Antiangiogenic agents in the management of non-small cell lung cancer

Figures & data

Figure 1 Mechanisms of action of approved and investigational antiangiogenic agents. (A) Diagram depicting inhibition of tumor cell receptors (1) and endothelial cell and pericyte receptors (3 and 4) by TKIs and ramucirumab, targeting of VEGF (2) molecules by bevacizumab and VEGFR trap (aflibercept) and (5) disruption of vascular integrity by VDAs. (B) Receptor tyrosine kinase-activated signaling pathways involved in angiogenesis. [Part (A) reprinted with permission ^©2006 Springer; part (B) reproduced with permission of Alphamed Press, Inc. in the format Journal via Copyright Clearance Center.]

Figure 2 Efficacy outcomes from phase III trials evaluating bevacizumab in combination with chemo-therapy in patients with NSCLC. OS and PFS curves from ECOG 4599 (A) and AVAiL (B).19,20 [(A) Reprinted with permission ^©2006 Massachusetts Medical Society. (B) Reprinted by permission of ^©2011 Oxford University Press and ^©2008 American Society of Clinical Oncology. All rights reserved.]

Table 1 Phase II and III clinical trials evaluating approved and investigational antiangiogenic antibodies in combination with chemotherapy for NSCLC

Trial	Study design	Endpoints	PFS (mo)	OS (mo)	TTP (mo)	RR (%)	Common grade ≥3 AEs (%)
Bevacizumab (first-line)
ECOG 4599; phase III; N = 878; completed17	A: Carbo/pac (n = 444) B: Carbo/pac + bev (n = 434)	OS	A: 4.5 B: 6.2 HR, 0.66; p < 0.001	A: 10.3 B: 12.3 HR, 0.79; p = 0.003	NR	A: 15 B: 35	Bleeding events (A, 0.7; B, 4.4), febrile neutropenia (2.0; 5.2), hyponatremia (1.1; 3.5), hypertension (0.7; 7.0), headache (0.5; 3.0), rash (0.5; 2.3)
AVAiL*; phase III; N = 1,043; completed19,20	A: Gem/cis + bev 7.5 mg/kg (n = 345) B: Gem/cis + bev 15 mg/kg (n = 351) C: Gem/cis + placebo (n = 347)	Primary: PFS Secondary: OS	A: 6.7 B: 6.5 C: 6.1 A vs. C: HR, 0.75; p = 0.003 B vs. C: HR, 0.82; p = 0.03	A: 13.6 B: 13.4 C: 13.1 A vs. C: HR, 0.93; p = 0.420 B vs. C: HR, 1.03; p = 0.761	NR	A: 34.1 B: 30.4 C: 20.1	Neutropenia (A, 40; B, 36; C, 32), thrombocytopenia (27; 23; 23), anemia (10; 10; 13)
Patel et al.; phase II; n = 50; completed22	Pem/carbo + bev (up to 6 cycles) followed by pem + bev maintenance	RR, PFS, OS	7.8	14.1	NR	55	Infection (10), fatigue (8), diverticulitis (8), anemia (6), thrombocytopenia (6), venous thrombosis (6), neutropenia (4)
SAiL; phase IV; N = 2,212; completed11	Bev + standard chemotherapy (up to 6 cycles) followed by bev maintenance	Primary: Safety	NR	14.6	7.8		Thromboembolism (8), hypertension (6), overall bleeding (4), proteinuria (3), gastrointestinal disorders (2), vascular disorders (2), pulmonary hemorrhage (1)
ARIES; OCS; phase IV; N = 1,970; completed26	Bev + chemotherapy (62% of patients received carbo/pac)	Efficacy and safety in NSCLC patient subpopulations	6.7	13.6	NR	NR	Pulmonary hemorrhage (0.8), bleeding excluding pulmonary hemorrhage (3.0), CNS bleeding (0.1)
