Table 2. Randomised clinical trials conducted with tyrosine kinase inhibitors (TKI) in 2012 and 2013

First author [ref.]	Study name	Study phase	Population	Patients n	Treatment	RR (%)	p-value	PFS months	p-value	Survival	p-value
First-line treatment
Inoue [26]	NEJ002	III	Stage IIIB/IV NSCLC	114	CBDCA/PTX			5.4	<0.001	26.6 months	0.483
			EGFR muted	114	Gefitinib			10.8		27.7 months
Lee [27]	TOPICAL	III	Unselected stage IIIB/IV NSCLC	350	Erlotinib	4.0		2.8	0.019	3.7 months	0.46
			Unsuitable for conventional chemotherapy	320	Placebo	2.0		2.6		3.6 months
Gridelli [28]	TORCH	III	Unselected stage IIIB/IV NSCLC	380	Erlotinib	8.7	<0.001	6.4	<0.05^#	8.7 months	<0.05^#
			Unselected stage IIIB/IV NSCLC	380	CDDP-GEM	25.6		8.9		11.6 months
Sequist [29]	LUX-LUNG3	III	Stage IIIB/IV ADC EGFR muted	230	Afatinib	56.0	0.001	11.1	0.001	16.6 months	0.60
			Stage IIIB/IV ADC EGFR muted	115	CDDP-PEM	23.0		6.9		14.8 months
Second-line treatment
Garassino [30]	TAILOR	III	Advanced NSCLC	110	DOC	15.5	0.003	2.9	0.02	8.2 months	0.05
			Wild-type EGFR	109	Erlotinib	3.0		2.4		5.4 months
Sun [31]	CONSORT	III	Asian never-smoker stage IIIB/IV ADC	68	Gefitinib	58.8	<0.001	9	0.0013	22.2 months	0.37
			Asian never-smoker stage IIIB/IV ADC	67	PEM	22.4		3		18.9 months
			EGFR muted					HR 0.30	0.005
			Wild-type EGFR					HR 0.56	0.099
Lee [32]		IIR	Stage III/IV never-smokers non-squamous NSCLC	76	PEM-erlotinib	44.7	<0.001	7.4	0.003	20.5 months	0.194
			Stage III/IV never-smokers non-squamous NSCLC	82	Erlotinib	29.3		3.8		22.8 months
			Stage III/IV never-smokers non-squamous NSCLC	80	PEM	10.0		4.4		17.7 months
Karamapeazis [33]		III	Unselected stage IIIB/IV NSCLC	166	PEM	11.4	0.469	2.9	0.136	10.1 months	0.986
			Unselected stage IIIB/IV NSCLC	166	Erlotinib	9.0		3.6		8.2 months
Shaw [34]		III	ALK positive advanced NSCLC	173	Crizotinib	65.0	<0.001	7.7	<0.001	20.3 months	0.54
			ALK positive advanced NSCLC	174	PEM or DOC	20.0		3.0		22.8 months
Maintenance treatment
Perol [24]		III	Unselected stage IIIB/IV NSCLC nonprogressing after 4 cycles of CDDP-GEM	155	Observation			1.9		10.8 months
			Unselected stage IIIB/IV NSCLC nonprogressing after 4 cycles of CDDP-GEM	154	GEM			3.8	<0.001	12.1 months	0.37
			Unselected stage IIIB/IV NSCLC nonprogressing after 4 cycles of CDDP-GEM	155	Erlotinib			2.9	0.003	11.4 months	0.30
Johnson [35]	ATLAS	III	Unselected stage IIIB/IV NSCLC nonprogressing after 4 cycles of chemotherapy-bevacizumab	373	Bevacizumab			3.7	<0.001	13.3 months	0.53
			Unselected stage IIIB/IV NSCLC nonprogressing after 4 cycles of chemotherapy-bevacizumab	370	Bevacizumab-erlotinib			4.8		14.4 months
Zhang [36]	INFORM	III	Unselected stage IIIB/IV NSCLC nonprogressing after 4 cycles of platinum doublet	148	Gefitinib	24.0	0.0001	4.8	<0.001	18.7 months	0.26
			Unselected stage IIIB/IV NSCLC nonprogressing after 4 cycles of platinum doublet	148	Observation	1.0		2.6		16.9 months
			EGFR muted					HR 0.17	<0.05^#
			Wild-type EGFR					HR 0.86	ns
Goss [37]	NCIC CTG BR19	III	Unselected completely resected stage I–IIIA NSCLC	251	Gefitinib					5.1 years	0.14
			Unselected completely resected stage I–IIIA NSCLC	252	Observation					NR
TKI intercalated with chemotherapy
Wu [38]	FASTACT-2	III	Unselected stage IIIB/IV NSCLC and chemotherapy (platinum-GEM); first line	226	Erlotinib	42.9	<0.001	10.0	<0.001	18.3 months	0.04
			Unselected stage IIIB/IV NSCLC and chemotherapy (platinum-GEM); first line	225	Placebo	18.2		7.4		15.2 months
			EGFR muted			84^¶/15⁺	<0.001	HR 0.25	<0.001	HR 0.48	0.009
			Wild-type EGFR			26^¶/19⁺	0.35	HR 0.97	0.85	HR 0.77	0.16
Aerts [39]	NVALT-10	IIR	Unselected advanced NSCL; salvage chemotherapy	115	Erlotinib	7		4.9	0.06	5.5 months	0.01
			Unselected advanced NSCL; salvage chemotherapy	116	Erlotinib+PEM or DOC	13		6.1		7.8 months
Salvage TKI after failure of previous EGFR TKI
Miller [40]	LUX-LUNG1	IIB/III	Stage IIIB/IV ADC	390	Afatinib	7.0	0.007	3.3	<0.0001	10.8 months	0.74
			Stage IIIB/IV ADC	195	Placebo	<1.0		1.1		12.0 months

RR: response rate; PFS: progression-free survival; EGFR: epidermal growth factor receptor; NEJ002: North East Japan 002; TOPICAL: Tarceva or Placebo in Clinically Advanced Lung Cancer; TORCH: Tarceva or Chemotherapy; TAILOR: Tarceva Italian Lung Optimization Trial; ATLAS: Avastin Tarceva Lung Adenocarcinoma Study; INFORM: Iressa in NSCLC for Maintenance; NCIC CTG BR13: National Cancer Institute of Canada Clinical Trials Group; FASTACT-2: First-Line Asian Sequential Tarceva and Chemotherapy Trial; NVALT: Nederlandse Vereniging van Artsen voor Longziekten Tuberculose; NSCLC: nonsmall cell lung cancer; ADC: adenocarcinoma; ALK: anaplastic lymphoma kinase; CDDP: cisplatin; GEM: gemcitabine; CBDCA: carboplatin; PTX: paclitaxel; DOC: docetaxel; PEM: pemetrexed; HR: hazard ratio ns: not statistically significant; NR: not reached. ^#: statistically significant; ^¶: patients who responded to the combination of erlotinib and chemotherapy; ⁺: patients who responded to chemotherapy alone.