Angiogenesis, the process leading to the formation of new blood vessels, is one of the hallmarks of cancer. Extensive studies established that i) vascular endothelial growth factor (VEGF) is a key driver of sprouting angiogenesis, ii) VEGF is overexpressed in most solid cancers, and iii) inhibition of VEGF can suppress tumor growth in animal models. This has led to the development of pharmacological agents for anti-angiogenesis to disrupt the vascular supply and starve the tumor of nutrients and oxygen, primarily through the blockade of VEGF/VEGF receptor signaling. This effort has resulted in 11 anti-VEGF drugs approved for certain advanced cancers, either alone or in combination with chemotherapy and other targeted therapies. However, inhibition of VEGF signaling is not effective in all cancers, and anti-angiogenics have often only limited impact on overall survival of cancer patients. This review focuses on the current status of FDA-approved anti-angiogenic antibodies and tyrosine kinase inhibitors and summarizes the progress and future directions of VEGF-targeted therapy.

Angiogenesis, the growth of new blood vessels from pre-existing blood vessels via a process called sprouting, is one of the hallmarks of cancer. Angiogenesis is a multistage process regulated by numerous growth factors and their receptors. Targeting angiogenesis as a tumor therapy was first hypothesized over 4 decades ago by Judah Folkman [1]. Of all the identified molecules leading to blood vessel formation, vascular endothelial growth factor A (VEGF-A) appears to be the main molecular driver of tumor angiogenesis. Indeed, VEGF-A is overexpressed in the majority of solid tumors and for this reason is the dominant target for anti-angiogenic drugs [2]. The main signaling tyrosine kinase receptor is VEGF receptor 2 (VEGFR2); 2 other VEGFRs include VEGFR1 (also known as FLT1) and VEGFR3 (also known as FLT3).

Three approaches have been developed for targeting the VEGF signaling pathway:

Ligand binding agents that block the binding of VEGF ligands to receptors (e.g., bevacizumab which binds to VEGF-A alone and aflibercept which binds to VEGF-A, VEGF-B, and placental growth factor (PLGF)); antibodies that block signaling though VEGFRs (e.g., ramucirumab which binds to VEGFR2); and tyrosine kinase inhibitors (TKIs) which block the kinase activity of VEGFR1, VEGFR2, and VEGFR3 (e.g., sorafenib, sunitinib, pazopanib) (table 1). TKIs often inhibit the kinase activity of some other receptor tyrosine kinases such as platelet-derived growth factor receptors (PDGFRs), c-KIT, and FLT3.

Table 1

FDA-approved vascular endothelial growth factor (VEGF)-targeted therapy for oncology

FDA-approved vascular endothelial growth factor (VEGF)-targeted therapy for oncology
FDA-approved vascular endothelial growth factor (VEGF)-targeted therapy for oncology

Antibody-Based Therapies

VEGF is overexpressed in a vast majority of solid tumors and is widely considered to be a key player in mediating tumor angiogenesis [2, 3]. For this reason, over the past decades, the development of anti-angiogenics predominantly focused on the development of VEGF/VEGFR inhibitors. Preclinical evidence showed that monotherapy of VEGF blockade inhibited tumor growth in subcutaneous human xenografts of many cancer types. Anti-VEGF treatment even resulted in a marked decrease in metastasis, in particular in preclinical colorectal cancer models [4].


Ferrara et al. [5, 6]designed and developed the first anti-angiogenic inhibitor, bevacizumab, a recombinant humanized monoclonal antibody (mAb) blocking VEGF-A. Intravenous administration of bevacizumab depletes VEGF in the bloodstream and in perfused tissues, inhibiting the interaction between VEGF and VEGFRs [3]. Several clinical trials of bevacizumab with chemotherapy showed increased overall survival (OS) and/or progression-free survival (PFS) in metastatic colorectal cancer (mCRC) (in first and second line) [7, 8, 9], as well as in cervical cancers, non-small cell lung cancer (NSCLC), ovarian cancer, and mesothelioma [10, 11, 12, 13, 14]. A combination of bevacizumab and interferon alpha immunotherapy is now one of the standards of care in metastatic renal cell carcinoma (mRCC) prolonging PFS [15].

