www.impactjournals.com/oncotarget/
Oncotarget, 2017, Vol. 8, (No. 32), pp: 53854-53872 Review
Strategies targeting angiogenesis in advanced non-small cell lung cancer Jun Wang1,*, Jianpeng Chen2,*, Yan Guo3, Baocheng Wang1 and Huili Chu1 1
Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan, China
2
Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
3
Department of Outpatient, Military Command of Shandong Province, Jinan, China
*
These authors have contributed equally to this work
Correspondence to: Jun Wang, email: [email protected] Keywords: NSCLC, angiogenesis, antiangiogenic agents, bevacizumab Received: January 06, 2017
Accepted: April 27, 2017
Published: May 17, 2017
Copyright: Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ABSTRACT Tumor angiogenesis is a frequent event in the development and progression of non-small cell lung cancer (NSCLC) and has been identified as a promising therapeutic target. The vascular endothelial growth factor (VEGF) family and other angiogenic factors, including fibroblast growth factor and platelet-derived growth factor, promote the growth of newly formed vessels from preexisting vessels and change the tumor microenvironment. To date, two antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab, which target VEGF-A and its receptor VEGF receptor-2, respectively, have been approved for the treatment of locally advanced or metastatic NSCLC when added to first-line standard chemotherapy. Numerous oral multitargeting angiogenic small molecule tyrosine kinase inhibitors (TKIs) have been widely evaluated in advanced NSCLC, but only nintedanib in combination with platinum-based doublet chemotherapy has demonstrated a survival benefit in the second-line setting. Additionally, small-molecule TKIs remain the standard of care for patients with mutated EGFR, ALK or ROS1. Moreover, immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) are changing the current strategy in the treatment of advanced NSCLC without driver gene mutations. The potential synergistic activity of antiangiogenic agents and TKIs or immunotherapy is an interesting topic of research. This review will summarize the novel antiangiogenic agents, antiangiogenic monotherapy, as well as potential combination therapeutic strategies for the clinical management of advanced NSCLC.
INTRODUCTION
remains the standard care for advanced NSCLC that do not harbor mutations of driver genes in the first-line setting. However, most patients experience disease progression following the standard chemotherapy, and the benefits and efficacy of second-line treatment are limited [2]. Recently, broad studies of tumor biology have allowed developing particular targeted therapies for patients with specific mutations in multiple driver genes, including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), as well as ROS proto-oncogene
Non-small cell lung cancer (NSCLC) accounts for nearly 85% of all lung cancer cases and is one of the frequently diagnosed malignancies. It has a high mortality worldwide, and a majority of patients with NSCLC are initially diagnosed with stage III or IV disease and are no longer eligible for surgical resection. Moreover, for patients with advanced NSCLC, the 5-year survival rate is less than 5% [1]. Platinum-containing chemotherapy www.impactjournals.com/oncotarget
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1 (ROS1). In the past 10 years, several randomized trials have established tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, afatinib and crizotinib, as approved first-line drugs in NSCLC with targetable driver mutations or rearrangements [3-6]. Moreover, approximately 2030% of patients with NSCLC display primary resistance to these target inhibitors and lack an excellent initial clinical activity, although they have a sensitive gene mutation. In addition, patients with sensitive mutations ultimately develop secondary resistance to these drugs after several months of therapy [7]. Thus, the need for new therapeutic strategies for advanced NSCLC is urgent. Angiogenesis refers to the growth of newly formed blood vessels from the pre-existing vasculature. This complex physiological process involves a dynamic balance between angiogenesis inducers and inhibitors that tightly coordinate with macrophages, endothelial cells, and pericytes. However, the tumor tends to change this balance towards releasing chemical signals that stimulate angiogenesis and induce other cells to produce high levels of pro-angiogenesis factors in the tumor microenvironment, which promote cancer invasion and metastasis. Tumor angiogenesis results in abnormally formed, tortuous, and poorly organized vessels that exhibit altered permeability [8, 9]. Specifically, microenvironment hypoxia within the tumor induces the expression of multiple angiogenesis-related molecules, including the vascular endothelial growth factor (VEGF), plateletderived growth factor (PDGF), and fibroblast growth factor (FGF) families [10-12]. Of these molecules, VEGF-A represents a dominant angiogenesis promoter that stimulates the proliferation of endothelial cell, migration, and the formation of new blood vessels, mainly by interacting with its receptor VEGF receptor-2 (VEGFR-2) [13]. In fact, increased micro-vessel density and elevated circulating expression of VEGF-A are significantly related to a poor survival in lung cancer [14, 15]. Therefore, the angiogenesis pathway has been viewed as an important therapeutic target in lung cancer and other cancer types [16]. The tumor mass of nutrients to tumor growth is significantly deprived via booking angiogenesis, with a normalization of newly formatted vessels. At present, antiangiogenic treatment can be based on two major strategies: blocking the pro-angiogenesis pathway and enhancing the levels of antiangiogenic factors [17]. Monoclonal antibodies that block the function of VEGF-A or its receptor VEGFR-2 and different small-molecule multitargeting TKIs that block VEGFR and other receptormediated signaling pathways have been discovered and developed in clinical practice. For example, bevacizumab is a humanized monoclonal antibody targeting VEGF, has been approved by the US Food and Drug Administration (FDA) as a standard regimen for advanced NSCLC in the first-line setting. The FDA has also approved an antibody targeting VEGFR-2, ramucirumab, plus docetaxel for www.impactjournals.com/oncotarget
metastatic NSCLC that has progressed after first-line therapy. Endostar, a recombinant human endostatin, has been approved by the China FDA in 2005 for the therapy of metastatic NSCLC. It specifically promotes cell apoptosis and potently inhibits endothelial cell proliferation and tumor growth. In this review, we will summarize the current state and recent advances in the clinical treatment of advanced NSCLC with angiogenesis inhibitors, including the combination of antiangiogenic therapy and chemotherapy (Table 1 and 2), the combination of antiangiogenic therapy and EGFR TKIs (Table 3) or immune checkpoint inhibitors (Table 4), and the use of antiangiogenic agents alone (Table 5).
