Molecularly targeted therapies for advanced or metastatic non-small-cell lung carcinoma

Table 1 Selected phase III and randomized phase II trials comparing epidermal growth factor receptor tyrosine kinase inhibitor and chemotherapy as first-line therapy in patients with advanced non-small cell lung cancer

Trial	n	Type of study	Study design	OS (mo)	P value	PFS (mo)	P value	ORR (%)	P value
				HR (95%CI)		HR (95%CI)		HR (95%CI)
Fukuoka et al[34]	261	Retrospective	Gefitinib vs PC	21.6 vs 21.9		9.6 vs 6.3		71.2 vs 47.3
				1.00 (0.76-1.33)	0.99	0.48 (0.36-0.64)	0.0001	2.75 (1.65-4.6)	0.0001
Han et al[98]	42	Retrospective	Gefitinib vs Cis + G	27.2 vs 25.6		8.0 vs 6.3		84.6 vs 37.5
				1.04 (0.49-2.18)	NA	0.54 (0.26-1.1)	0.086	9.16 (2.10-39.84)	0.002
Mitsudomi et al[99]	172	Prospective	Gefitinib vs Cis + D	35.5 vs 38.8		9.6 vs 6.6		62.1 vs 32.1
				1.18 (0.76-1.8)	0.44	0.52 (0.37-0.71)	0.001	3.44 (1.60-7.37)	0.0001
Maemondo et al[35], Inoue et al[100]	228	Prospective	Gefitinib vs PC	27.7 vs 26.6		10.8 vs 5.4		73.7 vs 30.7
				0.88 (0.63-1.24)	0.48	0.32 (0.23-0.43)	0.001	6.32 (3.55-11.25)	0.001
Chen et al[28]	154	Prospective	Erlotinib vs C + G	22.7 vs 28.85		13.7 vs 4.6		83 vs 36
				1.04 (0.69-1.58)	0.69	0.16 (0.10-0.26)	0.0001	NA	0.0001
Rosell et al[29]	173	Prospective	Erlotinib vs platinum-based doublets	19.3 vs 19.5		9.7 vs 5.2		581vs 151
				1.04 (0.65-1.68)	0.87	0.37 (0.25-0.54)	0.0001	NA	NA
Yang et a2l[101]	345	Prospective	Afatinib vs Cis + P	NM		11.13vs 6.93		56.13vs 22.63
						0.58 (0.43-0.78)	0.0004	NA	0.001
Jänne et al[102]	345	Prospective	Erlotinib vs erlotinib + PC	24.6 vs 19.8		5.0 vs 6.6		35 vs 46
				NA	NA	NA	NA	NA	NA

¹Intention-to-treat population;

²Only lung adenocarcinoma patients;

³By independent review. PC: Paclitaxel and carboplatin; Cis: Cisplatin; C: Carboplatin; G: Gemcitabine; D: Docetaxel; P: Pemetrexed; OS: Overall survival; HR: Hazard ratio; NM: Not yet mature; NA: Not available; PFS: Progression-free survival; ORR: Objective response rate; n: Number of patients enrolled in the study.

Table 2 Phase III clinical trials testing antiangiogenic tyrosine kinase inhibitors in combination with chemotherapy in non-small cell lung cancer

Trial	n	Study design	PE	OS (mo)	PFS (mo)	ORR (%)
Vandetanib second-line
ZEAL[103]	534	PV vs P	PFS	10.5 vs 9.2	17.6 wk vs 11.9 wk	19 vs 8
ZEST[104]	1240	EV vs E	PFS	6.9 vs 7.8	2.6 vs 2.0	12 vs 12
ZODIAC[105]	1391	DV vs D	PFS	10.6 vs 10.0	4.0 vs 3.2	NA
Vandetanib second or third-line
ZEPHYR[106]	924	V vs placebo	OS	8.5 vs 7.8	NA	2.6 vs 0.7
Sorafenib first-line
NEXUS[107]	904	G + Cis + S f/b S vs G + Cis f/b placebo	OS	376 d vs 379 d	183 d vs 168 d	28 vs 26
Motesanib first-line
MONET[6]	1090	PC + M vs PC	OS	13.0 vs 11.0	5.6 vs 5.4	40 vs 26
Cediranib first-line
BR29 (active, no longer recruiting, NCT00795340)	750	PC + Ced vs PC	OS	NA	NA	NA
Nintedanib second-line
LUME-Lung 1 (active, no longer recruiting, NCT00805194)	1300	D + Nin vs D	PFS	NA	NA	NA
LUME-Lung 2 (active, no longer recruiting, NCT00806819)	1302	P + Nin vs P	PFS	NA	NA	NA

PC: Paclitaxel and carboplatin; P: Pemetrexed; E: Erlotinib; D: Docetaxel; V: Vandetanib; DV: Docetaxel-vandetanib; EV: Erlotinib-vandetanib; G: Gemcitabine; Cis: Cisplatin; S: Sorafenib; f/b: Followed by; M: Motesanib; Ced: Cediranib; Nin: Nintedanib; OS: Overall survival; PE: Primary endpoint; PFS: Progression-free survival; ORR: Objective response rate; NSCLC: Non-small cell lung cancer; NA: Not available.