To date, bevacizumab is Food and Drug Administration (FDA)-approved for the treatment of CRC, NSCLC, glioblastoma, RCC, cervical cancer, ovarian cancer, fallopian tube cancer, and peritoneal cancer (table 1). However, in the majority of cancers, bevacizumab failed to increase survival, including breast, melanoma, pancreatic, and prostate cancer [16]. The precise explanation as to why anti-angiogenic agents show efficacy in some metastatic cancers and not others, is currently unknown. Conceivably, important differences in the vascular biology of these cancers may underlie the discrepant results seen with this approach across different tumors.

Of note, the history of anti-angiogenic therapy in the treatment of metastatic breast cancer is of significant interest. Bevacizumab was FDA-approved in combination with paclitaxel for the treatment of HER2-negative metastatic breast cancer in February 2008 under the FDA's accelerated approval program. 3 further phase III trials of bevacizumab in combination with chemotherapy in HER2-negative metastatic breast cancer (AVADO, RIBBON-1, and RIBBON-2) demonstrated an extension of PFS, but no effect on OS, when compared to chemotherapy alone [17, 18, 19]. As a consequence of these results, the FDA withdrew its approval for bevacizumab in this indication in November 2011.


Recently, 2 phase III studies evaluated the role of ramucirumab, a VEGFR2 mAb interfering with VEGFs binding to their receptor. The REGARD study evaluated ramucirumab as second-line therapy after disease progression on a first-line chemotherapy regimen in patients with advanced, unresectable gastroesophageal tumors [20]. Median OS was 5.2 months in the ramucirumab group and 3.8 months in the placebo group (p = 0.047). A longer PFS (2.1 months for ramucirumab vs. 1.3 months for placebo) was also reported. Overall, this study identified ramucirumab as the first biological treatment given as a single drug showing survival benefits in patients with advanced gastroesophageal adenocarcinomas progressing after first-line chemotherapy. A second phase III study (RAINBOW) investigated ramucirumab combined with paclitaxel, as second-line treatment in patients with metastatic gastric cancer who progressed after a first-line chemotherapy [21]. OS was significantly longer in the ramucirumab plus paclitaxel group than in the placebo group (9.6 vs. 7.4 months). Furthermore, ramucirumab plus paclitaxel significantly delayed disease progression (PFS 4.4 vs. 2.9 months) and increased the response rate (28 vs. 16%). Based on these results, ramucirumab was approved by the FDA and the European Commission either as a single agent or in association with paclitaxel in patients with advanced or metastatic gastric and gastroesophageal junction cancer after progression on fluoropyrimidine or platinum-containing regimens. Ramucirumab also showed increased OS when combined with docetaxel for second-line treatment of metastatic NSCLC [22] and mCRC [23], leading to FDA approval also in these indications.


Aflibercept is a novel fusion protein that binds to 3 VEGF family ligands: VEGF-A, VEGF-B, and PLGF. Aflibercept combined with chemotherapy as second-line treatment in mCRC patients showed a small OS (13.5 months in the aflibercept arm vs. 12 months in the control arm; p = 0.0032) and PFS (6.9 months in the aflibercept arm vs. 4.7 months in the control arm; p < 0.0001) benefit in a randomized phase II clinical trial [24]. Based on these data, aflibercept was recently approved for the treatment of mCRC when given in combination with chemotherapy. Furthermore, experimental models propose aflibercept as a promising candidate to treat hepatocellular carcinoma (HCC) [25], a highly vascular tumor with the development of neoarteries in parallel with tumor growth.

Small Molecule Inhibitors

In addition to monoclonal antibodies, TKIs were developed to inhibit VEGFRs and their downstream targets in order to suppress endothelial proliferation and disrupt the vascular supply of nutrients and oxygen. Multiple TKIs have been approved as single therapies in specific indications based on improvement of OS or PFS in phase III trials. These include sorafenib, sunitinib, axitinib, regorafenib, pazopanib, vandetanib, cabozantinib, and lenvatinib (table 1).

Among this class of agents, the pioneer drugs were sorafenib and sunitinib. Subsequently, other agents emerged with similar modes of action but better toxicity profiles. This second-generation of multi-kinase inhibitors shows improved target affinity combined with less off-target effects.

