PD-1/PD-L1 inhibitor – Cd38 Inhibitor1

Anti-VEGF/VEGFR2 Monoclonal Antibodies and their Combinations with PD-1/PD-L1 Inhibitors in Clinic

Feng Gao1,* and Chun Yang1

1BuChang (Beijing) Pharmaceutical Co. Ltd, Hongda Industrial Park, Hongda North Road, Beijing 100176, China

Abstract: The vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway is one of the most important pathways responsible for tumor angiogenesis. Currently, two monoclonal antibodies, anti-VEGF-A antibody Bevacizumab and anti-VEGFR2 antibody Ramuci- zumab, have been approved for the treatment of solid tumors. At the same time, VEGF/VEGFR2
signaling is involved in the regulation of immune responses. It is reported that the inhibition of this

A R T I C L E H I S T O R Y

Received: June 26, 2019
Revised: August 29, 2019
Accepted: September 19, 2019

DOI: 10.2174/1568009619666191114110359

pathway has the capability to promote vascular normalization, increase the intra-tumor infiltration of lymphocytes, and decrease the number and function of inhibitory immune cell phenotypes, including Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2 macrophages. On this basis, a number of clinical studies have been performed to investigate the therapeutic potential of VEGF/VEGFR2-targeting antibodies plus programmed cell death protein 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) inhibitors in various solid tumor types. In this context, VEGF/VEGFR2- targeting antibodies, Bevacizumab and Ramucizumab are briefly introduced, with a description of the differences between them, and the clinical studies involved in the combination of Bevacizu- mab/Ramucizumab and PD-1/PD-L1 inhibitors are summarized. We hope this review article will provide some valuable clues for further clinical studies and usages.

Keywords: Cancer immunotherapy, immune checkpoint inhibitors, combination cancer therapy, PD-1/PD-L1 mechanism, tu- mor angiogenesis, VEGF/VEGFR2 signaling.

1. INTRODUCTION
Tumor growth increases the consumption of nutrients and oxygen. Usually, when tumor cells are located more than 100 μm (the diffusion limit for oxygen) away from blood vessels, these cells undergo local hypoxia, leading to intracellular signaling regulation (such as hypoxia-inducible factor-1α), subsequent expression of energy supply, angiogenesis- associated factors, and tumor angiogenesis [1-3]. Tumor angiogenesis is a complicated process involved in various signaling pathways such as vascular endothelial growth fac- tor (VEGF), platelet-derived growth factor (PDGF), angio- poietin-1, and Notch signaling pathways [4-8]. Among them, VEGF is one of the most important and well-known pro- angiogenic mediators. VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF), to which ligands bind different VEGF receptors (VEGFRs) and exert various biological functions [9]. For example, it has been reported that VEGFR1 activation results in haematopoietic stem cell survival, monocyte trafficking, and inhibition of dendritic cell maturation [10-12], VEGFR2 activation increases vascular permeability and promotes en- dothelial cell proliferation, migration and tube formation [13,

*Address correspondence to this author at Room 8406, Hongda Industrial Park, Hongda North Road, Beijing 100176, China; Tel: +86-18301681506; E-mail: [email protected]

14], and VEGFR3 activation is associated with lymphangio- genesis [15-17]. Compared to other receptor subtypes, VEGFR2 signaling is more important in tumor angiogenesis.
Due to the importance of VEGF/VEGFR2 signaling in tumor angiogenesis, many effects have been assessed to de- velop VEGF/VEGFR2 signaling inhibitors for cancer ther- apy. Currently, in addition to small molecular VEGFR in- hibitors, there are two monoclonal antibodies available in the market: one is Bevacizumab (Avastin) which is an anti- VEGF-A antibody, and another one is Ramucizumab (Cyramza) which is specific to VEGFR2. Next, we briefly introduce these two antibodies, and summarize their combi- nation with programmed cell death protein 1 (PD- 1)/programmed cell death ligand 1 (PD-L1) inhibitors in the clinic.
2. ANTI-VEGF/VEGFR2 ANTIBODIES AVAILABLE IN THE MARKET: BEVACIZUMAB AND RAMUCI- ZUMAB
2.1. A Brief Summary of Bevacizumab and Ramucizu- mab
A brief summary of Bevacizumab and Ramucizumab has been shown in Table 1. As approved by the FDA for the therapy of metastatic colorectal cancer (mCRC) in 2004, Bevacizumab has been approved for the treatment of many types of solid tumors. As a result, its annual global sale has

Table 1. A brief summary of Bevacizumab and Ramucirumab.

Bevacizumab Ramucizumab
Trade name Avastin Cyramza
Company Genentech Inc/Roche Imclone LLC/Eli Lilly & Co
Approved Year 2004 2014
Target VEGF-A VEGFR2
Molecular format Humanized IgG1 monoclonal antibody Fully human IgG1 monoclonal antibody
Approved indications US
1) Metastatic colorectal cancer (mCRC) [18, 19], in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second- line treatment; in combination with fluoropyrimidineirinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy for second-line treatment in patients who have progressed on a first-line Bevacizu- mab-containing regimen;
2) Unresectable, locally advanced, recurrent or metastatic non- squamous non-small-cell lung cancer (NSCLC) [20], in combination with carboplatin and paclitaxel for first-line treatment;
3) Recurrent glioblastoma in adults [21];
4) Metastatic renal cell carcinoma (RCC) [22], in combination with interferon (IFN) alfa;
5) Persistent, recurrent, or metastatic cervical cancer [23-25], in com- bination with paclitaxel and cisplatin, or paclitaxel and topotecan;
6) Epithelial ovarian, fallopian tube, or primary peritoneal cancer [26- 28], in combination with carboplatin and paclitaxel, followed by Bevacizumab as a single agent, for stage III or IV disease following initial surgical resection; or in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for platinum-resistant recurrent disease who received no more than two prior chemotherapy regimens;
EU
In addition to mCRC, NSCLC and ovarican cancer, indicated for the treatment of metastatic breast cancer [29-32], in combination with paclitaxel for first-line treatment of metastatic breast cancer; in com- bination with capecitabine for first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options is not appropriate;
Japan
Indicated for the treatment of unresectable advanced or recurrent CRC, non-squamous NSCLC, inoperable or recurrent breast cancer, malignant glioma, ovarian cancer, advanced or recurrent cervical cancer. US and EU
1) As a single agent or in combination with paclitaxel for the treatment of advanced gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy [33-35]
2) In combination with docetaxel for the treatment of metastatic non-small-cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy, including squamous and nonsquamous histologies [36, 37];
3) In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil) chemotherapy for the treatment of patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with Bevacizumab, oxaliplatin and a fluoropyrimidine [38, 39]
US
Monotherapy for patients with hepatocellular carcinoma (HCC) who have an alpha fetoprotein (AFP) ≥400 ng/mL and have been previously treated with sorafinib [40, 41]
Japan
Indicated for unresectable advanced or recurrent gastric cancer; for the treatment of second-line mCRC; and for the treatment of unresectable advanced or recurrent NSCLC

reached 7 billion dollars in 2014 and kept relatively stable in recent years (Fig. 1A). In contrast, Ramucizumab was ap- proved by the FDA in 2014. Currently, approved indications for Ramucizumab have covered many cancer types and there still are a number of clinical trials undergoing. As shown in Fig. (1B), the annual global sale of Ramucizumab is in the evolution stage and reached 821.4 million dollars in 2018.