COMBINATION OF ANTIANGIOGENIC AGENTS AND CHEMOTHERAPY Bevacizumab plus chemotherapy As a humanized monoclonal antibody targeting VEGF-A, bevacizumab suppresses the binding of VEGF-A to its receptors to prevent its proangiogenic activity. The results from an early-randomized phase II trial showed that adding bevacizumab to standard doublet chemotherapy produced a higher objective response rate (ORR) and longer median time to progression (TTP) [18]. However, the median overall survival (OS) was similar between the bevacizumab and standard chemotherapy group. Moreover, hemoptysis events were observed in bevacizumab group, especially in a subset of patients with large tumors adjacent to major vessels or cavitary tumors, and patients with squamous cell histology. The subsequent ECOG 4599 study was the first randomized phase III trial evaluating first-line paclitaxel and carboplatin chemotherapy plus bevacizumab (n = 439) versus chemotherapy alone (n = 439) for NSCLC patients [19]. In particular, only cases with nonsquamous histology were enrolled in this trial. This study showed a significantly improved OS of 12.3 months in the combination arm versus 10.3 months in the chemotherapy arm. The ORR (35% versus 15%) and PFS significantly differed between the two arms. The combination regimen was well tolerated, but more grade 3 or 4 bleeding events occurred in 4.4% of patients with bevacizumab. Other main adverse events in the combination arm included neutropenia, hypertension, febrile neutropenia and proteinuria. In the AVAiL phase III trial, bevacizumab was also evaluated as an addition to gemcitabine and cisplatin chemotherapy in metastatic nonsquamous patients [20, 21]. A total of 1043 patients were enrolled to receive chemotherapy plus 7.5 mg/kg or 15 mg/kg bevacizumab or chemotherapy alone. Patients receiving bevacizumab and chemotherapy experienced prolonged PFS. However, prolonged OS was not observed in the 7.5 mg/kg or 15 mg/kg bevacizumab 53855
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group compared to the group receiving gemcitabine and cisplatin chemotherapy alone. The phase II JO19907 trail evaluated the efficacy of paclitaxel-carboplatin plus bevacizumab or placebo in Japanese patients with metastatic nonsquamous NSCLC. The ORR was 61% for bevacizumab compared with 31% for bevacizumab plus chemotherapy [22]. In the phase III BEYOND trail enrolling 276 Chinese patients, PFS was significantly different between the combination group (gemcitabinecisplatin plus bevacizumab) and the group receiving chemotherapy alone (9.2 versus 6.5 months), and the ORR (54% versus 26%) and OS (24.3 versus 17.7 months) were also significantly different between the two study arms [23]. The large SAiL study enrolling 2,212 patients confirmed that the combination therapy with bevacizumab and platinum-based chemotherapy has a manageable safety profile and offered a clinical survival benefit to patients with advanced NSCLC [24]. Subsequent subgroup
analyses revealed that the safety and efficacy in Asian or Chinese populations were consistent with those observed in several previous phase III trials [25, 26]. Recently, two meta-analyses proved that bevacizumab addition prolongs OS when it was added to doublet platinumcontaining chemotherapy in first-line setting [27, 28]. The addition of bevacizumab decreased the risk of mortality by nearly10%. In 2006, bevacizumab received FDA approval for treating patients with stage IV NSCLC. Subsequently, this antibody was also approved by the European Medicine Agency (EMA) for advanced nonsquamous NSCLC in the first-line setting. Additionally, retrospective data from the ECOG 4599 and the US Oncology network show that the continual use of bevacizumab until disease progression prolonged both PFS and OS [19, 29]. Many phase II trials have also evaluated the efficacy of bevacizumab maintenance for metastatic NSCLC after induction treatment with bevacizumab
Figure 1: VEGF-A-mediated inhibition of immune response and potential combination strategy with angiogenesis inhibitors and immunotherapy. Immune checkpoint inhibitors anti-PD-1 antibidy (nivolumab and pembrolizumab) or anti-PD-L1
antibody (atezolizumab) can combine with antiangiogenic agents (bevacizumab, ramucirumab, and oral small-molecule EGFR-TKIs) for targeting tumor. VEGF-A, vascular endothelial growth factor A; PD-1, programmed cell death protein-1; PD-L1, PD-ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; TGF-β, transforming growth factor-β; IL-10, interleukin-10; IL-35, interleukin-35; IL-27, interleukin-27; Treg, T- regulatory cell; DC: dendritic cell; VEC: vascular endothelial cell; CD4+ T: cluster of differentiation 4+ T cell; CD8+ T: cluster of differentiation 8+ T cell; IDO, indoleamine 2, 3 -dioxygenase; MDSC, myeloid-derived suppressor cell; VEGFR-2: vascular endothelial growth factor receptor-2; VEGFR-TKIs: vascular endothelial growth factor receptor tyrosine kinase inhibitors. www.impactjournals.com/oncotarget