PointBreak; phase III; N = 900; recruiting27	A: Carbo/pem + bev induction, followed by pem + bev maintenance B: Carbo/pac + bev induction, followed by bev maintenance	Primary: OS Secondary: ORR, DCR, PFS, TTP, safety/toxicity	NR	NR	NR	NR	NR
ECOG 5508; NCT01107626; phase III; N = 1,282; recruiting28	A: Bev maintenance B: Pem maintenance C: Bev + pem maintenance After carbo/pac/bev induction	Primary: OS Secondary: PFS, objective RR, toxicity, pharmacokinetics	NR	NR	NR	NR	NR
NCT00976456; phase III; N = 250; recruiting	A: Bev + pem B: Bev + pem/carbo	Primary: noninferiority of PFS with monochemotherapy Secondary: OS, overall RR, safety, QoL	NR	NR	NR	NR	NR
NCT00948675; phase III; N = 360; recruiting29	A: Pem/carbo followed by maintenance pem (n = 180) B: Pac/carbo + bev followed by maintenance bev (n = 180)	Primary: PFS without grade 4 toxicity; Secondary: OS, PFS, RR, DCR	NR	NR	NR	NR	NR
Bevacizumab (second-line)
BeTa; phase III; N = 636; completed25	A: Erlotinib B: Erlotinib + bev	Primary: OS Secondary: PFS, objective RR	A: 1.7 B: 3.4	A: 9.2 B: 9.3 HR, 0.97; p = 0.7583	NR	A: 6 B: 13 objective
Bevacizumab (adjuvant)
ECOG E1505; phase III; N = 1,500; recruiting; NCT0032480530	1 of 4 chemotherapies (vin/cis, doc/cis, gem/cis or pem/cis) with or without bev	Primary: OS Secondary: PFS, safety/toxicity, biomarker analysis	NR	NR	NR	NR
Bevacizumab (maintenance)
ATLAS; phase III; N = 768; active, no longer recruiting23,24	Following platinum-based doublet chemotherapy: A: Bev + erlotinib B: Bev + placebo	Primary: PFS Secondary: OS	A: 4.8 B: 3.7 HR, 0.722; p = 0.0012	A: 15.9 B: 13.9 HR, 0.90; p = 0.2686	NR	NR
Ramucirumab (first-line)
NCT00735696; phase II; N = 40; active, no longer recruiting32	Ramucirumab + carbo/pac (single-arm)	Primary: PFS at 6 mo Secondary: Safety/toxicity, PFS, objective RR, OS, OS at 1 y, DOR	5.7	NR	NR	67 objective
NCT01160744; phase II; N = 44; recruiting	Randomized (4-arm): pem + carbo or cis with ramucirumab or placebo; gem + carbo or cis with ramucirumab	Primary: PFS Secondary: Objective RR, OS, duration of response, pharmacokinetics	NR	NR	NR	NR
Ramucirumab (second-line)
NCT01168973; phase III; N = 1,156; recruiting	Randomized (2-arm): ramucirumab + doc vs. placebo vs. doc	Primary: OS Secondary: PFS, objective RR, DCR, improvement of symptoms, pharmacokinetics	NR	NR	NR	NR

AEs, adverse events; Bev, bevacizumab; Carbo, carboplatin; Cis, cisplatin; CNS, central nervous system; CT, chemotherapy; DCR, disease control rate; Doc, docetaxel; DOR, duration of response; Gem, gemcitabine; NR, not reported; NSCLC, non-small cell lung cancer; OCS, observational cohort study; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progression-free survival; QoL, quality of life; RR, response rate; TTP, time to disease progression; Vin, vinorelbine.

* First-or-second-line.