2.2. Molecular Mechanisms of Bevacizumab and Ra- mucizumab
Though both Bevacizumab and Ramucizumab are mono- clonal antibodies targeting to VEGF/VEGFR pathway, there still lie differences in their molecular mechanisms as shown in Fig. (2). Specific binding of Bevacizumab to VEGF-A

blocks the association of VEGF-A with VEGFR1 and VEGFR2, but it does not interfere with the interaction be- tween PlGF/VEGF-B/VEGF-C/VEGF-D and VEGFR1/ VEGFR2 [42-45]. In contrast, Ramucizumab specifically recognizes and attaches to VEGFR2 and completely inhibits the VEGFR2 activation mediated by different ligands, in- cluding VEGF-A, VEGF-C and VEGF-D, though Ramuci- zumab has no effect on VEGFR1 signaling [46-48]. The dif- ferences stated above have the potential to result in differen- tial biological effects.
At the same time, it has been reported that the treatment of Bevacizumab could increase the expression of PlGF, VEGF-C and VEGF-D [49]. Up-regulation of these ligands leads to further activation of VEGFR1 and VEGFR2, and

A 8000
6000

4000

2000

Bevacizumab

1000

800

600

400

200

Ramucizumab

Fig. (1). Annual sales of Bevacizumab and Ramucizumab. Data from Cortellis Database (Clarivate Analytics).

trafficking, inhibition of DC maturation

angiogenesis

Fig. (2). VEGF/VEGFR signaling regulation mediated by Bevacizumab and Ramucizumab. HSC, haematopoietic stem cell. DC, dendritic cell.

has been considered as one of the mechanisms behind resis- tance to Bevacizumab. By completely blocking VEGFR2 signaling, Ramucizumab has the potential to overcome the resistance to Bevacizumab [50]. As shown in Table 1, Ra- mucizumab plus chemotherapy has been approved for the therapy of mCRC patients resistant to Bevacizumab plus chemotherapy.

2.3. Efficacy and Safety of Bevacizumab and Ramucizu- mab
The differences in molecular mechanisms imply the po- tential divergence of clinical effects and safety between Bevacizumab and Ramucizumab. Next, we will make a brief comparison of clinical manifestations of these two antibod- ies.

2.3.1. Non-Small Cell Lung Carcinoma (NSCLC)
Hong et al. summarized the clinical studies of Bevacizu- mab and Ramucizumab on NSCLC, and selected eight stud- ies on Bevacizumab and one of Ramucizumab for compari- son [51]. The results showed that both treatments signifi- cantly improved OS and PFS to the same extent. Another meta-analysis involved in eighty-five randomized controlled trials suggested that in the NSCLC subgroup, Bevacizumab significantly increased the risk of all-grade bleeding and high-grade pulmonary hemorrhage, but no significant in- crease was observed for Ramucizumab [52].
Furthermore, two studies with similar combination strategies are listed below to compare the efficacy and safety of Bevacizumab and Ramucizumab in NSCLC. In a study, the combination of Ramucizumab and docetaxel signifi-

cantly improved median OS (10.5 months vs 9.1 months) and PFS (4.5 months vs 3.0 months) in the Ramucizumab group, compared to the placebo group. Grade 3-5 adverse events in the treatment group included neutropenia (306/627, 49%), anemia (18/627, 3%), thrombocytopenia (18/627, 3%), bleeding or hemorrhage (15/627, 2%), hypertension (35/627, 6%), proteinuria (1/627, ≤1%), venous thromboem- bolism (VTE) (11/627, 2%), arterial thromboembolism (ATE) (6/627, 1%), and gastrointestinal perforation (5/627, 1%) [36]. In contrast, in a study of NSCLC patients treated with Bevacizumab plus docetaxel or pemetrexed, median OS (12.6 months vs 8.6 months) and PFS (4.8 months vs 3.0 months) significantly improved in the Bevacizumab group, compared to the placebo group. Grade 3-5 adverse events in the treatment group included neutropenia (8/39, 21%), ane- mia (2/39, 5%), thrombocytopenia (1/39, 3%), bleeding or hemorrhage (3/39, 8%), hypertension (2/39, 5%), VTE (1/39, 3%), ATE (0/39, 0%), and gastrointestinal perforation (1/39, 3%) [53]. From the data stated above, we could say that compared to Bevacizumab, Ramucizumab treatment leads to a higher risk of neutropenia and a lower risk of bleeding or hemorrhage. There were no obvious differences in the risk of ATE and VTE.
2.3.2. Metastatic Colorectal Cancer (mCRC)
In a phase II study 14Y-IE-JCDB, Ramucizumab plus FOLFOX failed to show any improvement in OS and PFS in mCRC patients with progressive disease after irinotecan- based therapy [54]. However, in a phase III study, RAISE performed on patients with mCRC that progressed during or after first-line therapy with Bevacizumab, oxaliplatin, and fluoropyrimidine, the combination of Ramucizumab and second-line FOLFIRI significantly improved OS (with Ra- mucizumab, 13.3 months vs without Ramucizumab, 11.7 months) and PFS (with Ramucizumab, 5.7 months vs with- out Ramucizumab, 4.5 months). On the other hand, the com- bination significantly increased the safety concerns including grade 3 neutropenia (38% vs 23%) and arterial hypertension
(11% vs 3%) [38].
A number of clinical trials have been carried out to inves- tigate the efficacy and safety of Bevacizumab as a second- line therapy on patients with metastatic colorectal cancer. Berger et al. summarized these studies and compared them with studies on the Ramucizumab, indicating that both pos- sessed similar clinical efficacy but differential safety risks[55]. Bevacizumab treatment induced more ATE (3-4% vs 0.5-1%) and VTE (8-12% vs 4%), but the risk of neutro- penia was much lower than Ramucizumab (0-1% vs 38%). The risks of other adverse events are relatively similar, such as hypertension (2-11% vs 12%), proteinuria (1-4% vs 3%),
bleeding (0-3% vs 2-3%), and gastrointestinal perforation (0-
2% vs 1-2%).
2.3.3. Gastric Cancer
A systemic analysis performed by Bai, et al. covered six Phase III clinical trials performed on gastric cancer, includ- ing three studies involved in the combination of Bevacizu- mab and chemotherapy, two studies including Ramucizumab plus chemotherapy, and one study restricted to the single treatment of Ramucizumab after first-line therapy failed [56]. The analysis showed that compared to the placebo

