Table 2.

First-Line and Maintenance Efficacy

Reference	Study	Intervention	Outcome	No. of Patients Analyzed	OS	PFS	Response Rate
							No.	%
Rosell et al29	Eurtac	Erlotinib	PFS/TTP	86	Median, 19.3 months (95% CI, 14.7 to 26.8)	Median, 9.7 months (95% CI, 8.4 to 12.3)	48	56a
		Standard chemotherapy		87	Median, 19.5 months (95% CI, 16.1 to not assessable)	Median, 5.2 months (95% CI, 4.5 to 5.8)	13	15a
Statistics and significance					HR, 1.04 (95% CI, 0.65 to 1.68; P = .87)	HR, 0.37 (95% CI, 0.25 to 0.54; P < .001)
Quoix et al53		Four cycles carboplatin plus taxol	OSb	226 (144 received second line)	Median, 10.3 months (95% CI, 8.3 to 12.6)	Median, 6 months (95% CI, 5.5 to 6.8)	NR	27.1
		Five cycles vinorelbine or gemcitabine		225 (145 received second line)	Median, 6.2 months (95% CI, 5.3 to 7.3)	Median, 2.8 months (95% CI, 2.6 to 3.7)	NR	10.2
Statistics and significance					HR, 0.64 (95% CI, 0.52 to 0.78; P < .001)	P < .001	P < .001c
Maemondo et al20 Inoue et al21 Oizumi et al22	Maemondo (see EGFR PCO59)	Gefitinib	PFS/TTP	ITT, 114; PFS, 114; QoL, 72	Median, 27.7 months	Median, 10.8 months	84	73.7
		Carboplatin plus paclitaxel		ITT, 114; PFS, 110; QoL, 76	Median, 26.6 months	Median, 5.4 months	35	30.7
Statistics and significance				ITT, 228d; PFS, 214; QoL, 148	HR, 0.887 (P = .483)	HR, 0.32 (95% CI, 0.24 to 0.44; P < .001)e	P < .001
Georgoulias et al52		Docetaxel and gemcitabine	OS	157	Median, 9.4 months (95% CI, 0.5 to 52.7)	Median, 3.5 months (95% CI, 0.5 to 40.1)	42	26.8
		Docetaxel		155f	Median, 8.3 months (95% CI, 0.5 to 41.4)	Median, 2.3 months (95% CI, 0.5 to 35.8)	18	11.6
Statistics and significance					Log-rank P = .037g	Log-rank P = .054h	P < .001
Patel et al37	PointBreak	Pemetrexed, carboplatin, and bevacizumab followed by pemetrexed plus bevacizumab	OS	472	Median, 12.6 months (95% CI, 11.3 to 14.0)	Median, 6 months (95% CI, 5.6 to 6.9)	NR	34.1
		Paclitaxel, carboplatin, and bevacizumab followed by bevacizumab		467	Median, 13.4 months (95% CI, 11.9 to 14.9)	Median, 5.6 months (95% CI, 5.4 to 6.0)	NR	33.0
Statistics and significance					HR, 1.00 (95% CI, 0.86 to 1.16; P = .949)	HR, 0.83 (95% CI, 0.71 to 0.96; P = .012)
Barlesi et al33	AVAPERL	Maintenance bevacizumab 7.5 mg/kg	PFS/TTP	128	From random assignment: median, 12.8 months (range, 0 to 16); from time of first induction: median, 15.7 months (range, 2.8 to 18.8)	Median, 3.7 months	NR	50.0
		Bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m2		125	From time of first induction: not yet reached (range, 3.0 to 19)i	Median, 7.4 months	NRj	55.5
Statistics and significance						HR, 0.48 (95% CI, 0.35 to 0.66; P < .001)
Paz-Ares et al7,8	PARAMOUNT	Pemetrexed plus cisplatin induction and maintenance pemetrexed	PFS/TTP; PFS of maintenance arms	359	Median, 13.9 months (95% CI, 12.8 to 16.0)	Median, 4.4 months (95% CI, 4.1 to 5.7)k	Overall: n = 9 (3%) of 316
		Pemetrexed plus cisplatin induction and placebo		180	Median, 11 months (95% CI, 10.0 to 12.5)	Median, 2.8 months (95% CI, 2.6 to 3.0)
Statistics and significance					Unadjusted HR, 0.78 (95% CI, 0.64 to 0.96; log-rank P = .019)	HR, 0.60 (95% CI, 0.50 to 0.73; P < .001)7
Wu et al31	FASTACT-2	Chemotherapy plus erlotinib (intercalated erlotinib with gemcitabine plus platinum followed by erlotinib)	PFS/TTPk	226l	Median, 18.3 months (95% CI, 16.3 to 20.8)	Median, 7.6 months (95% CI, 7.2 to 8.3)	97	43.0
		Chemotherapy plus placebo (intercalated placebo with gemcitabine plus platinum followed by placebo)		225	Median, 15.2 months (95% CI, 12.7 to 17.5)	Median, 6 months (95% CI, 5.6 to 7.1)	41	18.0
Statistics and significance					HR, 0.79 (95% CI, 0.64 to 0.99; P = .042)	HR, 0.57 (95% CI, 0.47 to 0.69; P < .001)k	P < .001
Zukin et al55		Carboplatin plus pemetrexed	OS	103m	Median, 9.3 months (95% CI, 7.2 to 11.2)	Median, 5.8 months (95% CI, 4.7 to 6.9)	19	18.4
		Pemetrexed		102	Median, 5.3 months (95% CI, 4.1 to 6.5)	Median, 2.8 months (95% CI, 2.5 to 3.2)	7	6.9
Statistics and significance					HR, 0.62 (95% CI, 0.46 to 0.83; P = .001)	HR, 0.46 (95% CI, 0.35 to 0.63; P < .001)	P = .032n
Perol et al40		Continuation maintenance with gemcitabine	PFS/TTP	154	Median, 12.1 months	Median, 3.8 months
		Switch maintenance with erlotinib		155	Median, 11.4 months	Median, 2.9 months
		Observation		155	Median, 10.8 months	Median, 1.9 months
Statistics and significance					HR v gemcitabine, 0.89 (95% CI, 0.69 to 1.15; log-rank P = .3867); HR v erlotinib, 0.87 (95% CI, 0.68 to 1.13; log-rank P = .3043)	HR v gemcitabine, 0.56 (95% CI, 0.44 to 0.72; log-rank P < .001); HR v erlotinib, 0.69 (95% CI, 0.54 to 0.88; log-rank P = .003)
Zhou et al13 Chen et al14	OPTIMAL	Erlotinib	PFS/TTP	82	Deaths, 16 (20%) of 82o	Median, 13.7 months (95% CI, 10.6 to 15.3)	68	83.0
		Four cycles gemcitabine plus carboplatin		72	Deaths, 12 (17%) of 72	Median, 4.6 months (95% CI, 4.21 to 5.42)	26	36.0
Statistics and significance					Not yet reached13	HR, 0.164 (95% CI, 0.105 to 0.256; P < .001)14	P < .001
Fukuoka et al30 Thongprasert et al60	IPASS	Gefitinib versus carboplatin plus paclitaxel		609	Median, 18.8 monthsp	Median, 5.7 months		43.061
		Carboplatin plus paclitaxel		608	Median, 17.4 months	Median, 5.8 months		32.2
Statistics and significance					HR, 0.9 (95% CI, 0.79 to 1.02; P = .109)	HR, 0.74 (95% CI, 0.65 to 0.85)	OR, 1.59 (95% CI, 1.25 to 2.01; P < .001)
Sequist et al11	Lux	Afatinib	PFS/TTP	230	Median, not reached (16.6 months)	Median, 11.1 months	NR	56.0
		Cisplatin plus pemetrexed		115	Median, not reached (14.8 months)	Median, 6.9 months	NR	23.0
Statistics and significance					HR, 1.12 (95% CI, 0.73 to 1.73; P = .60; 25th percentile, 16.6 v 14.8 months)q	HR, 0.58 (95% CI, 0.43 to 0.78; P = .001)r	Other: DCR, 90% v 81%; median duration of response, 11.1 v 5.5 months; median duration of DC, 13.6 v 8.1 months
Mok et al6 Solomon et al54	PROFILE 1014	Crizotinib	OS	172	Median, not reached	Median, 10.9 months (95% CI, 8.3 to 13.9)	128	74.0
		Pemetrexed plus cisplatin or pemetrexed plus carboplatin		171	Median, not reached	Median, 7.0 months (95% CI, 6.8 to 8.2)	77	45.0
Statistics and significance					HR, 0.821 (95% CI, 0.536 to 1.255; P = .36)	HR, 0.454 (95% CI, 0.35 to 0.60; P < .001)	P < .001