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Table 1: Trials evaluating bevacizumab or ramucirumab in combination with chemotherapy in locally advanced or metastatic NSCLC Study
Design
Patients
n
Study arm
Control arm
mPFS/mTTP
mOS
ORR
PE, P value
Johnson et al. [18]
Phase II
NSCLC
99
Pac+Car+Bev
Pac+Car
7.4 (7.5 mg/kg) vs 17.7 (7.5 mg/kg) vs 4.3 (15 mg/kg) vs 11.6 (15 mg/kg) vs 4.2 m 14.9 m
31.5% (7.5 mg/ kg) vs 28.1% (15 TTP; p = 0.023 mg/kg) vs 18.8% (15 mg/kg)
ECOG 4599 [19]
Phase III
nsNSCLC
878
Pac+Car+Bev
Pac+Car
6.2 vs 4.5 m
35% vs 15%
First-line
12.3 vs 10.3 m
OS; p = 0.003
AVAIL [20, 21]
Phase III
nsNSCLC
1,043
Gem+Cis+Bev
Gem+Cis
6.7 (7.5 mg/kg) vs 13.6 (7.5 mg/kg) vs 6.5 (15 mg/kg) vs 13.4 (15 mg/kg) vs 6.1 m 13.1 m
34.1% (7.5 mg/ PFS; p = 0.0003 kg) vs 30.5% (15 (7.5 mg/kg), P = mg/kg) vs 20.1% 0.0154 (15 mg/ kg)
BEYOND [23]
Phase III
nsNSCLC
276
Pac+Car+Bev
Pac+Car
9.2 vs 6.5 m
24.3 vs 17.7 m
54.4 vs 23.3%
OS; p = 0.0154
JO19907 [22]
Phase II
nsNSCLC
180
Pac+Car+Bev
Pac+Car
6.9 vs 5.9 m
22.8 vs 23.4 m
60.7% vs 31%
PFS; p = 0.009
SAiL [24-26]
Phase IV
nsNSCLC
2,212
Patinum-based chemotherapy+Bev
7.8 m
14.6 m
51%
Camidge et al. [41]
Phase II
NSCLC
22
Pal+Car+Ram
7.85 m
16.85 m
55%
6-month 59%
Doebele et al. [42]
Phase II
nsNSCLC
140
Pem+Pla+Ram
7.2 vs 5.6 m
13.9 vs 10.4 m
49.3% vs 38.0%
PFS; p = 0.132
Leon et al. [30]
Phase II
nsNSCLC
49
Vin+Cis+Bev→Bev
6m
14.7 m
29%
PFS
Stevenson et al. [31]
Phase II
nsNSCLC
43
Pem+Car+Bev→Bev
7.1 m
17.1 m
47%
PFS
Patel et al. [32]
Phase II
nsNSCLC
50
Pem+Car+Bev→Pem+Bev
7.8 m
14.1 m
55%
PFS
376
Pem+cis+Bev →Pem+Bev
Pem+cis+Bev →Bev
7.4 vs 3.7 m
17.1 vs 13.2 m
55.5% vs 50.0%
PFS; p < 0.0001
939
Pem+Car+Bev →Pem+Bev
Pac+Car+Bev→Bev
6.0 vs 5.6 m
13.4 vs 12.6 m
34.1% vs 33.0%
OS; p = 0.949
3.91 vs 2.86 m
11.7 vs 10.5 m
23.6% vs 27.4%
G4PFS, 0.176
Pem+Pla
PFS:
Maintenance
AVAPERL [33, 34] POINTBREAK [35]
Phase III Phase III
nsNSCLC nsNSCLC
Phase III
nsNSCLC
371
Pac+Car+Bev→Bev
Pem+Car →Pem
Herbst et al. [37]
Phase II
nsNSCLC
81
Doc/Pem+Bev
Doc/Pem+Bev+Plac
4.8 vs 3.0 m
12.6 vs 8.6 m
12.5% vs 12.2%
PFS; HR: 0.38 (95%CI: 0.381.16)
REVEL [43]
Phase III
NSCLC
1,253
Doc+Ram
Doc+Plac
4.5 vs 3.0 m
10.5 vs 9.1 m
23% vs 14%
OS; p = 0.023
Yoh [44]
Phase II
NSCLC
197
Doc+Ram
Doc+Plac
5.22 vs 4.21 m
15.15 vs 14.65 m
28.9% vs 18.5%
PFS; 0.83 (0.591.16)
PRONOUNCE [36]
p
=
Second-line
NSCLC: non-small cell lung cancer; nsNSCLC: non-squamous non-small cell lung cancer; mPFS: median progression-free survival; mTTP: median time to progression; ORR: objective response rate; PE: Primary endpoint; Pac: paclitaxel; Car: carboplatin; Bev: bevacizumab; Ram: ramucirumab; Gem: Gemcitabine; Cis: cisplatin; Pla: platinum; Doc: docetaxel; Plac: placebo; G4PFS: PFS without grade 4 toxicity; HR: hazard ratio plus different platinum-based chemotherapy regimens, such as bevacizumab alone [30, 31] or combination with pemetrexed [32]. In several phase III trials, bevacizumab was also studied as a maintenance therapy after its association with induction chemotherapy with platinum-based regimen. In the AVAPERL randomized phase III trial, NSCLC patients receiving bevacizumab and pemetrexed maintenance therapy had a longer PFS than patients receiving bevacizumab maintenance (7.4 versus 3.7 months), but OS only numerically differed between the two groups (17.1 versus 13.2 months) [33, 34]. The POINTBREAK study evaluated the efficacy and safety of pemetrexed plus carboplatin plus bevacizumab followed by maintenance treatment with pemetrexed and bevacizumab versus those of paclitaxel plus carboplatin plus bevacizumab followed by maintenance treatment with bevacizumab in advanced nonsquamous NSCLC [35]. This trial failed to reach its primary endpoint of OS, although improvements were observed in PFS and the ORR. In the PRONOUNCE trial, after chemotherapy with pemetrexed
www.impactjournals.com/oncotarget
and carboplatin, maintenance treatment with pemetrexed did not prolong PFS without grade 4 toxicity compared to maintenance treatment with bevacizumab after paclitaxel plus carboplatin plus bevacizumab [36]. Overall, these trials fail to present sufficient data to identify the optimal regimen in the maintenance treatment setting (cytotoxic chemotherapy, bevacizumab, or cytotoxic chemotherapy plus bevacizumab). A randomized phase III ECOG 5508 trial would help to identify the superior treatment, the combination of pemetrexed and bevacizumab versus pemetrexed or bevacizumab monotherapy, as a switch maintenance approach beyond standard chemotherapy. Second-line treatment strategies are currently limited and include docetaxel or pemetrexed chemotherapy alone, with response rates of < 10%. Investigators have also evaluated the second-line combination of chemotherapy with bevacizumab versus chemotherapy alone. A phase II trial showed that the risk of disease progression or mortality was decreased by 34% in the chemotherapy plus bevacizumab group compared to patients treated with the