group, Bevacizumab treatment had no significant effect on the overall survival (OS, odds ratio=0.909, p=0.221) and progression-free survival (PFS, odds ratio=0.985, p=0.826) of patients, but Ramucizumab did improve the OS (odds ratio=0.719, p<0.001) of patients. At the same time, though the risks of hypertension, vomiting and anemia were similar after either treatment, Ramucizumab significantly increased the risk of neutropenia compared to Bevacizumab. Another meta-analysis also showed that in gastric cancer, the efficacy of Ramucizumab was better than Bevacizumab, but Bevaci- zumab was more tolerable [57]. 2.3.4. Mixed Cancer Types In a meta-analysis involving in eighty-five randomized controlled trials and covering different cancer types, the data showed that both Bevacizumab and Ramucizumab treatment significantly increased the risk of all-grade bleeding [52]. However, Bevacizumab, but not Ramucizumab, significantly increased the risk of high-grade bleeding. Arnold et al. performed a meta-analysis of Ramucizumab treatments including six randomized, double-blinded and placebo-controlled global phase III studies covering different cancer types. The data suggested that compared to the pla- cebo group, Ramucizumab treatments did not significantly increase the risks of high-grade bleeding/hemorrhage, high- grade gastrointestinal perforation, and VTE and ATE, which were different from other angiogenesis inhibitors [58]. In recent years, it has been reported that the treatments of various anti-VEGFR2 antibodies result in the occurrence of reversible grade 1-2 haemangiomas to different extents [59- 63]. For examples, in phase I studies, haemangiomas were observed in one of 37 patients (2.7%) after Ramucizumab treatments [59]; but for other two anti-VEGFR2 antibodies, alacizumab and tanibirumab, the incidence rates were 22.6% (7/31) and 61.5% (16/26), respectively [62, 63]. In contrast, there is no haemangioma risk reported after the treatments of Bevacizumab and small-molecule VEGFR inhibitors. 2.3.5. FDA Labelings As shown in the labeling, FDA’s black-box warnings for Bevacizumab include gastrointestinal perforation, wound healing complications and hemorrhage. For Ramucizumab, the only black-box warning is hemorrhage, though gastroin- testinal perforation and wound healing complications have been listed in warnings and precautions. Due to the impor- tance of angiogenesis in wound healing, Ramucizumab is required to discontinue before surgical procedures. In summary, clinical studies have shown that there lie differences in efficacy and safety profiles of Bevacizumab and Ramucizumab. For example, in gastric cancer, the effi- cacy of Ramucizumab plus chemotherapy is better than Bevacizumab in combination with chemotherapy. On the other hand, though bevacizumab plus chemotherapy has been approved by EMA for the first-line therapy of metas- tatic breast cancer, the combination of Ramucizumab and docetaxel failed to reach the endpoint in patients with unre- sectable, locally recurrent, or metastatic breast cancer [64]. Regarding the safety, it seems that compared to Bevacizu- mab, Ramucizumab treatment increases the risks of neutro- penia and haemangiomas, but decreases the incidence rates Table 2. PD-1/PD-L1 antibodies available in the market. Target Name IgG Subtype Approved Year Company PD-1 Nivolumab/Opdivo IgG4, human 2014 BMS/Ono PD-1 Pembrolizumab/Keytruda IgG4, humanized 2014 Merck&Co PD-L1 Atezolizumab/Atezo IgG1, humanized 2016 Roche PD-L1 Avelumab/Bavencio IgG1, human 2017 Merck-Serono PD-L1 Durvalumab/Imfinzi IgG1, human 2017 AstraZeneca PD-1 Cemiplimab/Libtayo IgG4, human 2018 Regeneron/Sanofi PD-1 Sintilimab/Tyvyt IgG4, human 2018 Innovent/Lilly PD-1 Toripalimab/Tuoyi IgG4, humanized 2018 TopAlliance PD-1 Camrelizumab IgG4, humanized 2019 HengRui Medicine Fig. (3). Annual sales of PD-1/PD-L1 inhibitors available in the market. Data from Cortellis Database (Clarivate Analytics). of ATE, VTE and bleeding/hemorrhage, especially high- grade bleeding/hemorrhage. In general, the adverse events listed above, including hy- pertension, proteinuria, ATE/VTE, bleeding/hemorrhage, and so on, are supposed to be associated with pharmacologi- cal mechanisms of Bevacizumab and Ramucizumab. Berger et al. have discussed the potential associations, but the de- tailed mechanisms are still not clear and further studies are needed [55]. 3. THE COMBINATION OF ANTI-VEGF/VEGFR2 ANTIBODIES WITH PD-1/PD-L1 INHIBITORS IN CLINICS 3.1. PD-1/PD-L1 Inhibitors Available on the Market In recent years, PD-1/PD-L1 inhibitors have achieved impressive success in therapy of a wide spectrum of cancer types. A huge number of articles have discussed the molecu- lar mechanisms behind the effects of PD-1/PD-L1 inhibitors. Generally, PD-L1 expressed on the surface of tumor cells binds to PD-1 located on activated T cells, B cells and macrophages, resulting in the suppression of anti-tumor im- mune responses and tumor immune evasion [65, 66]. PD-1 or PD-L1 blockade has the capability to recover the biologi- cal activity of tumor antigen-specific T cells and exert anti- tumor effects [66, 67]. In Table 2, we have listed the information of nine anti- PD-1/PD-L1 antibodies available in the market. The annual sales of these medications are shown in Fig. (3). 3.2. The Necessity of Anti-PD-1/PD-L1 Antibodies in Combination with other Anti-cancer Medications According to a follow-up report of Nivolumab in previ- ously treated NSCLC patients, five-year survival was ob- served in 16% of patients [68]. At the standard dose (3 mg/kg), five-year survival was 26%. At the same time, in PD-L1-positive patients and responders, the fiveyear survival rate was 43% and 55%, respectively. In contrast, before the occurrence of immunotherapy, the five-year survival of stan- dard care is only 5%. This study showed that immune check- point inhibitors have great advantages and result in the long- term survival of responders, but it is also suggested that only a subset of patients is responsive to and beneficial from these treatments. In order to predict the patients sensitive to PD-1/PD-L1 inhibitors, much effort has been made to discover and iden- tify effective predictive biomarkers. Currently, a panel of biomarkers has been tested in clinical studies, including PD- L1 expression, tumor-infiltrating lymphocytes (TIL), MSI/dMMR, tumor mutation burden (TMB) and so on[69]. Among them, PD-L1 expression and MSI-H/dMMR have been widely used in the clinic, and TMB