Anti-Angiogenic Therapy in the Treatment of Non-Small Cell Lung Cancer

Figures & data

Figure 1 VEGFR-2 signaling and 4 types of anti-angiogenic agents. VEGFR-2 activation promotes angiogenesis via up-regulating EC survival and proliferation along with vessel permeability through PI3K-Akt (-eNOS-NO) pathway, TSAd-Src-e-cadherin pathway, PKC-Raf-MEK-MAPK pathway and through regulating the secretion of IP₃. Anti-VEGF mAb and anti-VEGFR mAb bind with VEGF-A and VEGFR-2 respectively. Decoy VEGF-trap receptor competitively binds with VEGF-A. VEGFR-TKIs block intracellular signaling of VEGFR-2.

Abbreviations: PLCγ, phospholipase Cγ; IP3, inositol 3,4,5 trisphosphate; PKC, protein kinase C; E-cadherin, endothelial cadherin; PI3K, phosphoinositide 3 kinase; eNOS, endothelial nitric oxide synthase; TSAd, T cell-specific adaptor; PIP2, phosphatidyl inositol 4,5 bisphosphate; DAG, 1,2-diacylglycerol.

Figure 2 Tumor angiogenesis induces drug resistances through multiple mechanisms including inducing hypoxia, acidosis, and high IFP.

Abbreviations: CR, chemotherapy resistance; RR, radiotherapy resistance; IR, immunotherapy resistance; TME, tumor microenvironment; TIL, tumor-infiltrating lymphocyte; ROS, reactive oxygen species; IFP, interstitial fluid pressure.

Table 1 Four Types of Anti-Angiogenic Agents Approved for the Treatment of Malignant Tumors

Types	Agents
Anti-VEGF mAb	Bevacizumab
Anti-VEGFR mAb	Ramucirumab
VEGF-trap receptor	Aflibercept
TKIs	Nintedanib, Axitinib, Sorafenib, Sunitinib, Vatalanib, Cediranib, Pazopanib, Vandetanib, Cediranib, Pazopanib, Vandetanib, Regorafenib, Cabozantinib, Anlotinib, Motesanib, Apatinib, Lenvatinib

Abbreviations: TKI, tyrosine kinase inhibitor; mAb, monoclonal antibody.

Table 2 Previous Reported Stage III Clinical Trials of Anti-Angiogenic Therapy Combined with Chemotherapy in the Treatment of NSCLC