Table 2 Significantly higher rates of grade ≥ 3 adverse events with bevacizumab plus chemotherapy vs. chemotherapy alone (ECOG 4599 trial)17

Adverse event, %	Paclitaxel/carboplatin (n = 440)	Paclitaxel/carboplatin + bevacizumab (n = 427)	p value
Grade ≥ 3 bleeding	0.7	4.4	<0.001
Grade 4 neutropenia	16.8	25.5	0.002
Grade 4 thrombocytopenia	0.2	1.6	0.04
Grade 3 febrile neutropenia	1.8	4.0	0.02
Grade 3 hyponatremia	0.9	2.6	0.02
Grade 3 hypertension	0.5	6.8	<0.001
Grade 3 proteinuria	0	2.6	<0.001
Grade 3 headache	0.5	3.0	0.003
Grade 3 rash	0.5	2.3	0.02

Table 3 Phase II and III clinical trials testing aflibercept (VEGF trap) and ASA404 in combination with chemotherapy for NSCLC

Trial	Study design	Endpoints	PFS (mo)	OS (mo)	TTP (mo)	RR (%)	SD (%)	Common grade ≥ 3 AEs (%)
Aflibercept (first-line)
NCT00794417; phase I/II; N = 100; active, no longer recruiting	Aflibercept + pem/cis	Primary: ORR, PFS at 6 mo Secondary: Safety, pharmacokinetics	NR	NR	NR	NR	NR	NR
Aflibercept (second-line)
VITAL; NCT00532155; phase III; N = 900; active, no longer recruiting35	A: Docetaxel + aflibercept B: Docetaxel	Primary: OS; Secondary: PFS, TR, QoL	NR	A: 10.05 B: 10.41	NR	A: 23.3 B: 8.9	NR	NR
ASA404 (first- or second-line)
NCT00832494; phase I/II; N = 105; completed	A: Carbo/pac + ASA404 B: Carbo/pac	Primary: TR, TTP, DOR, safety/toxicity	NR	NR	NR	NR	NR	NR
ASA404 (first-line)
McKeage et al. 2009; phase II; N = 30; completed80	ASA404 + carbo/pac	Primary: Best overall TR, SD rate, TTP; Secondary: PFS, OS, safety, pharmacokinetics	5.5	14.9	5.5	37.9 PR	48.3	Neutropenia (81), leukopenia (39), infection (13), thrombocytopenia (13), nervous system disorders (19)
McKeage et al. 2008; phase II; N = 73; completed79	A: Carbo/pac + ASA404 (n = 36) B: Carbo/pac (n = 37)	Primary: OS, TTP, TR	NR	A: 14.0 B: 8.8	A: 5.4 B: 4.4	A: 31 B: 22 TR	A: 43.8 B: 32.3	Neutropenia (A, 62; B, 39), leukopenia (27; 28), alopecia (22; 28), hyperglycemia (14; 25), infection (11; 3), thrombocytopenia (11; 6), cardiac disorders (11; 3)
ATTRACT-1 NCT00662597; phase III; N = 1,299; terminated83,91	A: Carbo/pac + ASA404 (n = 649) B: Carbo/pac (n = 650)	Primary: OS; Secondary: OS in patients with squamous vs. non-squamous histology	A: 5.5 B: 5.5	A: 13.4 B: 12.7	NR	A: 24.7% B: 24.6%	A: 39.6 B: 39.5	Grade 4 neutropenia (A, 27; B, 19)
ASA404 (second-line)
ATTRACT-2 NCT00738387; phase III; N = 900; terminated	A: Docetaxel + ASA404 B: Docetaxel	Primary: OS Secondary: PFS, QoL, overall RR, biomarker analysis, pharmacokinetics	NR	NSD	NR	NR	NR	NR

AEs, adverse events; Carbo, carboplatin; Cis, cisplatin; DOR, duration of response; NR, not reported; NSCLC, non-small cell lung cancer; NSD, no significant difference; ORR, objective response rate; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progression-free survival; PR, partial response; QoL, quality of life; RR, response rate; SD, stable disease; TR, tumor response; TTP, time to disease progression; VEGF, vascular endothelial growth factor.