has also been listed in the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of lung cancer. To build up a basis for the application of TMB in the clinic, Charmers et al. analyzed the samples collected from a hundred thousand of cancer patients covering 167 cancer types [70]. The data indicated that the median TMB in all cancer types was around 3.6 mutations/Mb (range, 0-1241 Mutations/Mb), and the cancer types with the highest TMB were skin cancer and lung cancer (For example, skin basal cell carcinoma, 47.3 mutations/Mb; skin squamous cell car- cinoma, 45.2 mutations/Mb; skin melanoma, 14.4 muta- tions/Mb; lung large cell carcinoma, 12.2 mutations/Mb), which are consistent with clinical manifestations of PD- 1/PD-L1 inhibitors. TMB was found to be significantly in- creased in patients with MSI-H, and 97% of MSI-H patients had TMB ≥ 10 mutations/Mb. Most importantly, the results showed that a comprehensive genomic profiling (CGP) assay targeting 315 genes (1.1 Mb of coding genome) could accu- rately assess TMB compared with sequencing the whole exome. As a result, CGP-like assays have been widely used in clinical studies to establish the relationship between TMB and responsiveness to PD-1/PD-L1 inhibitors. Though some promising data have been released from the application of TMB in the prediction of responders, IHC staining of PD-L1 expression is still most widely used in clinics and there are some commercial and validated detec- tion kits available in the market [67, 71, 72]. However, due to the differences in test articles, assay kits, detection anti- bodies and cancer types, there are no unified stratification criteria for PD-L1 expression identified for patient selection, therefore, a case-by-case principle has been followed in clin- ics. For example, in different clinical studies involved in various PD-1/PD-L1 inhibitors and cancer types, different cutoff values of tumor proportion score (TPS) of PD-L1 ex- pression were used for patient selection, including 1%, 5%, 25%, 50%, and so on [73-77]. Discovery and validation of predictive biomarkers are helpful for identification of responders, but have no impact on non-responders. In order to extend the beneficial group of PD-1/PD-L1 inhibitors, a huge number of clinical trials are ongoing to test the efficacy of PD-1/PD-L1 in combination with other anti-cancer medications including other immune checkpoint inhibitors/immune-regulators, chemotherapy, angiogenesis inhibitors, bi-specific antibodies, chimeric anti- gen receptor T cell (CAR-T)/T cell receptor T cell (TCR-T), and so on [78-80]. In recent years, some of the combinations have shown higher response rates and improved efficacy, compared to non-combination groups. As a result, these combination therapies have been approved by the FDA as listed in Table 3. 3.3. Combinations of Anti-PD-1/PD-L1 Antibodies and Anti-VEGF/VEGFR2 Antibodies In addition to the combination strategies listed above, much effort has been made on the combination of anti-PD- 1/PD-L1 antibodies and VEGF/VEGFR2 antibodies. It has been well known that anti-PD-1/PD-L1 antibodies have the capability to unlock the inhibition of T cell function and re- store the specific killing of T cells. However, clinical studies have shown that TILs are absent in tumor tissues of a popu- lation of cancer patients, leading to the ineffectiveness of PD-1/PD-L1 inhibitors. Therefore, improving the infiltration of lymphocytes into tumor tissues will be helpful for enhanc- ing the efficacy of PD-1/PD-L1 inhibitors. Vessel normalization improves tumor vessel perfusion, leading to increased infiltration of lymphocytes into tumors [86]. Anti-VEGF/VEGFR antibodies have the ability to promote vascular normalization, leading to improved traf- ficking of lymphocytes and medications in tumor tissues [87, 88]. At the same time, due to the important role of VEGF/VEGFR signaling in tissue repair, the nature of VEGF/VEGFR signaling is immune-inhibitory. A number of evidence have suggested that the inhibition of this pathway has the potential to increase the infiltration of lymphocytes, promote the maturation of dendritic cell, down-regulate the induction and proliferation of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and inhibit the phenotype transition of macrophages from M1 to M2 [89- 93]. The increase in PD-L1 expression was also observed in some studies [90]. These evidence provide the theoretical basis on the combination of anti-PD-1/PD-L1 antibodies and anti-VEGF/VEGFR antibodies for cancer therapy. 3.3.1. Pre-clinical Studies Involved in the Combination of PD-1/PD-L1 Inhibitors and Anti-VEGF/VEGFR2 Antibod- ies A preclinical study performed by Terme et al. demon- strated that compared to mice not carrying tumors, VEGFR1- positive and VEGFR2-positive Tregs significantly increased in splenocytes derived from mice carrying colorectal carci- nomas[94]. However, anti-VEGFR2 antibody treatment sig- nificantly inhibited the proliferation of Tregs in splenocytes, but anti-VEGFR1 antibody treatment had no effect on Treg subsets. This study indicated that there may exist differences in the regulation of immune functions between Bevacizumab and Ramucizumab. In an autochthonous mouse model of small cell lung can- cer (SCLC), the authors reported that compared to anti- VEGF alone or anti-PD-L1 alone, combined VEGF and PD- L1 blockade displayed synergistic treatment effects as indi- cated by the improvement of progression-free survival (PFS) and overall survival (OS) [95]. At the same time, tumors relapsed 3 weeks after anti-PD-L1 treatment alone, and PD- 1/Tim-3 double-positive exhausted T-cell phenotype was determined in these mice. The addition of anti-VEGF treat- ment had the capability to abrogate the exhausted T-cell phenotype. It is known that as a T-cell exhaustion marker, the up-regulation of Tim-3 expression is associated with the failure of anti-tumor immune responses [96, 97]. Taken to- gether, Tim-3 may be a key regulator involved in improved anti-tumor effects of combined with VEGF and PD-L1 blockade. In a mouse Colon-26 cancer model, though both anti-PD-1 and anti-VEGFR2 alone treatment led to tumor growth inhibi- tion, a superior anti-tumor effect was observed in the combi- nation group [89]. Interestingly, though a tendency towards increased CD4+ T cells infiltration was seen in the combina- tion group, the combination did not have an impact on the infiltration of CD8+ T cells. In another study performed on different mouse cancer