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Table 2: Trials evaluating antiangiogenic TKIs in combination with chemotherapy in locally advanced or metastatic NSCLC as first or second-line therapy Study
Design
Patients
n
Experimental arm
Control arm
mPFS/mTTP
mOS
ORR
PE, p value
ESCAPE [49]
Phase III
NSCLC
926
Pac+Car+Sor
Pac+Car
4.6 vs 5.4 m
10.7 vs 10.6 m
27.4% vs 24.0%
OS; p = 0.915
NEXUS [50]
Phase III
nsNSCLC
772
Gem+Cis+Sor
Gem+Cis
6.0 vs 5.5 m
12.4 vs 12.5 m
28% vs 26%
OS; p = 0.401
MONET1 [51]
Phase III
nsNSCLC
1090
Pac+Car+Mot
Pac+Car
5.6 vs 5.4 m
13.0 vs 11.0 m
40% vs 26%
OS; p = 0.14
Pac+Car+Bev
14.0 (125 mg qd) vs 7.7 (125 mg qd) vs 5.8 (75 30% vs 23% vs 12.8 (75 mg bid) vs mg bid) vs 8.3 m 37% 14.0
First-line
NCT00369070 [52]
Phase II
nsNSCLC
186
Pac+Car+Mot
NCIC IND [53]
Phase I
NSCLC
20
Pac+Car+Ced
BR24 [54]
Phase II
NSCLC
251
Pac+Car+Ced
Pac+Car
5.6 vs 5.0 m
BR29 [55]
Phase III
NSCLC
306
Pac+Ced
Pac
5.5nvs 5.5 m
12.2 vs 12.1 m
52% vs 34%
OS; p = 0.72
N0528 [56]
Phase II
NSCLC
87
Gem+Cb+Ced
Gem+Car
6.3 vs 4.5 m
12 vs 9.9 m
19% vs 20%
ORR; p = 1.0
Heymach [57]
Phase II
NSCLC
108
Pac+Cb+Van
Pac+Car
24 vs 23 w
10.2 vs 12.6 m
32% vs 25%
PFS; p = 0.098
Aisner et al. [58]
Phase II
NSCLC
162
Pac+Cb+Van→van
Pac+Car+Van→Plac
4.5 vs 4.2 m
9.8 vs 9.4 m
Scagliotti et al. [59]
Phase II
nsNSCLC
106
Pem+Paz
Pem+Cis
25.0 vs 22.9 w
HR: 1.22; P = 0.55
23% vs 34%
PFS; p = 0.26 PFS; p = 0.36 (d1-21); p = 0.54 (d2-19)
7.6 m
ORR
45% PFS; p = 0.08
PFS; p = 0.07
Belani et al. [60]
Phase II
nsNSCLC
170
Pem+Cis+Axi
Pem+Cis+Axi
8.0 (d1-21) vs 7.9 (d2-19) vs 7.1 m
16.6 (d1-21) vs 14.7 (d2-19) vs 15.9 m
45.5% (d1-21) vs 39.7% (d12-19) vs 26.3%
Twelves et al. [61]
Phase II
nsNSCLC
118
Pac+Car+Axi
Pac+Car+Bev
5.7 vs 6.1 m
10.6 vs 13.3 m
29.3% vs 43.3%
PFS; p = 0.64
Ramalingam et al. [62]
Phase II
nsNSCLC
138
Pac+Car+Lin
Pac+Car
8.3 (7.5 mg) vs 7.3 (12.5 11.4 (7.5mg) vs 13.0 mg) vs 5.4 m (12.5 mg) vs 11.3 m
8.3 (7.5 mg) vs 7.3 (12.5 mg) vs 5.4 m
PFS; p = 0.022 (7.5 mg); p = 0.118 (12.5 mg)
Phase II
NSCLC
100
Sor+Pem
Pem
3.4 vs 4..1m
9.4 vs 9.1m 6.7 vs 10.5 vs 8.0 m (Sun alone)
22% vs 17% vs 14 (Sun alone)
PFS; p = 0.25
Second-line N0626 [63]
PFS; p = 0.22
CALGB30704 [64]
Phase II
NSCLC
130
Pem+Sun
Pem; Sun
3.7 vs 4.9 vs 3.3 m (Sun alone)
LUME-lung 1 [65]
Phase III
NSCLC
1,311
Doc+Nin
Doc
3.4 vs 2.7 m
10.0 vs 9.1 m
4.4% vs 3.3%
PFS; p 0.0019
=
LUME-lung 2 [66]
Phase III
nsNSCLC
713
Pac+Nin
Pac
4.4 vs 3.6 m
12.0 vs 12.7 m
9.1% vs 8.3%
PFS; p 0.0435
=
ZODIAC [65]
Phase III
NSCLC
1,391
Doc+Van
Doc
4.0 vs 3.2 m
10.6 vs 10.0 m
17% vs 10%
PFS; p 0.0001
Oncotarget, 2017, Vol. 8, (No. 32), pp: 53854-53872 Review
Strategies targeting angiogenesis in advanced non-small cell lung cancer Jun Wang1,*, Jianpeng Chen2,*, Yan Guo3, Baocheng Wang1 and Huili Chu1 1
Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Jinan, China
2
Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
3
Department of Outpatient, Military Command of Shandong Province, Jinan, China
*
These authors have contributed equally to this work
Correspondence to: Jun Wang, email: [email protected] Keywords: NSCLC, angiogenesis, antiangiogenic agents, bevacizumab Received: January 06, 2017
Accepted: April 27, 2017
Published: May 17, 2017
Copyright: Wang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ABSTRACT Tumor angiogenesis is a frequent event in the development and progression of non-small cell lung cancer (NSCLC) and has been identified as a promising therapeutic target. The vascular endothelial growth factor (VEGF) family and other angiogenic factors, including fibroblast growth factor and platelet-derived growth factor, promote the growth of newly formed vessels from preexisting vessels and change the tumor microenvironment. To date, two antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab, which target VEGF-A and its receptor VEGF receptor-2, respectively, have been approved for the treatment of locally advanced or metastatic NSCLC when added to first-line standard chemotherapy. Numerous oral multitargeting angiogenic small molecule tyrosine kinase inhibitors (TKIs) have been widely evaluated in advanced NSCLC, but only nintedanib in combination with platinum-based doublet chemotherapy has demonstrated a survival benefit in the second-line setting. Additionally, small-molecule TKIs remain the standard of care for patients with mutated EGFR, ALK or ROS1. Moreover, immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) and programmed cell death protein ligand 1 (PD-L1) are changing the current strategy in the treatment of advanced NSCLC without driver gene mutations. The potential synergistic activity of antiangiogenic agents and TKIs or immunotherapy is an interesting topic of research. This review will summarize the novel antiangiogenic agents, antiangiogenic monotherapy, as well as potential combination therapeutic strategies for the clinical management of advanced NSCLC.
