*6.1.1 Bevacizumab in metastatic CRC*

Trials with bevacizumab as a single agent in metastatic colorectal cancer (mCRC) failed to demonstrate activity, but early Phase I trials demonstrated that it has the potential to be combined with many chemotherapy agents [24]. In the advanced setting, several randomised Phase II and III clinical trials clearly demonstrated that bevacizumab improves response rates (ORR), progression free survival (PFS) and overall survival (OS) in mCRC, when added to standard chemotherapy in the first line setting [25, 26], and the second line setting [27] (**Table 1**). In February 2004, the US Food and Drug Administration (FDA) approved bevacizumab for the treatment of mCRC in combination with 5-fluorouracil-based chemotherapy regimens based on a pivotal Phase III study which demonstrated significant PFS and OS survival benefit [25]. Of clinical importance, bevacizumab in combination with a fluoropyrimidine has also demonstrated efficacy in elderly patients with mCRC [26].

Despite these data, only a small proportion of patients benefit from the addition of bevacizumab, and furthermore, some studies have demonstrated only an increase in PFS, with no increase in ORR or OS (**Table 1**) [28]. Additionally, even those who respond initially to bevacizumab combined with chemotherapy will inevitably develop resistance and relapse [29].

In the setting of colorectal liver-only metastasis (CRLM), it has been well demonstrated that preoperative chemotherapy improves outcome and metastatectomy rates [30]. With this in mind, and on the basis that bevacizumab can improve ORR, several groups set out to evaluate its role in the preoperative CRLM setting. Findings from a small non-randomised controlled trial of neoadjuvant conventional chemotherapy with bevacizumab in high-risk CRLM patients alluded to an improvement of CRC liver metastasis rate to 40% [31]. Data from retrospective, inter-trial studies have also suggested that the addition of bevacizumab to chemotherapy significantly improves pathological response in CRLM compared to when chemotherapy is administered alone [32]. Subgroup post hoc analyses extracted from large randomised controlled trials of unselected patients have failed to show significant improvements in resection rates with the addition of bevacizumab [33]. Without prospective randomised trials however, it is difficult to make conclusions regarding the efficacy of chemotherapy versus chemotherapy combined with bevacizumab in the CRLM setting.

The role of continuing bevacizumab beyond first progression in advanced colorectal cancer has also been examined. The results of two non-randomised

**43**

**Table 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.89667*

*Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

observational cohort studies (BRiTE and ARIES) demonstrated a significant correlation between the use of bevacizumab beyond progression and substantial improvement in OS [34, 35]. Benefit of treatment beyond progression following first line treatment was later confirmed in a prospective randomised trial [36]. The efficacy of bevacizumab has also been evaluated in the adjuvant setting in CRC patients. Two large randomised studies compared survival between the following arms: adjuvant chemotherapy alone for 6 months versus adjuvant chemotherapy in combination with bevacizumab for 6 months (followed by bevacizumab alone for 6 months). Both studies demonstrated that at 1 year there was an improvement in PFS in the bevacizumab arm. However, no significant difference in OS was observed between treatment arms when assessed at 3 or 5 years [37, 38]. In fact, an analysis at 5 years in the AVANT study demonstrated a possible detrimental effect on survival with the addition of bevacizumab, documenting a higher number of

*Studies investigating bevacizumab in metastatic colorectal cancer in the first line.*

Bevacizumab in combination with cytotoxic chemotherapy has also shown

In advanced non-squamous non-small cell lung cancer (NSCLC), two randomised controlled phase III trials demonstrated significant benefit in PFS when bevacizumab was added to platinum-based doublet chemotherapy [39, 40], but only one study reported an increase in OS [40]. To further understand this discrepancy, a recent metaanalysis pooling data from several studies including the aforementioned two, deduced a modest but significant improvement in OS [41]. More recently in metastatic nonsquamous NSCLC, the Impower150 phase 3 clinical trial investigated treatment with

relapses and deaths due to disease progression [37].

significant clinical efficacy in other tumour types.

*6.1.2 Bevacizumab in other tumour types*

*DOI: http://dx.doi.org/10.5772/intechopen.89667 Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*


#### **Table 1.**

*Current Cancer Treatment*

**6.1 Bevacizumab**

from activating the VEGF receptor [23].