models, including a polyoma middle T oncoprotein (PyMT) mammary carcinoma model (MMTV- Table 3. PD-1/PD-L1 inhibitors-based combination therapy approved by FDA. Combinational Medications Approved Indications Ref. Pembrolizumab Inlyta First-line therapy of advanced renal-cell carcinoma [81] Pembrolizumab Pemetrexed / carboplatin First-line therapy of metastatic nonsquamous NSCLC [82] Pembrolizumab carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel First-line therapy of metastatic, squamous NSCLC [83] Nivolumab Ipilimumab First-line therapy of advanced melanoma [84] Nivolumab Ipilimumab First-line therapy of advanced renal-cell carcinoma [85] PyMT) [90], the authors showed that anti-VEGFR2 treat- ment significantly enhanced the PD-L1 expression in relaps- ing tumors by up-regulating the expression of interferon- (IFN- ). Subsequently, a better anti-tumor outcome was observed in the combination group, compared to anti- VEGFR2 alone or anti-PD-1 alone group. Further mecha- nism studies showed that anti-VEGFR2 alone and the com- bination significantly increased the number and activity of DC and CD8+ T cells in responding tumors. The data also suggested that increased infiltration of immune cells into tumors in combination group is caused by vessel normaliza- tion and HEV formation. Due to the species specificity of monoclonal antibodies and species difference between modeling animals and hu- mans, there are not many pre-clinical studies involved in the combination of PD-1/PD-L1 inhibitors and anti- VEGF/VEGFR antibodies. Some inconsistencies have been shown in the studies listed above, including the phenotypes of infiltrating immune cells. These disagreements may be caused by multiple factors such as the target difference of test articles, different animal models, and so on. Further studies should be helpful for understanding of the mecha- nisms behind the combination of anti-VEGF/VEGFR and anti-PD-1/PD-L1. 3.3.2. Clinical Studies Involved in the Combination of PD- 1/PD-L1 Inhibitors and Anti-VEGF/VEGFR2 Antibodies The ongoing clinical trials involved in the combination of Bevacizumab/Ramucizumab and PD-1/PD-L1 inhibitors are listed in Table 4. Though most of the studies are still in early-stage, encouraging efficacy has been observed in some cancer types such as lung cancer, kidney cancer and hepato- cellular cancer. 4. SUMMARY/DISCUSSION As a breakthrough of cancer therapy, PD-1/PD-L1 inhibi- tors have achieved impressive success in a wide spectrum of cancer types, with low toxicity and long-term effects. How- ever, only a subset of patients is responsive to those treat- ments. Currently, much effort has been made to discover and identify the predictive biomarkers, and some biomarkers such as PD-L1 expression, dMMR/MSI and TMB have been widely used in clinical studies. In order to extend the advantages of immunotherapy, a substantial amount of clinical studies have been initiated to investigate the clinical combination of PD-1/PD-L1 inhibi- tors with other types of anti-cancer treatments, including anti-VEGF/VEGFR antibodies bevacizumab and ramucizu- mab. Anti-VEGF/VEGFR antibodies have the capability to promote the vascular normalization, increase the infiltration of lymphocytes into tumor tissues, and decrease the amount and function of immune-inhibitory Tregs, M2 macrophages and MDSCs, thus leading to a synergistic efficacy after combination with PD-1/PD-L1 inhibitors. As listed in Table 4, the combination of anti- VEGF/VEGFR2 antibodies and PD-1/PD-L1 inhibitors has shown synergistic clinical activity in many cancer types. For example, compared to Atezolizumab alone or Sunitinib alone, the combination of Atezolizumab and Bevacizumab has shown better efficacy and improved the response rate with tolerable toxicity in kidney cancer. Also, an encourag- ing response rate (ORR, 62%) has been observed in Naïve HCC patients treated with Atezolizumab and Bevacizumab. However, though the studies on NSCLC patients suggested that the efficacy of combination was not associated with PD- L1 expression, the combinations in some studies of kidney cancer and gastric cancer did show a potential positive rela- tionship between PD-L1 expression and efficacy. These studies provide valuable clues on cancer type selection and biomarker-based stratification for further combination stud- ies. All the studies listed in Table 4 are involved in the com- bination of anti-VEGF/VEGFR antibodies and anti-PD- 1/PD-L1 antibodies. At the same time, many small-molecule VEGFR inhibitors have been tested in clinical trials for the combination with PD-1/PD-L1 inhibitors. These studies are not listed here. In a study published recently, a small- molecule VEGFR inhibitor apatinib was combined with an anti-PD-1 antibody Camrelizumab (SHR-1210)[110]. The authors firstly preconditioned the mice carrying LLC tumors with apatinib to increase the TILs and down-regulate the amount and function of immune-inhibitory cells, and then treated mice with Camrelizumab. Based on the synergistic mechanisms, the sequential administration is reasonable. At the same time, the data indicated that the efficacy of combi- nation is better at a low dose of apatinib than that at a high dose of apatinib. Whether these observations are applicable for anti-VEGF/VEGFR antibodies or other VEGFR inhibi- tors is still questionable and further studies are needed. As discussed above, there exist differences in the mo- lecular mechanisms of anti-VEGF-A antibody bevacizumab and anti-VEGFR2 antibody ramucizumab, which may be responsible for the distinction in efficacy and safety profiles between these two antibodies. Based on these observations, a difference in efficacy and safety profiles could be expected after their combination with PD-1/PD-L1 inhibitors. As shown in Table 4, Grade 3 hemorrhage occurred in only 1 Table 4. The combination of anti-VEGF/VEGFR antibodies and PD-1/PD-L1 inhibitors in clinical trials. Clinical Phase Methods and Results Ref. Lung Cancer Ia/b Patients and treatments: 27 patients with previously treated advanced NSCLC. Treated with Ramucizumab at 10 mg/kg on Day 1 with Pembrolizumab 200 mg on Day 1 q3W. PD-L1 expression and detection assay: strong, TPS≥50%; weak, TPS 1-49%; negative, TPS<1%. DAKO PD-L1 22C3 IHC pharmDx assay Characteristics of Patients: 96% had a history of smoking; 78% had adenocarcinoma and 15% had squamous-cell carcinoma Median duration of treatment at data cutoff (As of 21-Nov-2016): 7.0 months (IQR 3.0-12.4) for Ram