INTRODUCTION
remains the standard care for advanced NSCLC that do not harbor mutations of driver genes in the first-line setting. However, most patients experience disease progression following the standard chemotherapy, and the benefits and efficacy of second-line treatment are limited [2]. Recently, broad studies of tumor biology have allowed developing particular targeted therapies for patients with specific mutations in multiple driver genes, including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), as well as ROS proto-oncogene
Non-small cell lung cancer (NSCLC) accounts for nearly 85% of all lung cancer cases and is one of the frequently diagnosed malignancies. It has a high mortality worldwide, and a majority of patients with NSCLC are initially diagnosed with stage III or IV disease and are no longer eligible for surgical resection. Moreover, for patients with advanced NSCLC, the 5-year survival rate is less than 5% [1]. Platinum-containing chemotherapy www.impactjournals.com/oncotarget
53854
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1 (ROS1). In the past 10 years, several randomized trials have established tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, afatinib and crizotinib, as approved first-line drugs in NSCLC with targetable driver mutations or rearrangements [3-6]. Moreover, approximately 2030% of patients with NSCLC display primary resistance to these target inhibitors and lack an excellent initial clinical activity, although they have a sensitive gene mutation. In addition, patients with sensitive mutations ultimately develop secondary resistance to these drugs after several months of therapy [7]. Thus, the need for new therapeutic strategies for advanced NSCLC is urgent. Angiogenesis refers to the growth of newly formed blood vessels from the pre-existing vasculature. This complex physiological process involves a dynamic balance between angiogenesis inducers and inhibitors that tightly coordinate with macrophages, endothelial cells, and pericytes. However, the tumor tends to change this balance towards releasing chemical signals that stimulate angiogenesis and induce other cells to produce high levels of pro-angiogenesis factors in the tumor microenvironment, which promote cancer invasion and metastasis. Tumor angiogenesis results in abnormally formed, tortuous, and poorly organized vessels that exhibit altered permeability [8, 9]. Specifically, microenvironment hypoxia within the tumor induces the expression of multiple angiogenesis-related molecules, including the vascular endothelial growth factor (VEGF), plateletderived growth factor (PDGF), and fibroblast growth factor (FGF) families [10-12]. Of these molecules, VEGF-A represents a dominant angiogenesis promoter that stimulates the proliferation of endothelial cell, migration, and the formation of new blood vessels, mainly by interacting with its receptor VEGF receptor-2 (VEGFR-2) [13]. In fact, increased micro-vessel density and elevated circulating expression of VEGF-A are significantly related to a poor survival in lung cancer [14, 15]. Therefore, the angiogenesis pathway has been viewed as an important therapeutic target in lung cancer and other cancer types [16]. The tumor mass of nutrients to tumor growth is significantly deprived via booking angiogenesis, with a normalization of newly formatted vessels. At present, antiangiogenic treatment can be based on two major strategies: blocking the pro-angiogenesis pathway and enhancing the levels of antiangiogenic factors [17]. Monoclonal antibodies that block the function of VEGF-A or its receptor VEGFR-2 and different small-molecule multitargeting TKIs that block VEGFR and other receptormediated signaling pathways have been discovered and developed in clinical practice. For example, bevacizumab is a humanized monoclonal antibody targeting VEGF, has been approved by the US Food and Drug Administration (FDA) as a standard regimen for advanced NSCLC in the first-line setting. The FDA has also approved an antibody targeting VEGFR-2, ramucirumab, plus docetaxel for www.impactjournals.com/oncotarget
metastatic NSCLC that has progressed after first-line therapy. Endostar, a recombinant human endostatin, has been approved by the China FDA in 2005 for the therapy of metastatic NSCLC. It specifically promotes cell apoptosis and potently inhibits endothelial cell proliferation and tumor growth. In this review, we will summarize the current state and recent advances in the clinical treatment of advanced NSCLC with angiogenesis inhibitors, including the combination of antiangiogenic therapy and chemotherapy (Table 1 and 2), the combination of antiangiogenic therapy and EGFR TKIs (Table 3) or immune checkpoint inhibitors (Table 4), and the use of antiangiogenic agents alone (Table 5).
