Differential effects of adjuvant EGFR tyrosine kinase inhibitors in patients with different stages of non-small-cell lung cancer after radical resection: an updated meta-analysis

Figures & data

Figure 1 Flowchart presenting study selection.

Table 1 Main characteristics of all the studies included in the meta-analysis

Study	EGFR mutation (%)	Usage of drug	Median treatment duration	Size	Design	Women (%)	Stage			Control arm	TKI arm number	Control arm number
							I	II	III
Yue et al (2018) (EVAN)^Citation17	100	E	12 m	102	RCT	NA	0	0	102	C	51	51
Wu et al (2017) (ADJUVANT)^Citation16	100	G	18 m	222	RCT	58.5	0	74	143	C	111	111
Kelly et al (2015) (RADIANT)^Citation15	16.5	E	11.9 m	973	RCT	65.1	499	320	153	P	623	350
Feng et al (2015)^Citation18	100	I	8 m	39	RCT	30.7	17	10	12	C	21	18
Lv et al (2015)^Citation19	100	G/E/I	18 m	138	RCS	41.6	69	21	48	C	31	107
Li et al (2014)^Citation27	100	G	6 m	60	RCT	40.9	0	0	60	C	30	30
Goss et al (2013) (BR19)^Citation14	4	G	4.8 m	503	RCT	46.1	260	175	67	P	251	252
D’Angelo et al (2012)^Citation28	100	G/E	18.6 m	286	RCS	73.4	213	32	42	P	84	202
Janjigian et al (2011)^Citation29	100	G/E	20 m	167	RCS	68.1	117	25	25	P	56	111

Abbreviations: C, chemotherapy; E, erlotinib; G, gefitinib; I, icotinib; P, placebo; RCS, retrospective comparative study; RCT, randomized controlled trial; TKI, tyrosine kinase inhibitor.

Figure 2 Forest plots of the HR of DFS (A) and OS (B) of adjuvant EGFR-TKI therapy vs control in patients with NSCLC after radical resection.

Abbreviations: DFS, disease-free survival; NSCLC, non-small-cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

Figure 3 Forest plots of the HR of DFS (A) and OS (B) of adjuvant EGFR-TKI therapy vs control in patients with EGFR-mutant NSCLC after radical resection.

Abbreviations: DFS, disease-free survival; NSCLC, non-small-cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

Table 2 Effects of adjuvant TKIs on DFS in relation to proportions of stage I and III NSCLC

Category		Studies divided into subgroups	HR [95% CI]
Stage I	>30	D’Angelo et al (2012)^Citation28, Feng et al (2015)^Citation18, Goss et al (2013) (BR19)^Citation14, Janjigian et al (2011)^Citation29, Kelly et al (2015) (RADIANT)^Citation15, Lv et al (2015)^Citation19	0.85 [0.74–0.99]
	≤30	Li et al (2014)^Citation27, Wu et al (2017) (ADJUVANT)^Citation16, Yue et al (2018) (EVAN)^Citation17	0.49 [0.36–0.67]
	>40	D’Angelo et al (2012)^Citation28, Feng et al (2015)^Citation18, Goss et al (2013) (BR19)^Citation14, Janjigian et al (2011)^Citation29, Kelly et al (2015) (RADIANT)^Citation15, Lv et al (2015)^Citation19	0.85 [0.74–0.99]
	≤40	Li et al (2014)^Citation27, Wu et al (2017) (ADJUVANT)^Citation16, Yue et al (2018) (EVAN)^Citation17	0.49 [0.36–0.67]
	>50	D’Angelo et al (2012)^Citation28, Goss et al (2013) (BR19)^Citation14, Janjigian et al (2011)^Citation29, Kelly et al (2015) (RADIANT)^Citation15	0.90 [0.77–1.04]
	≤50	Wu et al (2017) (ADJUVANT)^Citation16, Feng et al (2015)^Citation18, Li et al (2014)^Citation27, Lv et al (2015)^Citation19, Yue et al (2018) (EVAN)^Citation17	0.46 [0.35–0.60]
Stage III	>30	Feng et al (2015)^Citation18, Li et al (2014)^Citation27, Lv et al (2015)^Citation19, Wu et al (2017) (ADJUVANT)^Citation16, Yue et al (2018) (EVAN)^Citation17	0.47 [0.36–0.60]
	≤30	D’Angelo et al (2012)^Citation28, Goss et al (2013) (BR19)^Citation14, Janjigian et al (2011)^Citation29, Kelly et al (2015) (RADIANT)^Citation15	0.92 [0.79–1.07]
	>40	Li et al (2014)^Citation27, Wu et al (2017) (ADJUVANT)^Citation16, Yue et al (2018) (EVAN)^Citation17	0.49 [0.36–0.67]
	≤40	D’Angelo et al (2012)^Citation28, Feng et al (2015)^Citation18, Goss et al (2013) (BR19)^Citation14, Kelly et al (2015) (RADIANT)^Citation15, Lv et al (2015)^Citation19, Janjigian et al (2011)^Citation29	0.85 [0.74–0.99]
	>50	Li et al (2014)^Citation27, Wu et al (2017) (ADJUVANT)^Citation16, Yue et al (2018) (EVAN)^Citation17	0.49 [0.36–0.67]
	≤50	D’Angelo et al (2012)^Citation28, Feng et al (2015)^Citation18, Goss et al (2013) (BR19)^Citation14, Kelly et al (2015) (RADIANT)^Citation15, Lv et al (2015)^Citation19, Janjigian et al (2011)^Citation29	0.85 [0.74–0.99]