Abbreviations: DC, disease control; DCR, disease control rate; HR, hazard ratio; IFCT, Intergroupe Francophone de Cancérologie Thoracique; IPASS, Iressa Pan-Asia Study; ITT, intention to treat; NR, not reported; OS, overall survival; PCO, provisional clinical opinion; PFS, progression-free survival; QoL, quality of life; TTP, time to progression.

^aPartial response.

^bSurvival was censored at last follow-up or at final analysis.

^cResponse was assessable in 418 patients: 215 in monotherapy group and 203 in doublet chemotherapy group.

^dSample size in PFS group.

^eHR for death or disease progression with gefitinib, 0.36; P < .001.

^fFor response.

^g“Resulting in the premature termination of the study.”^52(p57)

^hTTP.

ⁱMedian OS from time of first induction (median, 10.9 months follow-up).

^jTreatment difference in best overall response rate, 5.5% (95% CI, 7.3% to 18.2%; P = .878).

^kInvestigator assessed.

^lPer protocol: 222 v 221 (patients with no majority protocol violations with at least one dose of drug).

^mStarted treatment.

ⁿEvaluable patients.

^oData for OS were not yet mature; 88 were still in follow-up as of January 2011.

^pEGFR positive: 21.6 v 21.9 (HR, 1; 95% CI, 0.76 to 0.133).

^qPreliminary (death threshold not yet reached).

^rAt time of data cutoff, investigators had observed 238 PFS events, with median PFS of 11.1 months for afatinib and 6.7 months for chemotherapy (HR, 0.49; 95% CI, 0.37 to 0.65; P = .001).