Trial	Disease	Treatment	Treatment Line	No. of Patient	ORR (%)	Median PFS (Months)	HR (95% CI) and P	Median OS (Months)	HR (95% CI) and P
ECOG4599^Citation52	Recurrent or advanced NSCLC	Bev + Car + Pac vs Car + Pac	-	878	35 vs 15	6.2 vs 4.5	HR=0.66(0.57–0.77) P<0.001*	12.3 vs 10.3	HR=0.79(0.67–0.92) P=0.003*
BEYOND^Citation53	Recurrent or advanced NSCLC	Bev + Car + Pac vs Car + Pac	First-line	276	54 vs 26	9.2 vs 6.5	HR=0.40(0.29–0.54) P<0.001*	24.3 vs 17.7	HR=0.68(0.50–0.93) P=0.0154*
AVAPERL^Citation54	Advanced nonsquamous NSCLC	Bev + Pem + Cis + maintenance (Bev + Pem) vs Bev + Pem + Cis + maintenance Bev	First-line	253	/	7.4 vs 3.7	HR=0.57(0.44–0.75) P<0.0001*	17.1 vs 13.3	HR=0.87(0.63–1.21) P=0.29
POINTBREAK^Citation55	Advanced nonsquamous NSCLC	Bev + Pem + Car + maintenance Pem + Bev vs Bev + Car + Pac + maintenance Bev	-	939	34 vs 33	6.0 vs 5.6	HR=0.83(0.71–0.96) P=0.012*	12.6 vs 13.4	HR=1.0(0.86–1.16) P=0.949
REVEL^Citation37	Stage IV NSCLC	Ram + Doc vs Doc	Second-line	1253	23 vs 14	4.5 vs 3.0	HR=0.76(0.68–0.86) P<0.0001*	10.5 vs 9.1	HR=0.86(0.75–0.98) P<0.023*
LUME-lung1^Citation58	Stage IIIB/IV NSCLC	Nin + Doc vs Doc	Second-line	1314	4.9 vs 1.5	3.4 vs 2.7	HR=0.79(0.68–0.92) P=0.0019*	10.1 vs 9.1	HR=0.94(0.83–1.05) P=0.2720
LUME-lung2^Citation59	Stage IIIB/IV or recurrent NSCLC	Nin + Doc vs Doc	Second-line	713	9.1 vs 8.3	4.4 vs 3.6	HR=0.83(0.70–0.99) P=0.0435*	12.0 vs 12.7	HR=1.01(0.85–1.21) P=0.8940
ALTER 0303**^Citation61	Advanced NSCLC	Anlotinib vs placebo	Third-line or further treatment	439	27 vs 1	5.4 vs 1.4	HR=0.25(0.19–0.31) P<0.001*	9.6 vs 6.3	HR=0.68(0.54–0.87) P=0.002*
ZODIAC^Citation68	Stage IIIB–IV NSCLC	Vandetanib + Doc vs Doc	Second-line	1391	17 vs 10	4.0 vs 3.2	HR=0.79(0.70–0.90) P<0.0001*	10.3 vs 9.9	HR=0.95(0.84–1.07) P=0.371
ZEAL***^Citation67	Advanced NSCLC	Vandetanib + Pem vs Pem	Second-line	534	19 vs 8	17.6 vs 11.9	HR=0.86(0.69–1.06) P=0.108	10.5 vs 9.2	HR=0.86(0.65–1.13) P=0.219
ESCAPE^Citation66	Unresectable stage IIIB/IV NSCLC	Sorafenib + Car + Pac vs Car + Pac	First-line	926	27 vs 24	4.6 vs 5.4	HR=0.99(0.84–1.16) P=0.433	10.7 vs 10.6	HR=1.15(0.94–1.41) P=0.915
NEXUS^Citation65	Unresectable stage IIIB to IV nonsquamous NSCLC	Sorafenib + Gem + Cis vs Gem + Cis	First-line	904	27.8 vs 25.8	6.0 vs 5.5	HR=0.83(0.71–0.97) P=0.008*	12.4 vs 12.5	HR=0.98(0.83–1.16) P=0.401
MONET-1^Citation64	Stage IIIB/IV or recurrent nonsquamous NSCLC	Motesanib + Car + Pac vs Car + Pac	-	1090	40 vs 26	5.6 vs 5.4	/ P<0.001*	13.0 vs 11.0	HR=0.9(0.78–1.04) P=0.14
AMG-706^Citation69	Stage IV or recurrent nonsquamous NSCLC	Motesanib + Car + Pac vs Car + Pac	-	401	60.1 vs 41.6	6.1 vs 5.6	HR=0.81(0.64–1.03) P=0.0825	NR vs 21.6	HR=0.90(0.62–1.29) P=0.5536
VITAL^Citation63	Advanced or metastatic nonsquamous NSCLC	Aflibercept + Doc vs Doc	Second-line	913	23.3 vs 8.9	5.2 vs 4.1	HR=0.82(0.72–0.94) P=0.0035*	10.1 vs 10.4	HR=1.01(0.87–1.17) P=0.90
BR29^Citation62	Advanced NSCLC	Cediranib + Car + Pac vs Car + Pac	–	306	52 vs 34	5.5 vs 5.5	HR=0.91(0.71–1.18) P=0.49	12.2 vs 12.1	HR=0.94(0.69–1.30) P=0.72

Notes: *P<0.05; **Not combined with chemotherapy; ***Estimated results.

Abbreviations: ORR, objective response rate; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; NSCLC, non-small cell lung cancer; NR, not reached; CI, confidence interval; Car, carboplatin; Pac, paclitaxel; Cis, cisplatin; Pem, pemetrexed; Doc, docetaxel; Gem, gemcitabine; Bev, bevacizumab; Ram, ramucirumab; Nin, nintedanib.