*6.1.1 Bevacizumab in metastatic CRC*

patients with mCRC [26].

inevitably develop resistance and relapse [29].

**6. The development of anti-angiogenic therapies**

Given the key role VEGF is proposed to play in tumour angiogenesis, it is unsurprising that it has become a major drug target. Various drugs designed to inhibit VEGF signalling have been developed, including VEGF neutralising antibodies (e.g. bevacizumab), novel fusion proteins which bind pro-angiogenic growth factors (e.g. aflibercept) and VEGF receptor tyrosine kinase inhibitors (e.g. sunitinib) [5, 21]. Such agents have shown promise in the treatment of several malignancies, including mCRC, metastatic renal cell carcinoma (mRCC), metastatic lung cancer, hepatocellular carcinoma (HCC) and pancreatic neuroendocrine tumours (PNET) [22].

Bevacizumab (Avastin®) is a recombinant humanised monoclonal antibody that binds to the VEGF-A isoform of human VEGF specifically and prevents the VEGF

Trials with bevacizumab as a single agent in metastatic colorectal cancer (mCRC) failed to demonstrate activity, but early Phase I trials demonstrated that it has the potential to be combined with many chemotherapy agents [24]. In the advanced setting, several randomised Phase II and III clinical trials clearly demonstrated that bevacizumab improves response rates (ORR), progression free survival (PFS) and overall survival (OS) in mCRC, when added to standard chemotherapy in the first line setting [25, 26], and the second line setting [27] (**Table 1**). In February 2004, the US Food and Drug Administration (FDA) approved bevacizumab for the treatment of mCRC in combination with 5-fluorouracil-based chemotherapy regimens based on a pivotal Phase III study which demonstrated significant PFS and OS survival benefit [25]. Of clinical importance, bevacizumab in combination with a fluoropyrimidine has also demonstrated efficacy in elderly

Despite these data, only a small proportion of patients benefit from the addition of bevacizumab, and furthermore, some studies have demonstrated only an increase in PFS, with no increase in ORR or OS (**Table 1**) [28]. Additionally, even those who respond initially to bevacizumab combined with chemotherapy will

In the setting of colorectal liver-only metastasis (CRLM), it has been well demonstrated that preoperative chemotherapy improves outcome and metastatectomy rates [30]. With this in mind, and on the basis that bevacizumab can improve ORR, several groups set out to evaluate its role in the preoperative CRLM setting. Findings from a small non-randomised controlled trial of neoadjuvant conventional chemotherapy with bevacizumab in high-risk CRLM patients alluded to an improvement of CRC liver metastasis rate to 40% [31]. Data from retrospective, inter-trial studies have also suggested that the addition of bevacizumab to chemotherapy significantly improves pathological response in CRLM compared to when chemotherapy is administered alone [32]. Subgroup post hoc analyses extracted from large randomised controlled trials of unselected patients have failed to show significant improvements in resection rates with the addition of bevacizumab [33]. Without prospective randomised trials however, it is difficult to make conclusions regarding the efficacy of chemotherapy

versus chemotherapy combined with bevacizumab in the CRLM setting.

The role of continuing bevacizumab beyond first progression in advanced colorectal cancer has also been examined. The results of two non-randomised

**42**

*Studies investigating bevacizumab in metastatic colorectal cancer in the first line.*

observational cohort studies (BRiTE and ARIES) demonstrated a significant correlation between the use of bevacizumab beyond progression and substantial improvement in OS [34, 35]. Benefit of treatment beyond progression following first line treatment was later confirmed in a prospective randomised trial [36].

The efficacy of bevacizumab has also been evaluated in the adjuvant setting in CRC patients. Two large randomised studies compared survival between the following arms: adjuvant chemotherapy alone for 6 months versus adjuvant chemotherapy in combination with bevacizumab for 6 months (followed by bevacizumab alone for 6 months). Both studies demonstrated that at 1 year there was an improvement in PFS in the bevacizumab arm. However, no significant difference in OS was observed between treatment arms when assessed at 3 or 5 years [37, 38]. In fact, an analysis at 5 years in the AVANT study demonstrated a possible detrimental effect on survival with the addition of bevacizumab, documenting a higher number of relapses and deaths due to disease progression [37].