Table 4 Phase II and III clinical trials testing investigational TKIs in combination with chemotherapy for NSCLC

Trial	Study design	Endpoints	PFS (mo)	OS (mo)	RR (%)	SD (%)	Common grade ≥ 3 AEs (%)
Vandetanib (second-line)
ZEAL; phase III; N = 534; completed41	A: Pem + vandetanib B: Pem + placebo	Primary: PFS Secondary: OS, objective RR, TTP, safety	A: 17.6 wks B: 11.9 wks	A: 10.5 B: 9.2	A: 19 B: 8 objective	NR	Rash (A, 6; B, 3), diarrhea (4; 2), anemia (1; 6)
ZEST; phase III; N = 1,240; completed42	A: Erlotinib + vandetanib B: Erlotinib + placebo	Primary: PFS Secondary: OS, objective RR, TTP, safety	A: 2.6 B: 2.0	A: 6.9 B: 7.8	A: 12 B: 12 objective	NR	Diarrhea (A, 5; B, 3), rash (3; 4), fatigue (4; 4), dyspnea (4; 6)
ZODIAC; phase III; N = 1,391; completed40	A: Doc + vandetanib B: Doc + placebo	Primary: PFS Secondary: OS, objective RR, DCR, TTP, safety	A: 4.0 B: 3.2	A: 10.6 B: 10.0	NR	NR	Rash (A, 9; B, 1), neutropenia (29; 24), leukopenia (14; 11), febrile neutropenia (9; 7)
Vandetanib (second-line or third-line)
ZEPHYR; phase III; N = 924; completed39	A: Vandetanib B: Placebo	Primary: OS Secondary: PFS, objective RR, DCR at 8 weeks	NR	A: 8.5 B: 7.8	A: 2.6 B: 0.7 objective	NR	NR
Vandetanib (maintenance)
NCT00687297; phase II; N = 162; completed44	A: Doc/carbo/vandetanib followed by maintenance vandetanib B: Doc/carbo/vandetanib followed by maintenance placebo	Primary: PFS Secondary: objective RR, safety	A: 4.5 B: 4.2	A: 9.8 B: 9.4	NR	NR	Rash (A, n = 5; B, n = 2), diarrhea (A, n = 3; B, n = 0), hypertension (A, n = 2; B, n = 0)a
Cediranib (first-line)
BR24; phase II/III; N = 296; active, no longer recruiting47	A: Carbo/pac + cediranib 30 mg B: Carbo/pac + placebo	Primary: PFS Secondary: OS, toxicity, QoL, biomarker analysis	NR	A: 10.5 B: 10.1	A: 38 B: 16	NR	Hypertension (A, 19; B, 2), diarrhea (15; 2), anorexia (6; 3), stomatitis (6; 0), fatigue (29; 19), dyspnea (10; 13)
BR29; phase III; N = 750; active, no longer recruiting; NCT00795340	A: Carbo/pac + cediranib 20 mg B: Carbo/pac + placebo	Primary: OS Secondary: PFS, objective RR, DOR, QoL, cost utility ratios, biomarker analysis	NR	NR	NR	NR	NR
NCT00326599; phase II; N = 102; active, no longer recruiting	A: Gem/carbo + cediranib B: Gem/carbo + placebo	Primary: Objective TR Secondary: DOR, PFS at 6 mo, TTP, OS at 1 y, safety/toxicity	NR	NR	NR	NR	NR
Cediranib (second-line or third-line)
NCT00410904; phase II; N = 74; recruiting49	A: Cediranib + pem (patients who have not received prior bev) B: Cediranib + pem (patients with prior bev)	Primary: RR Secondary: PFS, OS	A: 5.6	A: 11	A: 29 (n = 38)	NR	A: fatigue (22), neutropenia (14), diarrhea (14), infection (8), febrile neutropenia (5)
Nintedanib (first-line or second-line)
NCT00979576; phase II; n = 132; recruiting	Nintedanib + pem	Primary: safety, PFS Secondary: TR, OS, clinical improvement, QoL, pharmacokinetics	NR	NR	NR	NR	NR
Nintedanib (second-line)