Table 3 Major ongoing clinical trials with crizotinib for advanced non-small cell lung cancer¹

Trial number	Phase	Study design	Key entry criteria	PE
PROFILE 1007 (NCT00932893)	III	Crizotinib vs Pem or Doc as second-line	ALK(+) and 1 prior platinum-based chemo	PFS
PROFILE 1014 (NCT01154140)	III	Crizotinib + Pem + Cis/Carbo vs Pem + Cis/Carbo as first-line	ALK(+) and chemotherapy-naive	PFS
PROFILE 1005 (NCT00932451)	II	Crizotinib vs placebo as third-line	ALK(+) and PD in arm B of study PROFILE 1007	RR
PROFILE 1001 (NCT00965731)	I/II	Crizotinib + erlotinib vs erlotinib as second or third-line	Adenocarcinoma NSCLC and 1-2 prior chemo	MTD
PROFILE 1001 (NCT01121575)	I	Crizotinib + PF0299804	Acquired resistance to erlotinib or gefitinib	MTD

¹Data available at URL: http://www.cancer.gov/clinicaltrials. chemo: Chemotherapy; Pem: Pemetrexed; Doc: Docetaxel; Cis: Cisplatin; Carbo: Carboplatin; PD: Progressive disease; NSCLC: Non-small cell lung cancer; ALK: Anaplastic lymphoma kinase; PFS: Progression-free survival; RR: Response rate; MTD: Maximum tolerated dose; PE: Primary endpoint.

Table 4 Ongoing phase II/III clinical trials involving targeted agents for patients with advanced or metastatic non-small cell lung cancer

Study design	Clinical trial ID	Phase	Status	Key entry criteria
EGFR inhibition
Erlotinib vs docetaxel	NCT00637910	III	Recruiting	WT EGFR, prior platinum chemo, no prior taxanes
Erlotinib vs pazopanib	NCT01027598	II	Active, not recruiting	1 prior chemo
Erlotinib + OSI-906	NCT01221077	II	Recruiting	EGFR mutation (+), chemotherapy-naive
Erlotinib + ARQ197	NCT01377376	III	Recruiting	WT EGFR, prior platinum-based chemo
Erlotinib + ARQ197	NCT01244191	III	Recruiting	2 prior lines of chemo
Erlotinib + PC + Bev	NCT00976677	II	Active, not recruiting	Non-squamous, nonsmokers
Gefitinib (maintenance)	NCT01404260	III	Active, not recruiting	Stable disease after chemo, EGFR unknown, never or light smokers
Gefitinib vs Pem	NCT00891579	II	Recruiting	WT EGFR, prior platinum-based chemo
Afatinib	NCT00525148	II	Active, not recruiting	EGFR mutation (+)
Afatinib	NCT00711594	II	Active, not recruiting	Prior platinum-based chemo, progressed after erlotinib or gefitinib
PF00299804	NCT01000025	III	Recruiting	1 prior chemo
PF00299804 vs erlotinib	NCT01360554	III	Recruiting	1 prior chemo
BRAF inhibition
AZD6244 + erlotinib	NCT01229150	II	Recruiting	KRAS WT or KRAS mutant
Dasatinib	NCT01514864	II	Recruiting	Tumors harboring DDR2 mutation or inactivating B-RAF mutation
AKT inhibition
MK-2206 + erlotinib	NCT01294306	II	Recruiting	Progressed after initial response to erlotinib
MEK inhibition
GSK2118436	NCT01336634	II	Recruiting	BRAF mutation (+)
HDAC inhibitor
Vorinostat + gefitinib	NCT01027676	II/III	Recruiting	prior platinum-based chemo
Vorinostat + bortezomib	NCT00798720	II	Completed recruiting	2 prior chemo
Belinostat + Bev + PC	NCT01090830	II	Recruiting	Chemotherapy-naive
LBH589 + Pem	NCT00907179	II	Recruiting	1 prior chemo
KRAS mutations
AZD6244 + erlotinib	NCT01229150	II	Recruiting	Prior platinum-based chemo
Erlotinib + ARQ197 vs single-agent chemo	NCT01395758	II	Recruiting	KRAS mutation (+)
GSK1120212 vs docetaxel	NCT01362296	II	Recruiting	KRAS mutation (+)

PC: Paclitaxel and carboplatin; Bev: Bevacizumab; Pem: Pemetrexed; NSCLC: Non-small cell lung cancer; chemo: Chemotherapy; WT: Wild-type; EGFR: Epidermal growth factor receptor; HDAC: Histone deacetylase inhibitor.