#### *6.1.2 Bevacizumab in other tumour types*

Bevacizumab in combination with cytotoxic chemotherapy has also shown significant clinical efficacy in other tumour types.

In advanced non-squamous non-small cell lung cancer (NSCLC), two randomised controlled phase III trials demonstrated significant benefit in PFS when bevacizumab was added to platinum-based doublet chemotherapy [39, 40], but only one study reported an increase in OS [40]. To further understand this discrepancy, a recent metaanalysis pooling data from several studies including the aforementioned two, deduced a modest but significant improvement in OS [41]. More recently in metastatic nonsquamous NSCLC, the Impower150 phase 3 clinical trial investigated treatment with

#### *Current Cancer Treatment*

bevacizumab plus platinum doublet chemotherapy with or without the PDL1 inhibitor atezolizumab. Treatment with atezolizumab, bevacizumab and chemotherapy compared with bevacizumab and chemotherapy resulted in a significant improvement in PFS at 6 months (66.9% vs. 36.5%) and at 12 months (56.1% vs. 18%) [42]. In an interim analysis of OS, an improvement was again seen (**Table 2**) [42].

In advanced ovarian cancer, in the first- and second-line settings, the efficacy of bevacizumab has been assessed when added to platinum-based chemotherapy doublets. Two pivotal first line phase III studies utilising the same chemotherapy doublet (ICON7/AGO-OVAR and GOG-0218 trials) demonstrated a significant improvement in PFS [43]. An updated survival analysis failed to show a significant survival benefit [43].

Bevacizumab has been investigated in glioblastoma multiforme (GBM), in the recurrent setting following first line treatment with temozolamide and radiation therapy. In this setting bevacizumab monotherapy is ineffective, however in combination with lomustine it has resulted in improvement in PFS but not OS [44]. Bevacizumab has also been investigated in the first line setting with chemoradiation in a large randomised placebo controlled trial, but failed to improve outcomes [45].

Earlier phase III trials in RCC have demonstrated efficacy of bevacizumab in combination with sorafenib, sunitinib and interferon alpha (**Table 2**). More recently, bevacizumab has been combined with atezolizumab in metastatic RCC. A phase III randomised trial confirmed significant improvement in PFS for bevacizumab combined with atezolizumab compared with sunitinib monotherapy but mature OS data are still awaited [46].

Despite such encouraging results, bevacizumab has thus far failed to make a significant impact in several other indications, including metastatic breast cancer (mBC), melanoma, pancreatic cancer and prostate cancer. Interestingly, in breast cancer, pooled data from four large clinical trials demonstrated that it neither prolonged OS, nor delayed disease progression significantly, leading the FDA to revoke its initial approval of bevacizumab for mBC [47]. The variation in impact that bevacizumab has, not only across tumour types, but also within a single tumour type, is curious and needs to be better understood.

### **6.2 Ramucirumab**

Ramucirumab is a fully human IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2, blocking VEGF from activating the receptor [48]. Clinical efficacy and tolerability have been demonstrated in a number of preclinical studies and more recently in phase III trials. In the refractory metastatic gastric and gastro-oesophageal junction (GOJ) adenocarcinoma setting, ramucirumab significantly improved median OS compared with placebo but this only represented an absolute improvement of 1.4 months [49]. In the second line setting of advanced gastric and GOJ adenocarcinoma, the combination of ramucirumab and paclitaxel has become standard treatment based on the results of the pivotal RAINBOW trial showing significant improvement in OS compared with paclitaxel and placebo [50]. Ramucirumab has not shown benefit in the first line setting including combination with chemotherapy [51].

Ramucirumab has also been investigated in metastatic NSCLC but does not yet have an established role for this indication. After progression on first line platinum based chemotherapy, there was a small but statistically significant benefit in median OS of ramucirumab added to docetaxel [52]. Early results of the RELAY phase 3 clinical trial investigating ramucirumab in combination with erlotinib in the first

**45**

**Table 2.**

vs. 2.76 months) [53].

*DOI: http://dx.doi.org/10.5772/intechopen.89667*

*Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*

line setting of metastatic EGFR mutated NSCLC have indicated an improvement in

Ramucirumab has also been investigated in urothelial cancers. In a phase III trial of ramucirumab plus docetaxel compared with docetaxel plus placebo in patients with advanced urothelial carcinoma who had received platinum-based chemotherapy, there was a statistically significant improvement in median PFS (4.07 months

PFS however formal publication of the study findings are awaited.

