Recent advances and new insights in the management of early-stage epidermal growth factor receptor-mutated non-small-cell lung cancer

Table 1 Clinical trials of adjuvant epidermal growth factor receptor-mutated tyrosine kinase inhibitors in epidermal growth factor receptor-mutated non-small-cell lung cancer

Clinical trial	Type of trial	Sample size	Primary outcome	Stage	Treatment	Previous adjuvant chemotherapy	TKI Duration	DFS	OS
BR19, Goss et al[37]	Phase III	503 (15 with EGFR mutation)	OS	IB-IIIA	Gefitinib vs placebo	Yes (17% in gefitinib arm and 17% in placebo arm)	2 yr	HR 1.84; P = 0.3951	HR: 3.16; P = 0.151
RADIANT, Kelly et al[38]	Phase III	973 (161 with EGFR mutation)	DFS (ITT population)	IB-IIIA	Erlotinib vs placebo	Yes (45.1% in erlotinib arm and 55.9% in placebo arm)1	2 yr	46.4 vs 28.5 mo; HR: 0.61; P = 0.0391	Median OS NR in both arms; HR: 1.09; P < 0.0011
SELECT, Pennell et al[39]	Phase II	100	2-yr DFS	IA-IIIA	Erlotinib	Yes (not reported)	2 yr	Mean DFS NR; 2-yr DFS 88%; 5-yr DFS 56%	Median OS NR, 5-yr OS 86%
ADJUVANT/CTONG1104, Zhong et al[40,41]	Phase III	222	DFS	II-IIIA	Gefitinib vs cisplatin-vinorelbine	No	2 yr	28.7 vs 18 mo; HR: 0.60; P = 0.00543-yr DFS 39.6% vs 32.5%; P = 0.3165-yr DFS 22.6% vs 23.2%; P = 0.928	75.5 vs 62.8 mo; HR: 0.92; P = 0.674
IMPACT, Tada et al[42]	Phase III	234	DFS	II-III	Gefitinib vs cisplatin-vinorelbine	No	2 yr	36 vs 25.2 mo; HR: 0.92; P = 0.63	Median OS NR in both arms; HR: 1.03; P = 0.89
EVAN, Yue et al[43]	Phase II	102	2-yr DFS	IIIA	Erlotinib vs cisplatin-vinorelbine	No	2 yr	42.4 vs 21 mo; HR: 0.268; P < 0.00012-yr DFS 81.4% vs 44.6%; P = 0.00543-yr DFS 54.2% vs 19.8%; P = 0.0460	Median OS NR in both arms; HR: 0.165; P = 0.0013
Neal et al[44]	Phase II	46	2-yr DFS	IA-IIIA	Afatinib 3 mo vs 2 yr	Yes (52% in 3-mo arm and 45% in 2-yr arm)	3 mo vs 2 yr	42.8 vs 58.6 mo2-yr DFS 81% vs 70%; P = 0.55	Median OS NR in both arms
ADAURA, Wu et al[45]	Phase III	682	DFS in stages II-IIIA	IB-IIIA	Osimertinib vs placebo	Yes (60% in both arms)	3 yr	Stages II-IIIA: NR vs 19.6 mo; HR: 0.17; P < 0.0012-yr DFS 90% vs 44%ITT: NR vs 27.5 mo; HR: 0.20; P < 0.0012-yr DFS 89% vs 52%	Median OS NR in both arms (immature OS data)

¹Results in EGFR-mutated population. EGFR: Epidermal growth factor receptor; DFS: Disease-free survival; HR: Hazard ratio; ITT: Intention to treat; NR: Not reached; OS: Overall survival; TKI: Tyrosine kinase inhibitor.

Table 2 Clinical trials of neoadjuvant epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor-mutated non-small-cell lung cancer

Clinical trial	Study type	Sample size	Primary outcome	Stage	Treatment	TKI duration	RR	R0 resectability rate	PR	OS
Zhong et al[60]	Phase II	24 (12 with EGFR mutation)	RR	IIIA	Erlotinib (patients with EGFR mutation) vs carboplatin-gemcitabine (patients with native EGFR)	42 d	58.3% vs 25%; P = 0.18	50% vs 71.4; P = 0.59	16.7% vs 25%; P = 0.64	14.5 vs 28.1 mo; P = 0.201
Xiong et al[61]	Phase II	25	Resectability rate	IIIA	Erlotinib	56 d	42.1%	68.4%	50%	51.6 mo
Xiong et al[62]	Phase II	31 (15 with EGFR mutation)	Resectability rate	IIIA	Erlotinib vs cisplatin-based chemotherapy	4-7 wk	67% vs 19%	80% vs 50%	67% vs 38%	51 vs 20.9 mo
EMERGING-CTONG 1103, Zhong et al[63], Wu et al[64]	Phase II	72	RR	IIIA	Erlotinib vs cisplatin-gemcitabine	42 d (12 mo after surgery)	54.1% vs 34.3%; P = 0.092	73% vs 63%	MPR: 9.7% vs 0%	42.2 vs 36.9 mo; HR: 0.83; P = 0.513

EGFR: Epidermal growth factor receptor; HR: Hazard ratio; MPR: Major pathological response; OS: Overall survival; PR: Pathological response; RR: Response rate; TKI: Tyrosine kinase inhibitor.

Table 3 Clinical trials of pidermal growth factor receptor tyrosine kinase inhibitors in the management of unresectable pidermal growth factor receptor-mutated non-small-cell lung cancer

Clinical trial	Type of study	Sample size	Primary outcome	Stage	Treatment	TKI duration	RR	PFS	OS
RECEL, Xing et al[70]	Phase II	40	PFS	III unresectable	Erlotinib + RT vs cisplatin-etoposide + RT	2 yr	70% vs 61.9%; P = 0.744	24.5 vs 9 mo; HR: 0.104; P < 0.001	Not reported
Lee et al[71]	Phase II	59 (12 with EGFR mutation)	RR, toxicity and OS	III unresectable	EGFR mutation: erlotinib x 3 → erlotinib+RT → erlotinib x 6 vs erlotinib x 3 → cisplatin-irinotecan+RTNative/unknown EGFR: cisplatin-irinotecan × 3 → cisplatin-irinotecan+RT vs cisplatin-irinotecan+RT → cisplatin-irinotecan x 3	33 wk	EGFR mutation: 71.4% vs 80%Native/unknown EGFR: 70% vs 73.9%	EGFR mutation: 11.6 vs 8.1 moNative/unknown EGFR: 9 vs 12.3 mo	EGFR mutation: 39.3 vs 31.2 moNative/unknownEGFR: 16.3 vs 25.3 moMutated vs native EGFR: 74.8 vs 25.3 mo, P = 0.034
LOGIK0902/OLCSG0905, Saeki et al[73]	Phase II	20	2-yr OS	III unresectable	Gefitinib cisplatin-docetaxel+RT	8 wk	85%	2-yr PFS 36.9%	2-yr OS 90%

HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival; RR: Response rate; RT: Radiotherapy; TKI: Tyrosine kinase inhibitors.