Tyrosine kinase inhibitor combination therapy in first-line treatment of non-small-cell lung cancer: systematic review and network meta-analysis

Figures & data

Figure 1 Evidence network for progression-free survival.

Table 1 Summary of design and baseline patient characteristics for the studies included in the NMA

RCT	Treatment arms	Number randomized	Female, n (%)	Age (years), median (range)	ECOG PS, n (%)			Duration of treatment, median (range)
					0	1	2
Rosell et al,^Citation5 Leon et al^Citation17 and de Marinis et al,^Citation42 (EURTAC) Phase 3, open-label RCT Europe (France, Italy, Spain)	Erlotinib	86	58 (67)	65 (24–82)	27 (31)	47 (55)	12 (14)	8.2 (1–12.0) months Treatment scheduled until disease progression, development of toxic effects or withdrawal of consent
	Cisplatin plus docetaxel or gemcitabine	87	68 (78)	65 (29–82)	30 (34)	45 (52)	12 (14)	2.8 (1.0–2.6) months Chemotherapy scheduled for four 3-week cycles unless development of toxic effects or withdrawal of consent
Wu et al^Citation6,Citation8 (ENSURE) Phase 3, open-label RCT Asia (30 sites across China, Malaysia, Philippines)	Erlotinib	110	(61.8)	57.5 (33–79)	16 (14.7)	87 (78.9)	7 (6.4)	Treatment scheduled until progression/unacceptable toxicity
	Cisplatin plus gemcitabine	107	(60.7)	56.0 (30–78)	15 (14.4)	83 (79.8)	6 (5.8)	Chemotherapy scheduled for four 3-week cycles
Mitsudomi et al^Citation7 and Yoshioka et al^Citation35 (WTJOG3405) Phase 3, open-label RCT Japan (36 sites)	Gefitinib	88	59	64 (34–74)	56 (63.4)	30 (34.0)	NR	165 (22–1,100) days
	Cisplatin plus docetaxel	89	60	64 (41–75)	52 (58.4)	34 (38)	NR	64 (1–106) days
Maemondo et al^Citation9 and Inoue et al^Citation36 (NEJ002) Phase 3, RCT Japan (43 sites)	Gefitinib	114	72 (63.2)	(43–75)	54 (47.4)	59 (51.8)	1 (0.9)	308 (14–1,219) days
	Carboplatin plus Paclitaxel	114	73 (64.0)	(35–75)	57 (50.0)	55 (48.2)	2 (1.8)	Median 3-week cycles was 4 (1–7)
Seto et al^Citation19 and Hosomi et al^Citation41 (JO25567) Phase 2, open-label RCT Japan (30 sites)	Erlotinib	77	26 (34)	67.0 (60–73)	41 (53)	36 (47)	NR	254 (18–829) days
	Erlotinib plus bevacizumab	77	45 (60)	67.0 (59–75)	43 (57)	32 (43)	NR	431 (21–837) days for erlotinib and 325 (1–815) for bevacizumab
Zhou et al^Citation10,Citation37 and Chen et al^Citation11 (OPTIMAL) Phase 3, open-label RCT China (22 sites)	Erlotinib	83	48 (59)	57 (31–74)	75 (91)		7 (9)	55.5 (3.1–93.0) weeks
	Gemcitabine plus carboplatin	82	43 (60)	59 (36–78)	69 (96)		3 (4)	10.4 (1.0–18.9) weeks
Wu et al,^Citation12 Yang et al^Citation38 and Geater et al^Citation13 (LUX-Lung 6) Phase 3, open-label RCT China, Thailand and South Korea (36 sites)	Afatinib	242	155 (64.0)	58 (49–65)	48 (19.8)	194 (80.2)	NR	389 (173–537) days
	Cisplatin plus gemcitabine	122	83 (68.0)	58 (49–62)	41 (33.6)	81 (66.4)	NR	89 (60–119) days
Sequist et al^Citation14 and Yang et al^Citation15,Citation38 (LUX-Lung 3) Phase 3, open-label RCT Asia, North America, South America and Australia (25 sites)	Afatinib	230	147 (63.9)	61.5 (28–86)	92 (40.0)	138 (60.0)	NR	11 months
	Cisplatin plus pemetrexed	115	77 (67.0)	61.0 (31–83)	41 (35.7)	73 (63.5)	NR	Chemotherapy scheduled for up to six 3-week cycles
Park et al^Citation16 (LUX-Lung 7) Phase 2b, open-label RCT Canada, France, Germany, Ireland, Norway, Spain, Sweden, UK, Australia, China, Korea, Singapore and Taiwan (64 sites/13 countries)	Afatinib	160	57	63 (30–86)	51 (32)	109 (68)	NA	Treatment beyond progression allowed if deemed beneficial by investigator
	Gefitinib	159	67	63 (32–89)	48 (30)	111 (70)	NA

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; NA, not available; NMA, network meta-analysis; NR, not reported; RCT, randomized controlled trial.

Figure 2 Forest plot of PFS results for erlotinib + bevacizumab versus comparators (FE model).

Abbreviations: AF, acceleration factor; CrI, credible interval; FE, fixed-effect; PFS, progression-free survival.

