*6.4.1 Sunitinib*

Sunitinib is an orally active multi-kinase inhibitor, which targets VEGFR1–3, PDGFRα/β, c-Kit and FLT3 [58]. Xenograft models have clearly demonstrated that as well as inhibiting new blood vessel formation, sunitinib also induces regression of newly formed immature vessels and significantly stunts tumour growth [59]. Furthermore, immunohistochemical studies performed on human tissue derived from mRCC patients treated with sunitinib have demonstrated that this agent can induce a reduction in tumour vessel density [60].

In terms of outcome in the clinical setting, sunitinib initially showed efficacy, as a single agent, for second-line therapy in single-arm, Phase II studies in mRCC [61]. Patients treated with sunitinib showed promising outcomes in terms of ORR, response duration, PFS and OS. A pivotal Phase III study was subsequently conducted comparing sunitinib with interferon-α as a first-line treatment in mRCC, which demonstrated improved OS, PFS and ORR in the sunitinib arm [62]. Based on such data, sunitinib was approved by the FDA in 2006 for the first line treatment of mRCC. Other TKI's, with similar target specificity (sorafenib, pazopanib, cabozantinib and axitinib) also have activity in mRCC. Combination with immunotherapeutic agents has also shown promising results and we are seeing the treatment algorithm for mRCC change rapidly. In a recent landmark phase 3 trial of advanced RCC in the first line setting, axitinib was combined with the PD1 inihibitor pembrolizumab and compared with sunitinib monotherapy (KEYNOTE-426). The results are promising with a significant improvement in PFS and ORR with axitinib and pembrolizumab, however more mature OS data are awaited [63].

**47**

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

*6.4.2 Regorafenib*

strate favourable outcome, both for ORR and PFS [65].

for metastatic colorectal cancer in the third line setting in 2012.

allow for crossover which likely impacted on this finding [69].

**7. Potential mechanisms of synergy between bevacizumab and** 

cytotoxic chemotherapy and the same is true for aflibercept [21].

regorafenib demonstrated survival benefit [70].

**chemotherapy**

notion amongst many clinicians.

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

The role of such TKIs has also being evaluated in mCRC. The anti-tumour and anti-angiogenic effects of sunitinib have been well documented in a series of CRC xenograft tumour models [64]. In the clinical setting, however, sunitinib employed either as a single agent or with combination chemotherapy, has failed to demon-

Recently, another TKI called regorafenib has created a lot of interest in advanced

Regorafenib also has clinical utility in gastrointestinal stromal tumours (GIST) where it is currently employed in the third line setting after imatinib and sunitinib. This indication followed from a phase 3 randomised trial, demonstrating significantly improved PFS for regorafenib compared with placebo (4.8 months vs. 0.9 months) [69]. There was no significant difference in OS, however this trial did

Regorafenib has FDA approval for second line treatment of HCC following the positive results of the phase 3 RESORCE clinical trial. Compared with placebo,

Early phase clinical trials have demonstrated that bevacizumab, in combination with systemic cytotoxic chemotherapy, can potentiate treatment efficacy when given concomitantly [71]. In fact, in most clinical settings, with the exception of ovarian cancer where bevacizumab has been observed to have single agent activity [72], bevacizumab has only shown significant activity when it is combined with

It has been well-established that the tumour vasculature is dysfunctional and leaky, resulting in enhanced interstitial fluid pressure and thus preventing effective delivery of chemotherapy [73]. Evidence from preclinical studies showed that bevacizumab can 'normalise' the chaotic tumour vasculature, achieving reduced vessel tortuosity, reduced leakiness and reduced interstitial fluid pressure. Based on these studies, it was proposed that bevacizumab works in combination with chemotherapy to improve chemotherapy delivery [71, 73], which is now a widely accepted

However, this concept is also highly controversial, with some work even refuting the normalisation hypothesis. For example, one group demonstrated that bevacizumab persistently reduced both tumour perfusion and chemotherapy delivery when NSCLC patients were treated with bevacizumab-containing chemotherapy [74]. Therefore, other potential explanations for synergy between bevacizumab and

CRC. This agent inhibits VEGFR1-3, PDGFRα/β, KIT, RET, FGFR1 and Tie2. It is also a potent inhibitor of Raf-1 and suppresses both wild-type and V599E mutant BRAF activity *in vitro* and in mouse models [66]. Significant anti-tumour and anti-angiogenic effects in CRC xenograft models, both as a single agent and in combination with irinotecan chemotherapy have been reported [67]. In the clinical setting, the Phase III CORRECT trial demonstrated significant benefit for OS and PFS in advanced CRC patients, when it was used as a single agent compared to best supportive care, in a population who had failed previous standard therapy [68]. Based on this data, regorafenib was approved by the FDA as a multikinase inhibitor

The role of such TKIs has also being evaluated in mCRC. The anti-tumour and anti-angiogenic effects of sunitinib have been well documented in a series of CRC xenograft tumour models [64]. In the clinical setting, however, sunitinib employed either as a single agent or with combination chemotherapy, has failed to demonstrate favourable outcome, both for ORR and PFS [65].