LUME-Lung 1; NCT00805194; phase III; N = 1,300; active, no longer recruiting	A: Doc + Nintedanib B: Doc + placebo	Primary: PFS Secondary: OS, TR, safety, pharmacokinetics, QoL	NR	NR	NR	NR	NR
LUME-Lung 2; NCT00806819; phase III; N = 1,302; active, no longer recruiting	A: Pem + folic acid + Nintedanib B: Pem + folic acid + placebo	Primary: PFS Secondary: OS, TR, safety, QoL, clinical improvement, pharmacokinetics	NR	NR	NR	NR	NR
Sorafenib (first-line)
ESCAPE; phase III; N = 926; halted55	A: Carbo/pac + sorafenib B: Carbo/pac + placebo	Primary: OS Secondary: PFS	A: 4.6 B: 5.4	A: 10.7 B: 10.6	NR	NR	Rash (A, 9; B, 1), diarrhea (4; 3), hand-foot disease (8; 1)
NExUS; NCT00449033; phase III; N = 904b; completed56	A: Gem/cis + sorafenib followed by maintenance sorafenib B: Gem/cis + placebo followed by maintenance placebo	Primary: OS Secondary: PFS, safety, PROs	A: 183 d B: 168 d	A: 376 d B: 379 d	A: 28 B: 26	NR	Thrombocytopenia (A, 9.9; B, 6.2), hand-foot skin reaction (8.6; 0.3), fatigue (7.3; 3.6), rash/desquamation (5.7; 0.5), neutropenia (5.4; 6.2)
NCT00300885; phase III; N = 900; terminated	A: Carbo/pac + sorafenib B: Carbo/pac + placebo	Primary: OS Secondary: PFS, TR, DOR, QoL, PROs, biomarker analysis	NR	NR	NR	NR	NR
NCT00449033; phase III; N = 906; completed	A: Gem/cis + sorafenib B: Gem/cis + placebo	Primary: OS Secondary: PFS, safety/toxicity, PROs	NR	NR	NR	NR	NR
NCT00801801; phase II; N = 43; active, no longer recruiting	Doc + sorafenib	Primary: PFS at 2 mo Secondary: objective RR	NR	NR	NR	NR	NR
Sorafenib (second-line)
NCT00454194; phase II; N = 100; active, no longer recruiting58	A: Pem + sorafenib B: Pem + placebo	Primary: PFS Secondary: TTP, OS, safety/toxicity, TTP, DOR, biomarker analysis	A: 3.4 B: 4.1	A: 9.4 B: 9.7	NR	NR	NR
Sunitinib (first-line)
SABRE-L; phase II; N = 56; completed62	A: Carbo/pac + bev + sunitinib B: Carbo/pac + bev	Primary: TR Secondary: OS, PFS, safety	A: 3.8 B: 4.5	A: 6.6 B: NR	PR A: 8 B: 26	A: 80 B: 68	Neutropenia (A, 65.5; B, 50.0), thrombocytopenia (37.9; 19.2), leukopenia (27.6; 11.5), febrile neutropenia (13.8; 7.7), hypertension (10.3; 3.8)
NCT00695292; phase II; N = 35; active, no longer recruiting	Irinotecan + carbo + sunitinib	Primary: OS at 1 y Secondary: objective RR, TTP, safety/toxicity, OS	NR	NR	NR	NR	NR
Sunitinib (second-line)
CALGB 30704; NCT00698815; phase II; N = 225; recruiting	A: Sunitinib B: Pem C: Sunitinib + pem	Primary: PFS at 18 weeks Secondary: PFS, RR, duration of response, SD, OS, safety/toxicity, TR	NR	NR	NR	NR	NR
Sunitinib (salvage)
NCT01019798; phase II; n = 16; recruiting	Doc/cis + sunitinib	Primary: RR Secondary: TTP, OS, safety/toxicity	NR	NR	NR	NR	NR
Sunitinib (maintenance)
NCT00693992; phase III; N = 244; recruiting	A: Combination chemo + sunitinib maintenance B: Combination chemo + placebo maintenance	Primary: PFS Secondary: RR, OS, safety/toxicity	NR	NR	NR	NR	NR
Pazopanib (first-line)
NCT01179269; phase II; N = 53; recruiting	Pazopanib + pac	Objective RR	NR	NR	NR	NR	NR
NCT00871403; phase II; N = 107; completed	A: Pazopanib + pem B: Pem/cis	Primary: PFS Secondary: OS, best overall response, safety/toxicity	NR	NR	NR	NR	NR