Four of these FDA-approved agents, namely sorafenib, sunitinib, pazopanib, and axitinib, proved to be highly successful in mRCC and are FDA-approved in this setting. A phase III trial comparing sunitinib with pazopanib demonstrated that both drugs have similar efficacy [26], and single-agent therapy with either drug is now recommended as standard of care in the first line in mRCC. TKIs also showed single-agent activity in advanced HCC (sorafenib) and advanced pancreatic neuroendocrine tumors (PNET) (sunitinib). Regarding mCRC, despite the benefit observed when bevacizumab or aflibercept are combined with chemotherapy, efforts to combine anti-angiogenic TKIs with chemotherapy have so far generated disappointing results in terms of improving OS [27, 28]. However, single-agent treatment with the TKI regorafenib was recently demonstrated to moderately extend OS compared to placebo (6.4 vs. 5.0 months; p = 0.0052) and PFS (1.9 vs. 1.7 months; p < 0.0001) in mCRC patients who had previously progressed on standard therapies [29]. Regorafenib is now approved for the treatment of mCRC in this setting in Europe and the United States. Notably, in March 2016, Bayer pulled regorafenib back on the German market after the Federal Joint Committee (G-BA) decided that regorafenib has no added value for the treatment of CRC and that its disadvantages outweigh its benefits. The decision of the G-BA was described by the company as ‘incomprehensible', especially since such additional benefits of regorafenib had been previously recognized. The European approval, however, was not affected, and regorafenib is still available in other European countries. Regorafenib recently also obtained approval for the additional indication of gastrointestinal stromal tumors (GIST) and HCC. Regorafenib is the first and only treatment that has demonstrated a significant improvement in OS in second-line HCC patients [30].

Among the second-generation multi-kinase inhibitors, also pazopanib, cabozantinib, lenvatinib, axitinib, and vandetanib have been approved as monotherapies in specific indications (table 1).

Recently, based on the results of the phase III LUME-Lung 1 trial [31], the European Medicines Agency (EMA), but not FDA, approved the use of nintedanib, an oral multi-kinase inhibitor targeting VEGFR1-3, FRGFR1-3, PDGFRa-b, RET, FLT3, and Src family kinases, combined with docetaxel for the second-line treatment of NSCLC.

Cediranib is a pan-VEGFR inhibitor showing prolonged PFS when combined with platinum-based chemotherapy in relapsed platinum-sensitive ovarian cancer [32]. The OS endpoint is currently being analyzed for this clinical trial; however, the trial met the endpoint and therefore the drug will likely be approved by the FDA.

Among the antiangiogenic agents under investigation in gastric cancer is apatinib, an oral VEGFR2 inhibitor. In a phase III trial, patients progressing on second-line therapy were randomized to apatinib or placebo. Median OS (4.7 months with placebo vs. 6.5 months with apatinib) and PFS (1.8 vs. 2.6 months) were significantly improved [33].

Anti-angiogenic regimens targeting the excess of angiogenic inducers including bevacizumab or aflibercept show clinical benefits when associated with cytotoxic therapies, as reported above. In contrast, TKIs do not show any clinical improvement when administered with standard therapies. Attempts to combine anti-angiogenic TKIs with chemotherapy did not improve PFS in mCRC and metastatic breast cancer. Indeed, VEGFR TKIs exhibit single-agent activity and are effective as monotherapy while showing toxicity in combination with chemotherapy [34].

The overall benefits of anti-angiogenics from the perspective of impacting survival have left much to be desired, endorsing the need for developing more effective therapeutic regimens.

Especially, immune checkpoint inhibition has now been clinically validated as an effective treatment for various tumors with promising results and there is exceptional potential for combining immunotherapy agents with conventional cancer treatments.

The programmed death protein 1 (PD-1), its ligand the programmed death ligand 1 (PD-L1), and the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) are negative regulators of T-cell immune function. Direct stimulation of the immune system with antibodies against PD-1, PD-L1, and CTLA-4 leads to tremendous clinical efficacy in multiple cancers, having resulted in the FDA approval of the following immune checkpoint targeted immunotherapies: ipilimumab (Yervoy®, Bristol-Myers Squibb GmbH & Co. KGaA, Munich, Germany), pembrolizumab (Keytruda®, MSD Sharp & Dohme GmbH, Munich, Germany), nivolumab (Opdivo®, Bristol-Myers Squibb), atezolizumab (Tecentriq®, Roche Pharma AG, Grenzach-Whylen, Germany), avelumab (Bavencio®, Merck /Pfizer Pharma GmbH, Berlin, Germany), and durvalumab (Imfinzi®, AstraZeneca, Wedel, Germany).

