Table 1. Timeline of clinical trials evaluating the efficacy of EGFR TKIs in an unselected or EGFR-wt NSCLC population.

Trial title	Author(s)	Year	Trial phase	Treatment	Disease line and population	PFS (months)
ISEL	Thatcher et al.	2005	III	Gefitinib vs. placebo	Second; third-line chemotherapy refractory*; prior platinum mandatory; EGFR unselected	5.6 (g) vs. 5.1 (p); P=0.087
BR.21	Shepherd et al.	2005	III	Erlotinib vs. placebo	Second; third-line, prior combination chemotherapy and not eligible for further chemotherapy; EGFR unselected (EGFR expression testing optional)	2.2 (e) vs. 1.8 (p); P<0.001
ISTANA	Lee et al.	2008	III	Gefitinib vs. docetaxel	Second-line, platinum refractory or recurrence and candidate for further chemotherapy; EGFR unselected	3.4 (d) vs. 3.3 (g); P=0.0134
V-15-32	Maruyama et al.	2008	III	Gefitinib vs. docetaxel	Second; third-line, chemotherapy failure including platinum; EGFR unselected	2.0 (d) vs. 2.0 (g); P=0.335
INTEREST	Kim et al.	2008	III	Gefitinib vs. docetaxel	Second-line platinum refractory and non-refractory; EGFR unselected (EGFR copy number gain sub-group reported)	2.7 (d) vs. 2.2 (g); P=0.47
IPASS	Mok et al.	2008	III	Gefitinib vs. platinum-doublet chemotherapy	First line, EGFR-wt sub-group (EGFR mutated and unknown population also reported)	Not reported as absolute number, approx. 2 mo (g); significantly in favour of chemotherapy (HR =2.85; 95% CI, 2.05–3.98, P<0.001)
SATURN	Capuzzo et al.	2010	III	Erlotinib vs. placebo	Maintenance post first-line platinum chemotherapy; EGFR-unselected (EGFR testing mandatory with missing data)	2.9 (e) vs. 2.6 (p); P<0.0001
CTONG0806	Zhou et al.	2011	II	Gefitinib vs. pemetrexed	Second-line, platinum pre-treated; EGFR-wt	4.8 (p) vs. 1.6 (g); P<0.001
IFCT-GFPC	Pérol et al.	2012	III	Erlotinib or gemcitabine vs. observation	Maintenance post first-line platinum chemotherapy; EGFR-unselected (also included EGFR mutations)	3.8 (g) vs. 2.9 (e) vs. 1.9 (o); P=0.3867
TITAN	Ciuleanu et al.	2012	III	Erlotinib vs. docetaxel	Second-line; disease progression on platinum doublet chemotherapy* shared first line chemotherapy run-in phase with SATURN; EGFR-wt	2.0 (d) vs. 1.5 (e); P=0.089
TORCH	Gridelli et al.	2012	III	Erlotinib then second-line chemotherapy vs. chemotherapy then second-line erlotinib	First (and second-line), switch therapy; EGFR-wt and mutated	5.4 (c) vs. 2.2 (e) (P value not reported)
TAILOR	Garassino et al.	2013	III	Erlotinib vs. docetaxel	Second-line; recurrence or progression after failing platinum chemotherapy; EGFR-wt	2.9 (d) vs. 2.4 (e); P=0.02
DELTA	Kawaguchi et al.	2014	III	Erlotinib vs. docetaxel	Second; third-line; post chemotherapy (including platinum); EGFR-wt	3.2 (d) vs. 2.0 (e); P=0.09
HORG	Karampeazis et al.	2013	III	Erlotinib vs. pemetrexed	Second; third-line; disease progression after chemotherapy (platinum not mandatory in ≥65 years); EGFR unselected [subgroup (n=11/123) with EGFR mutation reported on]	3.6 (e) vs. 2.9 (p); P=0.136
LUX-Lung 8	Soria et al.	2015	III	Afatinib vs. erlotinib	Second-line; squamous histology, progression after prior platinum chemotherapy; EGFR unselected	2.4 (a) vs. 1.9 (e); P=0.043
IUNO	Cicènas et al.	2016	III	Maintenance erlotinib vs. placebo and late erlotinib at disease progression in placebo arm	Second-line; prior platinum chemotherapy without progression; EGFR-wt	Maintenance-3 (e) vs. 2.9 (p); P=0.48;
IUNO	Cicènas et al.	2016	III			‘Early’ vs. ‘Late’ erlotinib; P=0.4759

*, refractory defined as recurrent or progressive disease within 90 days of the last chemotherapy dose; PFS, progression free survival. g, gefitinib; p, placebo; e, erlotinib; d, docetaxel; o, observation; c, chemotherapy; a, afatinib.