Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

Table 1 Randomized phase III trials comparing first-generation epidermal growth factor receptor-tyrosine kinase inhibitors to platinum-based combination chemotherapy as a first-line treatment in patients with epidermal growth factor receptor-mutated non-small cell lung cancer

Ref.	Treatment	Number of patients	Age	Response rate (%)	Median PFS (mo)	Median OS (mo)
WJTOG3405[9]	gefitinib CDDP + TXT	86 86	< 75	62 32	9.2 6.3 HR, 0.48; P < 0.001	35.5 38.8 HR, 1.64; P = 0.211
NEJ002[10]	gefitinib CBDCA + PTX	114 114	< 75	74 31	10.8 5.4 HR, 0.30; P < 0.001	30.5 23.6 HR, 0.89; NS
OPTIMAL[11]	erlotinib CBDCA + GEM	82 72	≥ 18	83 36	13.1 4.6 HR, 0.16; P < 0.001	22.7 28.9 HR, 1.04 NS
EURTAC[12]	erlotinib Platinum + TXT/GEM	86 87	≥ 18	58 15	9.7 5.2 HR, 0.37; P < 0.001	19.3 19.5 HR, 1.04; NS

EGFR: Epidermal growth factor receptor; NSCLC: Non-small cell lung cancer; PFS: Progression-free survival; OS: Overall survival; CDDP: Cisplatin; TXT: Docetaxel; PTX: Paclitaxel; GEM: Gemcitabine; CBDCA: Carboplatin; NR: Not reached; HR: Hazard ratio; NS: Not significant.

Table 2 Quality of life assessment (first-generation epidermal growth factor receptor-tyrosine kinase inhibitors vs chemotherapy)

Study	Treatment	Methoda
		FACT-L	Pb	TOI		LCS	P
IPASS[7]	Gefitinib	70.2%	< 0.0001	70.2%	< 0.0001	75.6%	0.000
	CBDCA + PTX	44.5%		38.3%		53.9%
OPTIMAL[13]	Erlotinib	74.3%	< 0.0001	73%	< 0.0001	77%	< 0.0001
	CBDCA + GEM	31.5%		25.9%		31.5%

^aEvaluable for quality of life population; logistic regression model with covariates;

^b6-point improvement (FACT-L and TOI); 2-point improvement (LCS), maintained ≥ 21 d. EGFR-TKIs: Epidermal growth factor receptor tyrosine kinase inhibitors; FACT-L: Functional assessment of cancer therapy–lung; TOI: Trial outcome index; LCS: Lung cancer subscale; CBDCA: Carboplatin; PTX: Paclitaxel; GEM: Gemcitabine.

Table 3 Phase II trials of gefitinib in elderly patients with activated mutant epidermal growth factor receptor and in patients with poorer performance status

Ref.	Number of patients	Age	PS	Response rate	Median PFS (mo)	Median OS (mo)
Inoue et al[15]	29	50 ≤	1–4a	66%	6.5	17.8
Asami et al[16]	17	75 ≤	0–1	59%	12.9	27.4
Maemondo et al[17]	31	75 ≤	0–1	74%	12.8	33.8

^aPatients with PS (1-2) were all 80 yr or older. PS: Performance status; PFS: Progression-free survival; OS: Overall survival.

Table 4 Clinical trials of first-generation epidermal growth factor receptor tyrosine kinase inhibitors in patients with epidermal growth factor receptor-mutated non-small cell lung cancer who failed chemotherapy

Ref.	EGFR-TKI	Number ofpatients	Responserate (%)	Time to progression (mo)
Sutani et al[21]	Gefitinib	23	74	9.4
Han et al[22]	Gefitinib	17	64	21.7
Cortes-Funes et al[23]	Gefitinib	10	60	12.3
Kim et al[24]	Erlotinib	8	63	NR
Ahn et al[25]	Erlotinib	78	58	8.6

EGFR-TKIs: Epidermal growth factor receptor tyrosine kinase inhibitors; NSCLC: Non-small cell lung cancer; NR: Not reached.