Notably, VEGF was recognized as one of the critical molecules of immunosuppression. VEGF suppresses dendritic cell differentiation and activity [11] and expands T regulatory cells and myeloid-derived suppressor cells. In addition, in patients with CRC, VEGF inhibition by bevacizumab improved the antigen-presenting capacity of circulating dendritic cells [35], revealing an additional mechanism for bevacizumab on immune functions in the context of checkpoint blockade. The positive effect on immune response obtained by inhibiting the VEGF pathway can be further increased by combined blockade of angiopoietin-2 (Ang-2) [36, 37]. Besides VEGF, Ang-2 is an important player in angiogenesis. A bispecific antibody which binds both VEGF-A and Ang-2 showed a better effect as compared to single blockade in many preclinical models and synergized with PD-1 blockade [36, 38].

More recently, a preclinical study provided evidence that anti-PD-1 or anti-PD-L1 therapy sensitized and prolonged the efficacy of antiangiogenic therapy, and conversely, antiangiogenic therapy improved anti-PD-L1 treatment by supporting vascular changes such as high endothelial venule formation and vessel normalization that facilitate enhanced cytotoxic T-cell infiltration and subsequent tumor cell destruction [39]. In addition, Tian et al. [40]also proposed that CD4+ T-lymphocyte activation by immune checkpoint blockade increased vessel normalization, as indicated by increased pericyte coverage, improved tumor vessel perfusion, and reduced vascular permeability, resulting in altered tumor progression.

Based on these preclinical and translational data supporting synergy between anti-angiogenics and immunotherapy, multiple trials of combining VEGF-targeted therapy and checkpoint inhibitors are underway. Clinical trials in many different indications such as melanoma, CRC, RCC, NSCLC, and glioblastoma are evaluating e.g., i) bevacizumab in combination with ipilimumab, atezolizumab, nivolumab, or pembrolizumab, ii) aflibercept in combination with pembrolizumab, or iii) the TKIs sunitinib, axitinib, or cabozantinib in combination with nivolumab, pembrolizumab, or avelumab (

Recently, a clinical study of a combination therapy using the anti-CTLA4 antibody ipilimumab with the anti-VEGF antibody bevacizumab reported promising efficacy in patients with advanced melanoma resulting in a median OS of more than 2 years [41]. High-grade toxicity was more common than expected for either drug alone, but was manageable. Interestingly, the combination led to an accumulation of CD8+ T cells and dendritic cells in the tumor microenvironment - suggesting synergism of immunotherapeutic effector mechanisms and warranting further investigation of this combination.

Furthermore, nanotechnology-based approaches could improve the current pharmacokinetic profiles of anti-angiogenic drugs and favor their selective accumulation in tumors [42]. Recently, the humanized tri-specific nanobody BI 836880 comprising 2 single-variable domains blocking VEGF and Ang2, and an additional albumin module for half-life extension in vivo was generated. This novel VEGF/Ang2-blocking nanobody showed promising properties in vitro and in vivo which strongly support the evaluation of this molecule in the clinic. At present, 2 phase I dose escalating studies are underway in patients with advanced solid tumors exploiting this nanobody (NCT02689505, NCT02674152).

Clinical development of anti-angiogenic therapy was a success and translated into increased OS and PFS in many tumors. This is in line with the concept that tumor angiogenesis is a hallmark of cancer. However, the benefits are limited, and predictive biomarkers for this class of agent remain elusive. One explanation for the disappointing results is the existence of intrinsic or acquired resistance to anti-angiogenic therapy mediated by both tumor cells and stromal cells. Given the recent success of immunotherapies, and since VEGF promotes an immunosuppressive tumor microenvironment, combinations of anti-angiogenics with checkpoint blockers have become an attractive strategy. Other emerging directions for medical treatment targeting angiogenesis are bispecific antibodies binding VEGF and Ang-2 and nanotechnology approaches. In addition, understanding the mechanism through which stromal cells mediate resistance in the tumor would help to improve the efficacy and durability of anti-angiogenic therapy.

The authors have declared that no competing interests exist.

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