COMBINATION OF ANTIANGIOGENIC AGENTS AND CHEMOTHERAPY Bevacizumab plus chemotherapy As a humanized monoclonal antibody targeting VEGF-A, bevacizumab suppresses the binding of VEGF-A to its receptors to prevent its proangiogenic activity. The results from an early-randomized phase II trial showed that adding bevacizumab to standard doublet chemotherapy produced a higher objective response rate (ORR) and longer median time to progression (TTP) [18]. However, the median overall survival (OS) was similar between the bevacizumab and standard chemotherapy group. Moreover, hemoptysis events were observed in bevacizumab group, especially in a subset of patients with large tumors adjacent to major vessels or cavitary tumors, and patients with squamous cell histology. The subsequent ECOG 4599 study was the first randomized phase III trial evaluating first-line paclitaxel and carboplatin chemotherapy plus bevacizumab (n = 439) versus chemotherapy alone (n = 439) for NSCLC patients [19]. In particular, only cases with nonsquamous histology were enrolled in this trial. This study showed a significantly improved OS of 12.3 months in the combination arm versus 10.3 months in the chemotherapy arm. The ORR (35% versus 15%) and PFS significantly differed between the two arms. The combination regimen was well tolerated, but more grade 3 or 4 bleeding events occurred in 4.4% of patients with bevacizumab. Other main adverse events in the combination arm included neutropenia, hypertension, febrile neutropenia and proteinuria. In the AVAiL phase III trial, bevacizumab was also evaluated as an addition to gemcitabine and cisplatin chemotherapy in metastatic nonsquamous patients [20, 21]. A total of 1043 patients were enrolled to receive chemotherapy plus 7.5 mg/kg or 15 mg/kg bevacizumab or chemotherapy alone. Patients receiving bevacizumab and chemotherapy experienced prolonged PFS. However, prolonged OS was not observed in the 7.5 mg/kg or 15 mg/kg bevacizumab 53855
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group compared to the group receiving gemcitabine and cisplatin chemotherapy alone. The phase II JO19907 trail evaluated the efficacy of paclitaxel-carboplatin plus bevacizumab or placebo in Japanese patients with metastatic nonsquamous NSCLC. The ORR was 61% for bevacizumab compared with 31% for bevacizumab plus chemotherapy [22]. In the phase III BEYOND trail enrolling 276 Chinese patients, PFS was significantly different between the combination group (gemcitabinecisplatin plus bevacizumab) and the group receiving chemotherapy alone (9.2 versus 6.5 months), and the ORR (54% versus 26%) and OS (24.3 versus 17.7 months) were also significantly different between the two study arms [23]. The large SAiL study enrolling 2,212 patients confirmed that the combination therapy with bevacizumab and platinum-based chemotherapy has a manageable safety profile and offered a clinical survival benefit to patients with advanced NSCLC [24]. Subsequent subgroup
analyses revealed that the safety and efficacy in Asian or Chinese populations were consistent with those observed in several previous phase III trials [25, 26]. Recently, two meta-analyses proved that bevacizumab addition prolongs OS when it was added to doublet platinumcontaining chemotherapy in first-line setting [27, 28]. The addition of bevacizumab decreased the risk of mortality by nearly10%. In 2006, bevacizumab received FDA approval for treating patients with stage IV NSCLC. Subsequently, this antibody was also approved by the European Medicine Agency (EMA) for advanced nonsquamous NSCLC in the first-line setting. Additionally, retrospective data from the ECOG 4599 and the US Oncology network show that the continual use of bevacizumab until disease progression prolonged both PFS and OS [19, 29]. Many phase II trials have also evaluated the efficacy of bevacizumab maintenance for metastatic NSCLC after induction treatment with bevacizumab
Figure 1: VEGF-A-mediated inhibition of immune response and potential combination strategy with angiogenesis inhibitors and immunotherapy. Immune checkpoint inhibitors anti-PD-1 antibidy (nivolumab and pembrolizumab) or anti-PD-L1