*Studies investigating anti-VEGF agents in NSCLC and RCC.*

*DOI: http://dx.doi.org/10.5772/intechopen.89667 Angiogenesis and Its Role in the Tumour Microenvironment: A Target for Cancer Therapy*


#### **Table 2.**

*Current Cancer Treatment*

survival benefit [43].

outcomes [45].

**6.2 Ramucirumab**

with chemotherapy [51].

mature OS data are still awaited [46].

type, is curious and needs to be better understood.

bevacizumab plus platinum doublet chemotherapy with or without the PDL1 inhibitor atezolizumab. Treatment with atezolizumab, bevacizumab and chemotherapy compared with bevacizumab and chemotherapy resulted in a significant improvement in PFS at 6 months (66.9% vs. 36.5%) and at 12 months (56.1% vs. 18%) [42]. In an

In advanced ovarian cancer, in the first- and second-line settings, the efficacy of bevacizumab has been assessed when added to platinum-based chemotherapy doublets. Two pivotal first line phase III studies utilising the same chemotherapy doublet (ICON7/AGO-OVAR and GOG-0218 trials) demonstrated a significant improvement in PFS [43]. An updated survival analysis failed to show a significant

Bevacizumab has been investigated in glioblastoma multiforme (GBM), in the

recurrent setting following first line treatment with temozolamide and radiation therapy. In this setting bevacizumab monotherapy is ineffective, however in combination with lomustine it has resulted in improvement in PFS but not OS [44]. Bevacizumab has also been investigated in the first line setting with chemoradiation in a large randomised placebo controlled trial, but failed to improve

Earlier phase III trials in RCC have demonstrated efficacy of bevacizumab in combination with sorafenib, sunitinib and interferon alpha (**Table 2**). More recently, bevacizumab has been combined with atezolizumab in metastatic RCC. A phase III randomised trial confirmed significant improvement in PFS for bevacizumab combined with atezolizumab compared with sunitinib monotherapy but

Despite such encouraging results, bevacizumab has thus far failed to make a significant impact in several other indications, including metastatic breast cancer (mBC), melanoma, pancreatic cancer and prostate cancer. Interestingly, in breast cancer, pooled data from four large clinical trials demonstrated that it neither prolonged OS, nor delayed disease progression significantly, leading the FDA to revoke its initial approval of bevacizumab for mBC [47]. The variation in impact that bevacizumab has, not only across tumour types, but also within a single tumour

Ramucirumab is a fully human IgG1 monoclonal antibody that binds to the extracellular domain of VEGFR-2, blocking VEGF from activating the receptor [48]. Clinical efficacy and tolerability have been demonstrated in a number of preclinical studies and more recently in phase III trials. In the refractory metastatic gastric and gastro-oesophageal junction (GOJ) adenocarcinoma setting, ramucirumab significantly improved median OS compared with placebo but this only represented an absolute improvement of 1.4 months [49]. In the second line setting of advanced gastric and GOJ adenocarcinoma, the combination of ramucirumab and paclitaxel has become standard treatment based on the results of the pivotal RAINBOW trial showing significant improvement in OS compared with paclitaxel and placebo [50]. Ramucirumab has not shown benefit in the first line setting including combination

Ramucirumab has also been investigated in metastatic NSCLC but does not yet have an established role for this indication. After progression on first line platinum based chemotherapy, there was a small but statistically significant benefit in median OS of ramucirumab added to docetaxel [52]. Early results of the RELAY phase 3 clinical trial investigating ramucirumab in combination with erlotinib in the first

interim analysis of OS, an improvement was again seen (**Table 2**) [42].

**44**

*Studies investigating anti-VEGF agents in NSCLC and RCC.*

line setting of metastatic EGFR mutated NSCLC have indicated an improvement in PFS however formal publication of the study findings are awaited.

Ramucirumab has also been investigated in urothelial cancers. In a phase III trial of ramucirumab plus docetaxel compared with docetaxel plus placebo in patients with advanced urothelial carcinoma who had received platinum-based chemotherapy, there was a statistically significant improvement in median PFS (4.07 months vs. 2.76 months) [53].