## *6.4.2 Regorafenib*

*Current Cancer Treatment*

Aflibercept is a recombinant fusion protein that binds to VEGF-A, VEGF-B and placental growth factor (PLGF), all of which have been implicated in angiogenesis and/or the survival of newly formed blood vessels [54]. As it binds to additional pro-angiogenic targets (compared to bevacizumab which binds only VEGF-A), aflibercept may provide further anti-angiogenic effects compared to targeting VEGF-A alone. In preclinical studies, it demonstrated a broad range of anti-tumour and anti-angiogenic activity both alone and in combination with chemotherapy, which was also observed in phase I clinical trials [55]. Recently, a large randomised phase III clinical trial (VELOUR) in advanced CRC patients, receiving second line therapy, demonstrated that the addition of aflibercept to systemic chemotherapy significantly improved outcomes compared to chemotherapy alone [56]. Based on this data, aflibercept was recently approved for use in the second line setting in mCRC when given in combination with chemotherapy. Importantly, results from a subanalysis of VELOUR showed that there was no significant impact of prior exposure to bevacizumab, illustrating the benefit that it provides as a multiple angiogenic factor trap, in a setting where resistance to bevacizumab may have

Several small molecule inhibitors of VEGF receptor tyrosine kinase activity now have an established role in the treatment of certain tumour types, including mRCC, HCC and advanced CRC. These small molecule inhibitors readily diffuse through the cell membrane to compete for ATP binding to the intracellular tyrosine kinase

Sunitinib is an orally active multi-kinase inhibitor, which targets VEGFR1–3, PDGFRα/β, c-Kit and FLT3 [58]. Xenograft models have clearly demonstrated that as well as inhibiting new blood vessel formation, sunitinib also induces regression of newly formed immature vessels and significantly stunts tumour growth [59]. Furthermore, immunohistochemical studies performed on human tissue derived from mRCC patients treated with sunitinib have demonstrated that this agent can

In terms of outcome in the clinical setting, sunitinib initially showed efficacy, as a single agent, for second-line therapy in single-arm, Phase II studies in mRCC [61]. Patients treated with sunitinib showed promising outcomes in terms of ORR, response duration, PFS and OS. A pivotal Phase III study was subsequently conducted comparing sunitinib with interferon-α as a first-line treatment in mRCC, which demonstrated improved OS, PFS and ORR in the sunitinib arm [62]. Based on such data, sunitinib was approved by the FDA in 2006 for the first line treatment of mRCC. Other TKI's, with similar target specificity (sorafenib, pazopanib, cabozantinib and axitinib) also have activity in mRCC. Combination with immunotherapeutic agents has also shown promising results and we are seeing the treatment algorithm for mRCC change rapidly. In a recent landmark phase 3 trial of advanced RCC in the first line setting, axitinib was combined with the PD1 inihibitor pembrolizumab and compared with sunitinib monotherapy (KEYNOTE-426). The results are promising with a significant improvement in PFS and ORR with axitinib and

**6.3 Aflibercept**

developed [57].

*6.4.1 Sunitinib*

domain of VEGF receptor 2.

**6.4 Receptor tyrosine kinase inhibitors (TKIs)**

induce a reduction in tumour vessel density [60].

pembrolizumab, however more mature OS data are awaited [63].

**46**

Recently, another TKI called regorafenib has created a lot of interest in advanced CRC. This agent inhibits VEGFR1-3, PDGFRα/β, KIT, RET, FGFR1 and Tie2. It is also a potent inhibitor of Raf-1 and suppresses both wild-type and V599E mutant BRAF activity *in vitro* and in mouse models [66]. Significant anti-tumour and anti-angiogenic effects in CRC xenograft models, both as a single agent and in combination with irinotecan chemotherapy have been reported [67]. In the clinical setting, the Phase III CORRECT trial demonstrated significant benefit for OS and PFS in advanced CRC patients, when it was used as a single agent compared to best supportive care, in a population who had failed previous standard therapy [68]. Based on this data, regorafenib was approved by the FDA as a multikinase inhibitor for metastatic colorectal cancer in the third line setting in 2012.

Regorafenib also has clinical utility in gastrointestinal stromal tumours (GIST) where it is currently employed in the third line setting after imatinib and sunitinib. This indication followed from a phase 3 randomised trial, demonstrating significantly improved PFS for regorafenib compared with placebo (4.8 months vs. 0.9 months) [69]. There was no significant difference in OS, however this trial did allow for crossover which likely impacted on this finding [69].

Regorafenib has FDA approval for second line treatment of HCC following the positive results of the phase 3 RESORCE clinical trial. Compared with placebo, regorafenib demonstrated survival benefit [70].