and 8.3 months (IQR 3.3-12.4) for Pembro. Results: DCR, 85%; ORR, 30% (n=8, including PD-L1 unknown, n=1; negative, n=2; strongly positive, n=5); Median PFS was 9.7 mo (95% CI 4.6-11.5) and OS rate at 6 months was 84.9%. TRAEs, 25 (93%) patients, most commonly hypertension (26%) and asthenia (19%). Five (19%) experienced grade 3 TRAEs. No grade 4-5 TRAEs occurred. No additive toxicities. Clinical trial identification: NCT02443324 JVDF [98] Gastric Cancer Ia/b Patients and treatments: 40 patients with previously treated gastric or gastroesophageal juncture (GEJ) cancer. Cohort A (Ramucizuamb 8 mg/kg on Days 1&8, n=23) and Cohort B (Ramucizumab 10 mg/kg on Day 1, n=17), given with Pembrolizumab 200 mg on Day 1 q3W. PD-L1 expression and detection assay: positive, TPS≥1%; negative, TPS<1%. DAKO PD-L1 22C3 IHC pharmDx assay Characteristics of Patients: 48% of patients were PD-L1 positive, and 70% received study treatment as third or subsequent regimen. Median duration of treatment at data cutoff (As of 23-Jun-2016): 2.1 months and 4.1 months for Cohort A and B, respectively. Results: DCR, 45%; ORR, 7.5% (n=3, including 1 CR and 2 unconfirmed PR. PD-L1 negative, n=1; PD-L1 posi- tive, n=2). Median PFS was 2.10 months (95% CI, 1.18 to 4.04) and 2.60 months (1.38, NR) for Cohorts A and B, respectively. TRAEs, 31 (78%) patients and similar between cohorts; TRAEs in ≥10% of pts were fatigue (30%), infusion-related reaction (12.5%), decreased appetite (12.5%), pruritus (10%), maculopapular rash (10%), and hy- pertension (10%). Ten (25%) patients had grade 3-4 TRAEs, most commonly colitis (7.5%) and hypertension (7.5%). One treatment-related death occurred (pneumocystis pneumonia and pulmonary sepsis). Clinical trial information: NCT02443324. [99] Ia/b Patients and treatments: 28 patients with treatment naïve advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Ramucirumab was administered at 8 mg/kg on Days 1 & 8 with Pembrolizumab 200 mg on Day 1 q3W. PD-L1 expression and detection assay: positive, TPS≥1%; negative, TPS<1%. DAKO PD-L1 22C3 IHC pharmDx assay Characteristics of Patients: 68% of patients were PD-L1 positive. Median treatment duration at data cutoff (As of 31-July-2017): 4.3 months (IQR 2-7); Median duration of fol- low-up: 8.1 months (IQR 6-10). Results: DCR, 68%; ORR, 25% (n=7, including 6 positive and 1 negative for PD-L1). Median time to response, 2.7 months (95% CI 1.3-2.8); median duration of response, 10 months (95% CI 9.7-10.3). Median PFS, 5.3 months (95% CI 3.2-11). Median OS, not reached. TRAEs, 27 (96%) 1patients; TRAEs in ≥15% of patients were fatigue (36%), hypertension (25%) and headache (18%). Seventeen (61%) patients experienced grade 3 TRAEs, most commonly hypertension (14%), diarrhea (11%), and elevated alanine (7%) or aspartate (7%) aminotransferase. No grade 4-5 TRAEs occurred. Clinical trial information: NCT02443324. [100] Ia/b Patients and treatments: 29 patients with confirmed G/GEJ adenocarcinoma with prior progression on 1 or 2 lines of systemic therapy. Treated with 8 mg/kg Ramucirumab and 750 mg of Durvalumab, both intravenously, every 2 weeks for a 28-day cycle. PD-L1 expression and assay: high, ≥25%. SP-263 IHC assay. MSI assay: PCR Characteristics of Patients: 48% had PD-L1 ≥25%, 3.5% were MSI-high; 72% received study treatment as second line for advanced disease. Median duration of treatment at data cutoff (As of 26-May-2017): 2.5 months for Ramucizumab, 3.0 months for Durvaluamb. Results: ORR, 17%(n=5, including the only one MSI-high patient). Median PFS, 2.6 months (95% CI, 1.45 to 6.28). ORR for patients with PD-L1 ≥25%, 36%. TEAEs, 29 (100%) patients. 21 (72%) patients experienced grade 3/4 TEAEs. TRAEs, 24 (83%) patients; none resulted in treatment discontinuation. Ten (35%) patients had grade 3 TRAEs, and no grade 4 or 5. All grade TRAEs occurring in ≥10% of pts were hypertension (34%), fatigue (31%), headache (24%), diarrhea (21%), pyrexia (10%) and decreased appetite (10%). Five patients (17%) reported a seri- ous adverse event related to study treatment. Clinical trial information: NCT02572687. [101] (Table 4) contd…. Clinical Phase Methods and Results Ref. I/II Patients and treatments: 46 patients with previously treated advanced gastric adenocarcinoma. Treated with Nivolumab (3mg/kg, Q2W) and Ramucizumab (8mg/kg, Q2W). Six patients from phase 1 clinical trial and addi- tional 40 patients from phase 2 clinical trial. PD-L1 expression and detection assay: positive, TPS≥1%; negative, TPS<1%. DAKO PD-L1 22C3 IHC pharmDx assay. Characteristics of Patients: PD-L1 positive rate, 44%. Median follow-up time At data cutoff: 10.2 month. Results: DCR, 62.2%; ORR, 26.7%; 6-month PFS rate, 37.4% (90% CI 25.7-49.2%); median PFS, 2.9 months; median OS, 9.0 months. No DLT observed in 6 patients from Phase I study. Grade 3 or 4 TRAEs were hypertension (n = 2), diarrhea (n = 2), perforation at jejunum (n = 1), hemorrhage (n = 1), colitis (n = 1), pancreatitis (n = 1), liver dysfunction (n = 1), cholangitis (n = 1), hematoma (n = 1), neutropenia (n = 1) and proteinuria (n = 1). No treat- ment-related deaths. Clinical trial information: NCT02999295. [102, 103] Carci- noma of Urethral Epithe- lium Ia/b Patients and treatments: 24 patients with transitional cell carcinoma of the urothelium (bladder, urethra, or renal pelvis) with prior progression on platinum-based systemic therapy. Treated with Ramucirumab at 10 mg/kg on Day 1 with Pembrolizumab 200 mg on Day 1 q3W. PD-L1 expression and detection assay: positive, TPS≥1%; negative, TPS<1%. DAKO PD-L1 22C3 IHC pharmDx assay. Characteristics of Patients: 50% of patients with PD-L1 expression ≥1, 67% received study treatment as third or subsequent regimen. Median duration of treatment at data cutoff (As of 23-Jun-2016): 2.14 months for Ramucizumab, 2.37 months for Pembrolizumab. Results: ORR, 8% (n=2); DCR: 50% (n=12); PR, 8% (n=2, both with PD-L1 positive); SD, 42% (n=10); PD, 42% (n=10); no evaluable for response at the time of analysis, 8% (n=2). Median duration of response, not reached (>2.92 mo). Median PFS was 1.87 months (95% CI, 1.28 to 3.38). All grades TRAEs, 13 (54%) patients; TRAEs occurring in ≥10% of patients were fatigue (21%), nausea (17%), pyrexia (13%), elevated alanine aminotransferase (13%) and elevated aspartate aminotransferase (13%). Three (13%) patients had grade 3 TRAEs (hypertension, colitis, pulmonary embolism; n=1 each). No grade 4 or 5 TRAEs occurred.
Clinical trial information: NCT02443324.