Abbreviations: DFS, disease-free survival; NSCLC, non-small-cell lung cancer; TKIs, tyrosine kinase inhibitors.

Figure 4 Forest plots of the HR of DFS (A) and OS (B) of adjuvant EGFR-TKI therapy vs control in subgroups in which >50% and <50% of patients were diagnosed with stage I NSCLC after radical resection.

Abbreviations: DFS, disease-free survival; NSCLC, non-small-cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

Figure 5 Forest plots of the HR of DFS (A) and OS (B) of adjuvant EGFR-TKI therapy vs control in subgroups in which >30% and <30% of patients were diagnosed with stage III NSCLC after radical resection.

Abbreviations: DFS, disease-free survival; NSCLC, non-small-cell lung cancer; OS, overall survival; TKI, tyrosine kinase inhibitor.

Table 3 Characteristics of patients in ongoing studies

Study	Study type	Usage of drug	Estimated enrollment	Allocation	Intervention model	Masking	Stage	Actual study start date	Estimated primary completion date	ClinicalTrials.gov drug identifier
NCI (2020)	Interventional	E	450	Randomized	Parallel assignment	None	IB–IIIA	2014-08-18	2020-11-04	NCT02193282
Wang (2020) (CORIN)	Interventional	I	128	Randomized	Parallel assignment	None	IB	2015-01	2020-01	NCT02264210
CLCSG (2017)	Interventional	E	80	Non-randomized	Parallel assignment	None	IIIA	2011-05	2017-07	NCT01410214
Lecia V (2019)	Interventional	A	92	Randomized	Parallel assignment	None	I–III	2013-01	2019-08	NCT01746251
Betta (2020) (EVIDENCE)	Interventional	I	320	Randomized	Parallel assignment	None	II–IIIA	2015-05	2020-12	NCT02448797
AstraZeneca (2021) (ADAURA)	Interventional	AZ	700	Randomized	Parallel assignment	Triple	IB–IIIA	2015-10	2021-11	NCT02511106

Abbreviations: A, afatinib; AZ, AZD9291; E, erlotinib; I, icotinib.

Figure S1 Risk-of-bias graph and summary for the included randomized control trials.

Table S1 Newcastle–Ottawa scale for quality assessment of non-randomized cohort studies

Study	Selection				Comparability	Exposure			Total score
	1	2	3	4	1	1	2	3
D’Angelo et al (2012)^Citation7	b	a	a	b	ab	a	a	A	8
Janjigian et al (2011)^Citation8	b	a	a	a	ab	a	a	B	9
Lv et al (2015)^Citation9	b	a	a	b	a	a	a	A	7

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