39.3%; non-Asian, 96.9%	PFS for Cb + T + E, 5.1 mo; PFS for Cb + T + P, 4.9	NR	n = 228 (21.1%); activating mutation, 29	NR
IPASS[8]	G (n = 609) vs Cb + T (n = 608)	First line; only Asians with ADC and never or light former smokers	PFS for G, 5.7 mo; PFS for Cb + T, 5.8 mo; HR = 0.74; P < 0.001		n = 437 (35.9%); activating mutation, 261	EGFR mutated: PFS HR, 0.83; EGFR wt: PFS HR, 2.85; interaction P < 0.001
First- SIGNAL[15]	G (n = 159) vs C + Gem (n = 154)	First line; only Asians with ADC and never smokers	PFS for G, 5.8 mo; PFS for C + Gem, 6.4 mo; HR = 1.198, P = 0.138; OS for G, 22.3 mo; OS for C + Gem, 22.9 mo; HR = 0.932; P = 0.604		n = 96 (31%); activating mutation, 42	EGFR mutated: PFS HR, 0.54; EGFR wt: PFS HR, 1.41
SATURN[16]	E (n = 438) vs P (n = 451)	Maintenance; no progression after prior platinum-doublet; nonADC, 55%; non-Asian, 85%	PFS for E, 3 mo; PFS for P, 2.77 mo; HR = 0.71; P < 0.001; OS for E, 12 mo; OS for P, 11 mo; HR = 0.81; P = 0.0088	Squamous PFS HR, 0.76; non-Asian PFS HR, 0.75; squamous OS HR, 0.86; non-Asian OS HR, 0.86+	n = 446 (50.1%); EGFR activating mutation, 49	EGFR mutated: PFS HR, 0.10; EGFR wt: PFS HR, 0.78; interaction P < 0.001; EGFR mutated: OS HR, NR; EGFR wt: OS HR, 0.77

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.

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.