[104]

Biliary Tract Cancer

I Patients and treatments: 26 patients with previously treated advanced or metastaticbiliary tract cancer. Ramuci- rumab 8 mg/kg was administered intravenously on days 1 and 8 with intravenous Pembrolizumab 200 mg on day 1 Q3W.
PD-L1 expression and detection assay: positive, TPS≥1%; negative, TPS<1%. DAKO PD-L1 22C3 IHC pharmDx assay. Characteristics of Patients: PD-L1 positive, 46.2% (n=12); PD-L1 negative, 46.2% (n=12); unknown, 7.7% (n=2). Median duration of treatment At data cutoff: 9 weeks (6-16.6) for Ram, 9.3 weeks (6-18) for Pembro. Median number of cycles: 3 (2-6). Results: ORR, 3.8% (n=1, PD-L1 positive); DCR, 38.5% (n=10); PR, 3.8% (n=1); SD, 34.6% (n=9); PD, 50% (n=13); not evaluable, 11.5% (n=3). Time to response, 2.7 months; Duration of response, 6.0 months; Median dura- tion of SD, 3.9 months (95% CI, 2.2-9.8). Median PFS, 1.64 months (95% CI, 1.38-2.76); 3-month PFS rate, 27%; 6-month PFS rate, 18%. Median OS, 6.44 months (95% CI, 4.17-13.27); 6-month OS rate, 61.8%; 12-month rate, 30%. Most frequently reported TRAEs (any grade) were fatigue, hypertension, nausea, diarrhea, and hypothyroid- ism. Grade 3 TRAEs, 34.6% (n=9), hypertension is most frequently reported; Grade 4 TRAEs, 3.8% (n=1, neutro- penia). One patient discontinued treatment due to treatment-related elevation of transaminases. No treatment-related deaths. Clinical trial information: NCT02443324. [105] Kidney cancer II Patients and treatments: 305 patients with untreated metastatic renal cell carcinoma (mRCC). Sunitinib, 50 mg (4 wk on, 2 wk off), n=101; Atezolizumab, 1200 mg, IV, q3w, n=103; Atezolizumab 1200 mg IV + Bevacizumab 15 mg/kg q3w, n=101. Crossover to atezolizumab + Bevacizumab after disease progression was allowed for patients receiving atezolizumab or sunitinib. PD-L1 expression and detection assay: positive, TPS≥1%; negative, TPS<1%. SP-142 IHC assay Characteristics of Patients: Sunitinib arm, PD-L1 positive, 59% (n=60); Atezolizumab arm, PD-L1 positive, 52% (n=54); Atezolizuamab plus Bevacizumab arm, PD-L1 positive, 50% (n=50). Median survival follow up at data cutoff: 20.7 months. Results: Median PFS (months): Atezo+Bev, 11.7 (95% CI, 8.4, 17.3); Atezo, 6.1 (5.4, 13.6); Sun, 8.4 (7.0, 14.0). Median PFS in PD-L1 positive patients (months): Atezo+Bev, 14.7 (95% CI, 8.2, 25.1); Atezo, 5.5 (3.0, 13.9); Sun, 7.8 (3.8, 10.8). 12-month PFS: Atezo+Bev, 50%; Atezo, 41%; Sun, 42%. 12-month PFS in PD-L1 positive patients: Atezo+Bev, 52%; Atezo, 37%; Sun, 34%. HR: Atezo+Bev vs Sun, 1.00 (95% CI, 0.69, 1.45), p=0.982; Atezo vs Sun, 1.19 (0.82, 1.71), p=0.358. HR in PD-L1 positive patients: Atezo+Bev vs Sun, 0.64 (95% CI, 0.38, 1.08), p=0.095; Atezo vs Sun, 1.03 (0.63, 1.67), p=0.917. ORR: Atezo+Bev, 32%, n=32; Atezo, 25%, n=26; Sun, 29%, n=29. ORR in PD-L1 positive patients: Atezo+Bev, 46%, n=23; Atezo, 28%, n=15; Sun, 27%, n=16. Grade 3-4 TRAEs were seen in 40%, 16% and 57% of patients in the atezo + bev, atezo and sun arms, respectively. AEs leading to death occurred in 3%, 2% and 2% of patients, respectively. Clinical trial information: NCT01984242. [106] (Table 4) contd…. Clinical Phase Methods and Results Ref. III Patients and treatments: 915 patients with untreated Metastatic Renal Cell Carcinoma (mRCC). Atezolizumab 1200mg IV q 3 weeks + Bevacizumab 15 mg/kg IV q3w, n=454; sunitinib 50mg PO daily 4 week on/2week off, n=461. PD-L1 expression and detection assay: positive, TPS≥1%; negative, TPS<1%. SP-142 IHC assay. Characteristics of Patients: PD-L1 positive: atezolizumab+Bevacizumab arm, 39.2% (n=178); sunitinib arm, 39.9% (n=184). Median survival follow-up At data cutoff: 15 months. Results: Median PFS (months): Atezo+Bev, 11.2 (95% CI, 9.6, 13.3); Sun, 8.4 (7.5, 9.7). Median PFS in PD-L1 positive patients (months): Atezo+Bev, 11.2 (95% CI, 8.9, 15); Sun, 7.7 (6.8, 9.7). ORR: Atezo+Bev, 37%; Sun, 33%. ORR in PD-L1 positive patients: Atezo+Bev, 43%; Sun, 35%. Duration of response (months): Atezo+Bev, 16.6; Sun, 14.2. Duration of response in PD-L1 positive patients (months): Atezo+Bev, not estimable; Sun, 12.9. PFS HR: Atezo+Bev vs Sun, 0.83 (95% CI, 0.7, 0.97), p=0.0219; PFS HR in PD-L1 positive patients: Atezo+Bev vs Sun, 0.74 (95% CI, 0.57, 0.96), p=0.0217. TRAEs: 40% of atezo + bev–treated patients and 54% of sun-treated patients had Grade 3-4 TRAEs; 12% and 8% of TRAEs led to discontinuation, respectively. Clinical trial information: NCT02420821. [107] Hepato- cellular Carci- noma Ib Patients and treatments: 26 Patients with unresectable or metastatic HCC who were naive to systemic Treatment. Treated with Atezolizumab(1200 mg) + Bevacizumab (15 mg/kg) IV q3w PD-L1 expression and detection assay: not reported At data cutoff (as of 24-Oct-2017): 21 efficacy-evaluable patients. minimum follow-up, 16 weeks; median survival follow-up, 8.3 months. Results: ORR: 62% (n=13), regardless of HCC etiology, region (Asia or US), baseline a-fetoprotein levels (≥ or < 400 ng/mL) or extrahepatic spread of tumor. Median PFS, DOR, TTP, OS, not reached. 