NCT00866528; phase II; N = 180; active, no longer recruiting	A: Pazopanib + pac B: Carbo/pac	Primary: safety/tolerability, PFS Secondary: pharmacokinetics, clinical activity, OS, best overall response	NR	NR	NR	NR	NR
Pazopanib (second-line)
NCT01107652; phase II; N = 72; recruiting	A: Pazopanib + pem B: Pazopanib	Primary: DCR Secondary: CR + PR rate, PFS, OS, safety/toxicity, biomarker analysis	NR	NR	NR	NR	NR
Pazopanib (maintenance)
NCT01313663; phase II; N = 200; recruiting	A: Pazopanib B: Pemetrexed	Primary: PFS Secondary: OS, best overall response, safety	NR	NR	NR	NR	NR
Linifanib (first-line)
NCT00716534; phase II; N = 120; recruiting	A: Carbo/pac B: Carbo/pac + linifanib 7.5 mg C: Carbo/pac + linifanib 12.5 mg	Primary: PFS Secondary: OS, OS at 1 y, TTP, objective RR, best RR, TR	NR	NR	NR	NR	NR
Axitinib (first-line)
NCT00735904; phase II; N = 38; active, no longer recruiting	(squamous NSCLC) Axitinib + gem/cis	Primary: objective RR Secondary: OS at 2.5 y, PFS, DOR, safety	NR	NR	NR	NR	NR
NCT00768755; phase I/II; N = 180; active, no longer recruiting	Axitinib + pem/cis	Primary: efficacy Secondary: safety/toxicity	NR	NR	NR	NR	NR
NCT00600821; phase II; N = 119; active, no longer recruiting	A: Carbo/pac + axitinib B: Carbo/pac + bev	Primary: PFS Secondary: pharmacokinetics, OS, DOR, safety, biomarker analysis	NR	NR	NR	NR	NR
Motesanib (first-line)
NCT00369070; phase II; N = 186; active, no longer recruiting77	A: Carbo/pac + motesanib 125 mg once daily B: Carbo/pac + motesanib 75 mg twice daily C: Carbo/pac + bevacizumab	Primary: objective RR Secondary: pharmacokinetics, PFS, OS, safety	A: 7.7 B: 5.8 C: 8.3	A: 14.0 B: 12.8 C: 14.0	A: 30 B: 23 C: 37 objective	A: 35 B: 50 C: 42	Diarrhea (A, 19; B, 11; C, 3), fatigue (A, 17; B, 5; C, 8), dehydration (A, 17; B, 11; C, 3), anorexia (A, 12; B, 2; C, 3)
MONET1; NCT00460317; phase III; N = 1,090; active, no longer recruiting78	A: Carbo/pac + motesanib B: Carbo/pac + placebo	Primary: OS Secondary: PFS, safety, objective RR	A: 5.6 B: 5.4	A: 13.0 B: 11.0	A: 40 B: 26 objective	NR	Neutropenia (A, 22; B, 15), diarrhea (A, 9; B, 1), hypertension (A, 7; B, 1), cholecystitis (A, 3; B, 0)

AEs, adverse events; Bev, bevacizumab; Carbo, carboplatin; Cis, cisplatin; CR, complete response; DCR, disease control rate; Doc, docetaxel; DOR, duration of response; Gem, gemcitabine; NR, not reported; NSCLC, non-small cell lung cancer; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progression-free survival; PR, partial response; PROs, patient-reported outcomes; QoL, quality of life; RR, response rate; SD, stable disease; TKI, tyrosine kinase inhibitor; TR, tumor response; TTP, time to progression.

a During maintenance phase.

b Of 904 patients randomized, 132 were excluded from primary analyses (squamous cell histology) leaving 772 patients evaluable for efficacy and 769 patients evaluable for safety.

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