Table 5 First-generation epidermal growth factor receptor tyrosine kinase inhibitor plus chemotherapy for unselected patients with non-small cell lung cancer

Ref.	Treatment	Number of patients	Response rate (%)	Median PFS (mo)	Median OS (mo)
INTACT-1[37]	CDDP + GEM + placebo	363	47	6	10.9
	CDDP + GEM + gefitiniba	365	51	5.8	9.9
	CDDP + GEM + gefitinibb	365	50	5.5	9.9
INTACT-2[38]	CDDP + PTX + placebo	345	29	5.0	9.9
	CDDP + PTX + gefitiniba	345	30	5.3	9.8
	CDDP + PTX + gefitinibb	347	30	4.6	8.7
TRIBUTE[39]	CDDP + PTX + placebo	540	19	4.9	10.5
	CDDP + PTX + erlotinib	539	22	5.1	10.6
TALENT[40]	CDDP + GEM + placebo	586	30	5.6	10.1
	CDDP + GEM + erlotinib	586	32	5.4	9.9

^aDose of gefitinib is 250 mg;

^bDose of gefitinib is 500 mg. EGFR-TKIs: Epidermal growth factor receptor tyrosine kinase inhibitors; NSCLC: Non-small cell lung cancer; PFS: Progression-free survival; OS: Overall survival; CDDP: Cisplatin; GEM: Gemcitabine; PTX: Paclitaxel.

Table 6 Clinical trials of second-generation epidermal growth factor receptor tyrosine kinase inhibitors (afatinib, dacomitinib) against non-small cell lung cancer expressing activated mutant epidermal growth factor receptor

Ref.	Phase	Treatment	Number of patients	Response rate (%)	PFS (mo)	OS (mo)
LUX-Lung 2[46]	II	Afatinib	106a	66	15.0	32
LUX-Lung 3[47]	III	CDDP + PEM	104	NE	6.9	NE
		Afatinib	204	NE	13.6	NE
LUX-Lung 6[48]	III	CDDP+GEM	122	23	5.6	NE
		Afatinib	242	67	11.0	NE
Kris et al[51]	III	dacomitinib	46	74	18.2	NE

^aOf the 129 patients enrolled in the study, 106 patients tested positive for activating epidermal growth factor receptor mutations, including the exon 19 deletion mutation and L858R. PFS: Progression-free survival; OS: Overall survival; CDDP: Cisplatin; PEM: Pemetrexed; GEM: Gemcitabine; NE: Not evaluated.

Table 7 Ongoing trials for advanced activating epidermal growth factor receptor -mutated non-small cell lung cancer

Line	Trial	Phase	Treatment	Primary endpoint
First	LUX-Lung 7 (NCT01466660)	IIb	Afatinib vs Gefitinib	PFS/OS
	ARCHER-1050 (NCT01774721)	III	Dacomitinib vs Gefitinib	PFS
	Tamiya et al[65] (UMIN000005503)	II	CBDCA + TS-1 + gefitinib	PFS
	NEJ 009 (UMIN000006340)	III	CBDCA + PEM + gefitinib vs Gefitinib	OS
Second/third	WJOG (UMIN000002014)	III	Gefitinib vs Erlotinib	PFS
	IMPRESS (NCT01544179)	III	Continuation of gefitinib + CDDP + PEM vs CDDP+PEM	PFS
	JMTO12-01 (UMIN000007765)	II	Continuation of gefitinib + DOC/PEM vs DOC/PEM	PFS

EGFR: Epidermal growth factor receptor; NSCLC: Non-small cell lung cancer; PFS: Progression-free survival; OS: Overall survival; CBDCA: Carboplatin; PEM: Pemetrexed; CDDP: Cisplatin; DOC: Docetaxel.