26 patients evaluable for safety. All-grade TRAEs, 81% (n=21). Grade 3-4 TRAEs, 35% (n=9), most commonly hypertension (19%, n = 5). No grade 5 AEs were observed. Two patients (8%) experienced 3 Treatment-related grade 3 serious AEs (autoim- mune encephalitis, mental status change and intra-abdominal hemorrhage). Immune-related AEs requiring corticos- teroid Treatment occurred in 3 patients (12%). Clinical trial information: NCT02715531. [108] Glioblas- toma II Patients and treatments: 6 patients with recurrent glioblastoma (rGBM). Pembrolizumab 200 mg Q3W and Bevacizumab 10 mg/kg Q2W. If dose level 1 exceeded maximum tolerated dose (MTD), Pembrolizumab interval would be extended to 4 or 6 weeks. PD-L1 expression and detection assay: not reported. Characteristics of Patients: first recurrence, n=2; second recurrence, n=4. Median duration at data cutoff: 3 months (range 1-9.3). Results: PR, n=1; SD, n=2; PD, n=3. Median OS, 6.8 months. All patients discontinued study therapy due to PD. Two patients remain alive (327 and 328 days) while 4 have died. The most common AEs that were at least probably related to study therapy were fatigue (grade 2, n = 2; grade 1, n = 2) and hypertension (grade 3, n = 2; grade 1, n = 1). No patient experienced a DLT and none required dose modification, interruption or discontinuation due to toxic- ity. Clinical trial information: NCT02337491. [109] Abbreviations: AE, adverse event; CR, complete response; DCR, disease control rate; DLT, dose limiting toxicity; HR, hazard ratio; MSI, microsatellite instability; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression free survival; PR, partial response; SD, stable disease; TEAE, treatment emergent adverse event; TPS, tumor proportion score; TRAE, treatment-related adverse event; TTP: time to progression. gastric cancer patient (1/46) after treatment with Nivolumab plus Ramuciumab but observed in 3 HCC patients (3/26) treated with Atezolizumab plus Bevacizumab. However, since most of the combination studies are still in the early clinical stage, currently, not enough data are available for detailed evaluation. Further studies and long-term observa- tions will be helpful for the comparison of the combination with Bevacizumab or Ramucizumab. CONCLUSION As anti-angiogenesis agents, anti-VEGF/VEGFR anti- bodies bevacizumab and ramucizumab have been widely used in the clinic for cancer therapy. However, the difference in target recognization between these two agents leads to the variation in efficacy, safety profiles and approved indica- tions. As shown above, Ramucizumab plus chemotherapy has been approved for the therapy of mCRC patients resis- tant to Bevacizumab plus chemotherapy. Since both bevaci- zumab and ramucizumab have been approved for NSCLC and mCRC, the differences between these two drugs as summarized above will be useful for clinicians to make a better decision on drug selection according to patients’ con- ditions. Along with the rapid development of cancer immuno- therapy, anti-PD-1/PD-L1 antibodies have become a type of breakthrough tool for cancer therapy. Due to the role of VEGF/VEGFR signaling in immunosuppression, a number of clinical trials have been attempted to test whether the ad- dition of VEGF/VEGFR inhibitors could improve the anti- tumor effects of PD-1/PD-L1 inhibitors. On renal cancer and HCC, impressive anti-tumor effects of combination therapy have been observed. At the same time, it looks like that PD- L1 expression status still matters in combination therapy. This fact implicates that though simultaneous blockade of two pathways is helpful for expanding responders responsive to PD-1/PD-L1 inhibitors, we still need to look for another strategy to treat non-responders. Since the understanding of the interplay between VEGF/VEGFR and PD-1/PD-L1 sig- naling pathways is still poor, further studies will tell us more and contribute to the design of strategy used for the treat- ment of non-responders.

AUTHORS’ CONTRIBUTIONS
FG was involved in writing of the manuscript. FG and CY were involved in the conception of the review. Tables and Figures were contributed by FG. Careful revision of the manuscript was performed by FG and CY. All authors read and approved the submitted manuscript.

LIST OF ABBREVIATIONS
AE = Adverse Event
ATE = Arterial Thromboembolism CR = Complete Response
DCR = Disease Control Rate DLT = Dose Limiting Toxicity HR = Hazard Ratio
MDSC = Myeloid-derived Suppressor Cell

FUNDING
None.

CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS
The authors would like to thank Dr. Jin-hua Wang (Insti- tute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China) for his useful discussion and review of the manuscript.

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