antibody (atezolizumab) can combine with antiangiogenic agents (bevacizumab, ramucirumab, and oral small-molecule EGFR-TKIs) for targeting tumor. VEGF-A, vascular endothelial growth factor A; PD-1, programmed cell death protein-1; PD-L1, PD-ligand 1; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; TGF-β, transforming growth factor-β; IL-10, interleukin-10; IL-35, interleukin-35; IL-27, interleukin-27; Treg, T- regulatory cell; DC: dendritic cell; VEC: vascular endothelial cell; CD4+ T: cluster of differentiation 4+ T cell; CD8+ T: cluster of differentiation 8+ T cell; IDO, indoleamine 2, 3 -dioxygenase; MDSC, myeloid-derived suppressor cell; VEGFR-2: vascular endothelial growth factor receptor-2; VEGFR-TKIs: vascular endothelial growth factor receptor tyrosine kinase inhibitors. www.impactjournals.com/oncotarget
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Table 1: Trials evaluating bevacizumab or ramucirumab in combination with chemotherapy in locally advanced or metastatic NSCLC Study
Design
Patients
n
Study arm
Control arm
mPFS/mTTP
mOS
ORR
PE, P value
Johnson et al. [18]
Phase II
NSCLC
99
Pac+Car+Bev
Pac+Car
7.4 (7.5 mg/kg) vs 17.7 (7.5 mg/kg) vs 4.3 (15 mg/kg) vs 11.6 (15 mg/kg) vs 4.2 m 14.9 m
31.5% (7.5 mg/ kg) vs 28.1% (15 TTP; p = 0.023 mg/kg) vs 18.8% (15 mg/kg)
ECOG 4599 [19]
Phase III
nsNSCLC
878
Pac+Car+Bev
Pac+Car
6.2 vs 4.5 m
35% vs 15%
First-line
12.3 vs 10.3 m
OS; p = 0.003
AVAIL [20, 21]
Phase III
nsNSCLC
1,043
Gem+Cis+Bev
Gem+Cis
6.7 (7.5 mg/kg) vs 13.6 (7.5 mg/kg) vs 6.5 (15 mg/kg) vs 13.4 (15 mg/kg) vs 6.1 m 13.1 m
34.1% (7.5 mg/ PFS; p = 0.0003 kg) vs 30.5% (15 (7.5 mg/kg), P = mg/kg) vs 20.1% 0.0154 (15 mg/ kg)
BEYOND [23]
Phase III
nsNSCLC
276
Pac+Car+Bev
Pac+Car
9.2 vs 6.5 m
24.3 vs 17.7 m
54.4 vs 23.3%
OS; p = 0.0154
JO19907 [22]
Phase II
nsNSCLC
180
Pac+Car+Bev
Pac+Car
6.9 vs 5.9 m
22.8 vs 23.4 m
60.7% vs 31%
PFS; p = 0.009
SAiL [24-26]
Phase IV
nsNSCLC
2,212
Patinum-based chemotherapy+Bev
7.8 m
14.6 m
51%
Camidge et al. [41]
Phase II
NSCLC
22
Pal+Car+Ram
7.85 m
16.85 m
55%
6-month 59%
Doebele et al. [42]
Phase II
nsNSCLC
140
Pem+Pla+Ram
7.2 vs 5.6 m
13.9 vs 10.4 m
49.3% vs 38.0%
PFS; p = 0.132
Leon et al. [30]
Phase II
nsNSCLC
49
Vin+Cis+Bev→Bev
6m
14.7 m
29%
PFS
Stevenson et al. [31]
Phase II
nsNSCLC
43
Pem+Car+Bev→Bev
7.1 m
17.1 m
47%
PFS
Patel et al. [32]
Phase II
nsNSCLC
50
Pem+Car+Bev→Pem+Bev
7.8 m
14.1 m
55%
PFS
376
Pem+cis+Bev →Pem+Bev
Pem+cis+Bev →Bev
7.4 vs 3.7 m
17.1 vs 13.2 m
55.5% vs 50.0%
PFS; p < 0.0001
939
Pem+Car+Bev →Pem+Bev
Pac+Car+Bev→Bev
6.0 vs 5.6 m
13.4 vs 12.6 m
34.1% vs 33.0%
OS; p = 0.949
3.91 vs 2.86 m
11.7 vs 10.5 m
23.6% vs 27.4%
G4PFS, 0.176
Pem+Pla
PFS:
Maintenance
AVAPERL [33, 34] POINTBREAK [35]
Phase III Phase III
nsNSCLC nsNSCLC
Phase III
nsNSCLC
371
Pac+Car+Bev→Bev
Pem+Car →Pem
Herbst et al. [37]
Phase II
nsNSCLC
81
Doc/Pem+Bev
Doc/Pem+Bev+Plac
4.8 vs 3.0 m
12.6 vs 8.6 m
12.5% vs 12.2%
PFS; HR: 0.38 (95%CI: 0.381.16)
REVEL [43]
Phase III
NSCLC
1,253
Doc+Ram
Doc+Plac
4.5 vs 3.0 m
10.5 vs 9.1 m
23% vs 14%
OS; p = 0.023
Yoh [44]
Phase II
NSCLC
197
Doc+Ram
Doc+Plac
5.22 vs 4.21 m
15.15 vs 14.65 m
28.9% vs 18.5%
PFS; 0.83 (0.591.16)
PRONOUNCE [36]
p
=
Second-line
NSCLC: non-small cell lung cancer; nsNSCLC: non-squamous non-small cell lung cancer; mPFS: median progression-free survival; mTTP: median time to progression; ORR: objective response rate; PE: Primary endpoint; Pac: paclitaxel; Car: carboplatin; Bev: bevacizumab; Ram: ramucirumab; Gem: Gemcitabine; Cis: cisplatin; Pla: platinum; Doc: docetaxel; Plac: placebo; G4PFS: PFS without grade 4 toxicity; HR: hazard ratio plus different platinum-based chemotherapy regimens, such as bevacizumab alone [30, 31] or combination with pemetrexed [32]. In several phase III trials, bevacizumab was also studied as a maintenance therapy after its association with induction chemotherapy with platinum-based regimen. In the AVAPERL randomized phase III trial, NSCLC patients receiving bevacizumab and pemetrexed maintenance therapy had a longer PFS than patients receiving bevacizumab maintenance (7.4 versus 3.7 months), but OS only numerically differed between the two groups (17.1 versus 13.2 months) [33, 34]. The POINTBREAK study evaluated the efficacy and safety of pemetrexed plus carboplatin plus bevacizumab followed by maintenance treatment with pemetrexed and bevacizumab versus those of paclitaxel plus carboplatin plus bevacizumab followed by maintenance treatment with bevacizumab in advanced nonsquamous NSCLC [35]. This trial failed to reach its primary endpoint of OS, although improvements were observed in PFS and the ORR. In the PRONOUNCE trial, after chemotherapy with pemetrexed