Table 2 Treatment comparisons for PFS: 1/AF (95% CrI), FE model (base case)

Treatment A	Treatment B					SUCRA
	Chemotherapy	Afatinib	Erlotinib	Erlotinib + bevacizumab	Gefitinib
Chemotherapy		2.07 (1.84, 2.32)	2.16 (1.87, 2.49)	4.08 (2.89, 5.74)	1.87 (1.66, 2.10)	0.00
Afatinib	0.48 (0.43, 0.54)		1.04 (0.87, 1.25)	1.97 (1.37, 2.82)	0.90 (0.79, 1.03)	0.50
Erlotinib	0.46 (0.40, 0.53)	0.96 (0.80, 1.15)		1.89 (1.39, 2.57)	0.87 (0.72, 1.04)	0.75
Erlotinib + bevacizumab	0.24 (0.17, 0.34)	0.51 (0.35, 0.73)	0.53 (0.39, 0.72)		0.46 (0.32, 0.66)	1.00
Gefitinib	0.53 (0.48, 0.60)	1.11 (0.97, 1.27)	1.15 (0.96, 1.39)	2.18 (1.52, 3.13)		0.25

Notes: Results that do not include the null value are shown in bold. Comparisons of row versus column.

Abbreviations: AF, acceleration factor; CrI, credible interval; FE, fixed-effect; PFS, progression-free survival; SUCRA, surface under cumulative ranking curve.

RosellRCarcerenyEGervaisRErlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trialLancet Oncol201213323924622285168

 PubMed Web of Science ®Google Scholar

LeonLFGolsorkhiALiuSDrozdowskyARosellROverall survival analyses of first-line erlotinib versus chemotherapy in the EURTAC study population controlling for the use of post-study therapyAnn Oncol201425suppl 4iv447iv448

 Google Scholar

de MarinisFVergnenegreAPassaroAErlotinib-associated rash in patients with EGFR mutation-positive non-small-cell lung cancer treated in the EURTAC trialFuture Oncol201511342142925675123

 PubMedGoogle Scholar

WuYZhouCWuGQuality of life (QOL) analysis from ensure, a phase 3, open-label study of first-line erlotinib versus gemcitabine/cisplatin (GP) in Asian patients with epidermal growth factor receptor (EGFR) mutation-positive (MUT+) non-small-cell lung cancer (NSCLC)J Thorac Oncol201494 suppl 1S37

 Google Scholar

WuYLZhouCLiamCKFirst-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study+Ann Oncol20152691883188926105600

 PubMed Web of Science ®Google Scholar

MitsudomiTMoritaSYatabeYGefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trialLancet Oncol201011212112820022809

 PubMed Web of Science ®Google Scholar

YoshiokaHMitsudomiTMoritaSFinal overall survival results of WJTOG 3405, a randomized phase 3 trial comparing gefitinib (G) with cisplatin plus docetaxel (CD) as the first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring mutations of the epidermal growth factor receptor (EGFR)J Clin Oncol2014325sabstr8117

 Google Scholar

MaemondoMInoueAKobayashiKGefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFRN Engl J Med2010362252380238820573926

 PubMed Web of Science ®Google Scholar

InoueAKobayashiKMaemondoMUpdated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naive non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002)Ann Oncol2013241545922967997

 PubMed Web of Science ®Google Scholar

SetoTKatoTNishioMErlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 studyLancet Oncol201415111236124425175099

 PubMed Web of Science ®Google Scholar

HosomiYSetoTNishioMErlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced non-squamous non-small-cell lung cancer (NSCLC) with activating EGFR mutation (mt): JO25567 exploratory subgroup analysisAnn Oncol201526ix127ix147

 Google Scholar

ZhouCWuYLChenGErlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 studyLancet Oncol201112873574221783417

 PubMed Web of Science ®Google Scholar

ZhouCWuYLChenGFinal overall survival results from a randomised, phase III study of erlotinib versus chemotherapy as first-line treatment of EGFR mutation-positive advanced non-small-cell lung cancer (OPTIMAL, CTONG-0802)Ann Oncol20152691877188326141208

 PubMed Web of Science ®Google Scholar

ChenGFengJZhouCQuality of life (QoL) analyses from OPTIMAL (CTONG-0802), a phase III, randomised, open-label study of first-line erlotinib versus chemotherapy in patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC)Ann Oncol20132461615162223456778

 PubMed Web of Science ®Google Scholar

WuYLZhouCHuCPAfatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trialLancet Oncol201415221322224439929

 PubMed Web of Science ®Google Scholar

YangJWuYLSchulerMAfatinib vs cisplatin-based chemotherapy for EGFR mut positive lung adenocarcinoma (LUX-lung 3 and LUX-Lung 6): analysis of OS data from two randomized phase 3 trialsLancet Oncol201516214115125589191

 PubMed Web of Science ®Google Scholar

GeaterSLXuCRZhouCSymptom and quality of life improvement in LUX-lung 6: an open-label Phase III study of afatinib versus cisplatin/gemcitabine in Asian patients with EGFR mutation-positive advanced non-small-cell lung cancerJ Thorac Oncol201510688388925933111

 PubMed Web of Science ®Google Scholar

SequistLVYangJCHYamamotoNPhase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutationsJ Clin Oncol201331273327333423816960

 PubMed Web of Science ®Google Scholar

YangJCHHirshVSchulerMSymptom control and quality of life in lux-lung 3: a phase III study of afatinib or cisplatin/pemetrexed in patients with advanced lung adenocarcinoma with EGFR mutationsJ Clin Oncol201331273342335023816967

 PubMed Web of Science ®Google Scholar

ParkKTanEHO’ByrneKAfatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trialLancet Oncol201617557758927083334

 PubMed Web of Science ®Google Scholar