Table 3 Clinical Trials of Anti-Angiogenic Therapy Combined with Immunotherapy in the Treatment of NSCLC

Trial	Phase	Disease	Anti-Angiogenic Agent(s)	ICI(s)	Chemotherapy	Status
NCT3377023	I/II	Metastatic NSCLC	Nintedanib	Nivolumab/Ipilimumab	-	Recruiting
NCT4040361	II	Stage IB/II/IIIA NSCLC	Ramucirumab	Pembrolizumab	-	Not yet recruiting
NCT3836066	II	NSCLC	Bevacizumab	Atezolizumab	-	Recruiting
NCT3616691	II	NSCLC	Bevacizumab	Atezolizumab	-	Not yet recruiting
NCT3896074	II	NSCLC	Bevacizumab	Atezolizumab	-	Not yet recruiting
NCT3971474	II	Stage IV or recurrent NSCLC	Ramucirumab	Pembrolizumab	Docetaxel/Gemcitabine (Hydrochloride)/Pemetrexed (Disodium)	Recruiting
NCT2681549	II	Melanoma NSCLC	Bevacizumab	Pembrolizumab	-	Recruiting
NCT3527108	II	NSCLC	Ramucirumab	Nivolumab	-	Not yet recruiting
NCT3991403	III	NSCLC	Bevacizumab	Atezolizumab	Pemetrexed/Carboplatin/Paclitaxel/Cisplatin	Not yet recruiting
NCT1454102 (CheckMate 012)	I	NSCLC	Bevacizumab	Nivolumab/Ipilimumab	Pemetrexed/Carboplatin/Paclitaxel/Cisplatin/Gemcitabine	Active, not recruiting*
NCT3689855	II	NSCLC	Ramucirumab	Atezolizumab	-	Recruiting
NCT3713944	II	Stage IV or recurrent NSCLC	Bevacizumab	Atezolizumab	Pemetrexed/Carboplatin	Recruiting
NCT2366143 (Impower150)	III	NSCLC	Bevacizumab	Atezolizumab	Pemetrexed/Carboplatin	Active, not recruiting*
NCT4147351	II	Stage IIIB/IV NSCLC	Bevacizumab	Atezolizumab	-	Not yet recruiting
NCT4245085	II	EGFR-mutant Stage IIIB/C or IV Nonsquamous NSCLC	Bevacizumab	Atezolizumab	Pemetrexed/Carboplatin/Paclitaxel	Not yet recruiting
NCT4194203	III	NSCLC	Bevacizumab	Atezolizumab	Pemetrexed/Carboplatin/Paclitaxel	Not yet recruiting
NCT2443324 (JVDF)	I	Gastric Adenocarcinoma NSCLC Biliary Tract Cancer	Ramucirumab	Pembrolizumab	-	Active, not recruiting*
NCT3786692	II	Stage IV NSCLC	Bevacizumab	Atezolizumab	Pemetrexed/Carboplatin	Recruiting
NCT3647956	II	EGFR-mutant Stage IIIB/IV NSCLC	Bevacizumab	Atezolizumab	Pemetrexed/Carboplatin	Recruiting
NCT2572687	I	Gastric Cancer Gastroesophageal Junction Adenocarcinoma NSCLC Hepatocellular Carcinoma	Ramucirumab	Durvalumab	-	Active, not recruiting
NCT2574078	I/II	NSCLC	Bevacizumab	Nivolumab	Pemetrexed/Carboplatin/Paclitaxel/Cisplatin/Gemcitabine/Docetaxel	Active, not recruiting
NCT4151563	I/II	NSCLC	Ramucirumab	Nivolumab/Ipilimumab	Docetaxel	Not yet recruiting
NCT4046614	I/II	Lung adenocarcinoma	Nintedanib	Nivolumab	-	Recruiting
NCT3117049	III	NSCLC	Bevacizumab	Nivolumab	Carboplatin/Paclitaxel	Active, not recruiting
NCT3307785	I	Metastatic or stage IIIB NSCLC	Bevacizumab	Dostarlimab/TSR-022	Pemetrexed/Carboplatin/Paclitaxel/Cisplatin	Active, not recruiting
NCT4211896	II	NSCLC	Anlotinib	Nivolumab	-	Not yet recruiting
NCT4164745	II	NSCLC	Anlotinib	Pembrolizumab	-	Recruiting
NCT4165330	I/II	Soft tissue sarcoma NSCLC SCLC	AL3818 (Anlotinib Hydrochloride)	Nivolumab	-	Recruiting
NCT4094909	II	Stage IV NSCLC	Rh-endostatin	Pembrolizumab	-	Not yet recruiting
NCT3472560	II	NSCLC Urothelial cancer	Axitinib	Avelumab	-	Active, not recruiting
NCT4213170	II	NSCLC with brain metastases	Bevacizumab	Sintilimab	-	Recruiting
NCT4124731	II	NSCLC	Anlotinib	Sintilimab	Pemetrexed/Carboplatin/Cisplatin/Gemcitabine	Not yet recruiting
NCT4201990	I/II	Lung cancer	Apatinib	Camrelizumab	-	Not yet recruiting
NCT4379739	II	NSCLC	Apatinib	Camrelizumab	-	Not yet recruiting
NCT4203485	III	PD-L1 positive NSCLC	Apatinib	Camrelizumab	Pemetrexed disodium/Paclitaxel/Carboplatin	Not yet recruiting
NCT4133337	I/II	NSCLC	Apatinib	Camrelizumab	–	Not yet recruiting
NCT4239443	II	Advanced NSCLC Uterine cancer Soft tissue sarcoma	Apatinib	Camrelizumab	–	Recruiting
NCT4303130	II	NSCLC	Endostar	Camrelizumab	–	Recruiting