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and carboplatin, maintenance treatment with pemetrexed did not prolong PFS without grade 4 toxicity compared to maintenance treatment with bevacizumab after paclitaxel plus carboplatin plus bevacizumab [36]. Overall, these trials fail to present sufficient data to identify the optimal regimen in the maintenance treatment setting (cytotoxic chemotherapy, bevacizumab, or cytotoxic chemotherapy plus bevacizumab). A randomized phase III ECOG 5508 trial would help to identify the superior treatment, the combination of pemetrexed and bevacizumab versus pemetrexed or bevacizumab monotherapy, as a switch maintenance approach beyond standard chemotherapy. Second-line treatment strategies are currently limited and include docetaxel or pemetrexed chemotherapy alone, with response rates of < 10%. Investigators have also evaluated the second-line combination of chemotherapy with bevacizumab versus chemotherapy alone. A phase II trial showed that the risk of disease progression or mortality was decreased by 34% in the chemotherapy plus bevacizumab group compared to patients treated with the
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Table 2: Trials evaluating antiangiogenic TKIs in combination with chemotherapy in locally advanced or metastatic NSCLC as first or second-line therapy Study
Design
Patients
n
Experimental arm
Control arm
mPFS/mTTP
mOS
ORR
PE, p value
ESCAPE [49]
Phase III
NSCLC
926
Pac+Car+Sor
Pac+Car
4.6 vs 5.4 m
10.7 vs 10.6 m
27.4% vs 24.0%
OS; p = 0.915
NEXUS [50]
Phase III
nsNSCLC
772
Gem+Cis+Sor
Gem+Cis
6.0 vs 5.5 m
12.4 vs 12.5 m
28% vs 26%
OS; p = 0.401
MONET1 [51]
Phase III
nsNSCLC
1090
Pac+Car+Mot
Pac+Car
5.6 vs 5.4 m
13.0 vs 11.0 m
40% vs 26%
OS; p = 0.14
Pac+Car+Bev
14.0 (125 mg qd) vs 7.7 (125 mg qd) vs 5.8 (75 30% vs 23% vs 12.8 (75 mg bid) vs mg bid) vs 8.3 m 37% 14.0
First-line
NCT00369070 [52]
Phase II
nsNSCLC
186
Pac+Car+Mot
NCIC IND [53]
Phase I
NSCLC
20
Pac+Car+Ced
BR24 [54]
Phase II
NSCLC
251
Pac+Car+Ced
Pac+Car
5.6 vs 5.0 m
BR29 [55]
Phase III
NSCLC
306
Pac+Ced
Pac
5.5nvs 5.5 m
12.2 vs 12.1 m
52% vs 34%
OS; p = 0.72
N0528 [56]
Phase II
NSCLC
87
Gem+Cb+Ced
Gem+Car
6.3 vs 4.5 m
12 vs 9.9 m
19% vs 20%
ORR; p = 1.0
Heymach [57]
Phase II
NSCLC
108
Pac+Cb+Van
Pac+Car
24 vs 23 w
10.2 vs 12.6 m
32% vs 25%
PFS; p = 0.098
Aisner et al. [58]
Phase II
NSCLC
162
Pac+Cb+Van→van
Pac+Car+Van→Plac
4.5 vs 4.2 m
9.8 vs 9.4 m
Scagliotti et al. [59]
Phase II
nsNSCLC
106
Pem+Paz
Pem+Cis
25.0 vs 22.9 w
HR: 1.22; P = 0.55
23% vs 34%
PFS; p = 0.26 PFS; p = 0.36 (d1-21); p = 0.54 (d2-19)
7.6 m
ORR
45% PFS; p = 0.08
PFS; p = 0.07
Belani et al. [60]
Phase II
nsNSCLC
170
Pem+Cis+Axi
Pem+Cis+Axi
8.0 (d1-21) vs 7.9 (d2-19) vs 7.1 m
16.6 (d1-21) vs 14.7 (d2-19) vs 15.9 m
45.5% (d1-21) vs 39.7% (d12-19) vs 26.3%
Twelves et al. [61]
Phase II
nsNSCLC
118
Pac+Car+Axi
Pac+Car+Bev
5.7 vs 6.1 m
10.6 vs 13.3 m
29.3% vs 43.3%
PFS; p = 0.64
Ramalingam et al. [62]
Phase II
nsNSCLC
138
Pac+Car+Lin
Pac+Car
8.3 (7.5 mg) vs 7.3 (12.5 11.4 (7.5mg) vs 13.0 mg) vs 5.4 m (12.5 mg) vs 11.3 m
8.3 (7.5 mg) vs 7.3 (12.5 mg) vs 5.4 m
PFS; p = 0.022 (7.5 mg); p = 0.118 (12.5 mg)
Phase II
NSCLC
100
Sor+Pem
Pem
3.4 vs 4..1m
9.4 vs 9.1m 6.7 vs 10.5 vs 8.0 m (Sun alone)
22% vs 17% vs 14 (Sun alone)
PFS; p = 0.25
Second-line N0626 [63]
PFS; p = 0.22
CALGB30704 [64]
Phase II
NSCLC
130
Pem+Sun
Pem; Sun
3.7 vs 4.9 vs 3.3 m (Sun alone)
LUME-lung 1 [65]
Phase III
NSCLC
1,311
Doc+Nin
Doc
3.4 vs 2.7 m
10.0 vs 9.1 m
4.4% vs 3.3%
PFS; p 0.0019
=
LUME-lung 2 [66]
Phase III
nsNSCLC
713
Pac+Nin
Pac
4.4 vs 3.6 m
12.0 vs 12.7 m
9.1% vs 8.3%
PFS; p 0.0435
=
ZODIAC [65]
Phase III
NSCLC
1,391
Doc+Van
Doc
4.0 vs 3.2 m
10.6 vs 10.0 m
17% vs 10%
PFS; p 0.0001