Abbreviations: NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer; ICI, immune checkpoint inhibitor.

Table 4 Stage III Clinical Trials of Anti-Angiogenic Therapy Combined with Anti-EGFR Agents in the Treatment of NSCLC

Trial	Disease	Treatment	Treatment Line	No. of Patient	ORR (%)	Median PFS (Months)	HR (95% CI) and P	Median OS (Months)	HR (95% CI) and P
NEJ026^Citation95,Citation96	Stage IIIB–IV or recurrent nonsquamous EGFR-mutant NSCLC	Bev + Erl vs Erl	Second-line	224	72 vs 66	16.9 vs 13.3	HR=0.605(0.417–0.877) P=0.016*	50.7 vs 46.2	HR=1.007(0.681–1.490) P=0.973
Be Ta^Citation94	Recurrent or refractory NSCLC	Bev + Erl vs Erl	Second-line	636	38 vs 19	3.4 vs 1.7	HR=0.62(0.52–0.75) P-	9.3 vs 9.2	HR=0.97(0.80–1.18) P=0.7583
(Wang et al, 2017)^Citation97	Stage II–IV NSCLC	Bev + Erl + panitumumab vs Erl	Second-line	297	-	4.6 vs 1.9	HR- P=0.003*	10.4 vs 8.9	HR- P=0.031*
CTONG 1509^Citation98	Advanced nonsquamous NSCLC harboring EGFR-mutation	Bev + Erl vs Erl	First-line	311	86.3 vs 84.7	18.0 vs 11.3	HR=0.55(0.41–0.75) P<0.001*	-	-
ATLAS^Citation99	Stage IIIB/IV, or recurrent NSCLC	Bev + Erl vs Bev	First-line	743	-	4.8 vs 3.7	HR=0.71(0.58–0.86) P<0.001*	14.4 vs 13.3	HR=0.92(0.70–1.21) P=0.5341
(Scagliotti et al, 2012)^Citation100	recurrent NSCLC	Sunitinib + Erl vs Erl	Second-line	960	10.6 vs 6.9	3.6 vs 2.0	HR=0.807(0.695–0.937) P=0.0023*	9.0 vs 8.5	HR=0.922(0.797–1.067) P=0.1388

Note: *P<0.05.

Abbreviations: ORR, objective response rate; PFS, progression-free survival; OS, overall survival; HR, hazard ratio; NSCLC, non-small cell lung cancer; Bev, bevacizumab; Erl, erlotinib.

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