Cancer Chemotherapy and Pharmacology

, Volume 72, Issue 1, pp 1–12

Anti-vascular endothelial growth factor therapy in the era of personalized medicine

Authors

  • Luis R. Féliz
    • Phase I Clinical Trials Program, Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer Center
    • Phase I Clinical Trials Program, Department of Investigational Cancer TherapeuticsThe University of Texas MD Anderson Cancer Center
Review Article

DOI: 10.1007/s00280-013-2124-y

Cite this article as:
Féliz, L.R. & Tsimberidou, A.M. Cancer Chemother Pharmacol (2013) 72: 1. doi:10.1007/s00280-013-2124-y

Abstract

Purpose

To review the role of anti-vascular endothelial growth factor (anti-VEGF) therapies in the personalized medicine era.

Methods

We searched PubMed for prospective clinical trials published through October 2012 of anti-VEGF agents approved by the U.S. Food and Drug Administration or the European Medicines Agency.

Results

The use of anti-VEGF drugs as single agents or in combination with other targeted or cytotoxic agents was associated with improved response rates and progression-free survival. Anti-VEGF therapy exerts its action by blocking tumor vessel formation and, thus, proliferation. Some investigators demonstrated modest to no improvement in overall survival, although the maintenance of anti-VEGF therapy beyond progression was shown to result in longer overall survival. The use of anti-VEGF therapy was associated with adverse events (i.e., thromboembolism, hemorrhage, myocardial infarction, and hypertension) and transformation to a more invasive phenotype.

Conclusions

The development of multikinase targeting agents that include anti-VEGF properties warrants further investigation. The role of anti-VEGF therapy is evolving in the era of personalized medicine, and its use needs to be reassessed in tumor types with effective FDA-approved targeted agents, especially in light of its relatively high cost.

Keywords

Vascular endothelial growth factorAngiogenesisPersonalized medicineTargeted therapy

Introduction

Angiogenesis is a very complex and highly regulated process by which tumors larger than 1 mm are thought to develop new vasculature [13]. This constitutes an essential feature of cancer, considering that in order for cancer cells to proliferate, a continuous supply of oxygen is needed [13]. Without neovascularization, tumor growth is arrested [4].

The mechanisms through which tumors acquire neovascularity are (a) endothelial “sprouting,” wherein normal luminal endothelial cells migrate through the basement membrane into the underlying extracellular matrix and to the tumor, developing a morphology that resembles plant sprouts; (b) co-option of pre-existing vasculature, wherein tumor cells grow around blood vessels; (c) vasculogenic mimicry, wherein aggressive tumor cells develop microvascular channels; and (d) tumor neovascularization per se, wherein the release of proangiogenic factors, such as VEGF, fibroblast growth factor, and platelet-derived growth factor (PDGF), by endothelial, stromal, and tumor cells, causes endothelial activation (also known as the “angiogenic switch” [5]), vessel growth, and tumor expansion [610].

The VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor 1 and 2) and their corresponding VEGF tyrosine kinase receptors (VEGFR-1, VEGFR-2, and VEGFR-3) have emerged as promising targets because they have an important role in angiogenesis and in the growth of tumors. This is especially true of serum VEGF-A, the levels of which are higher in tumor tissue than in normal tissue, specifically in cancers of the breast, lung, colon, uterus, and ovary, which has been associated with poor prognosis [1115]. When VEGF-A binds to its receptor (VEGFR-2 and less specifically to VEGFR1), it activates a signaling cascade mediated by MAP kinase and PI3 K/Akt/mTOR that results in the development of angiogenesis, increased vascular permeability, and lymphangiogenesis [16, 17].

The idea that blocking angiogenesis could be used as a therapeutic strategy in cancer biology was initially suggested in 1971 [4]; since then, several agents targeting angiogenesis have been approved and more are being extensively investigated as anticancer therapies.

To date, the United States Food and Drug Administration (FDA) has approved eight agents for anti-VEGF therapy: bevacizumab [Avastin® (Genentech, San Francisco, CA)], sunitinib [Sutent® (Pfizer, Inc.)], sorafenib [Nexavar® (Bayer Pharmaceuticals Corporation and Onyx Pharmaceuticals, Inc.)], ziv-aflibercept [Zaltrap® (Sanofi U.S., Inc.)], regorafenib [Stivarga® (Bayer HealthCare Pharmaceuticals, Inc.)], vandetanib [Caprelsa® (AstraZeneca Pharmaceuticals LP)], axitinib [Inlyta® (Pfizer, Inc.)], and pazopanib [Votrient® (GlaxoSmithKline)] (Table 1).
Table 1

Selected anti-VEGF drugs and their therapeutic targets

Angiogenesis inhibitors

Therapeutic targets

Monoclonal antibody

 

 Bevacizumab [18]

All VEGF isoforms

Soluble receptor

 

 Aflibercept (VEGF Trap) [69]

VEGFA-B and PIGF

Small molecule tyrosine kinase inhibitors

 

 Axitinib [67]

VEGFR 1-3

 Pazopanib [62]

VEGFR 1-3, PDGFR-α and -β, FGFR-1 and -3, c-Kit, ltk, Lck, and c-Fms

 Regorafenib [71]

RET, VEGFR 1-3, c-Kit, PDGFR-α and -β, FGFR 1-2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, SAPK2, PTK5, and Abl

 Sorafenib [57]

CRAF, BRAF, VEGFR 2-3, PDGFR-β, FLT-3, c-Kit, and p38-alpha

 Sunitinib [52]

VEGFR 1-3, c-Kit, PDGFR-α and -β, RET, CSF-1R, and FLT3

 Vandetanib [65]

EGFR, VEGFR, RET, BRK, TIE2, EPH, and Src

Abl Abelson murine leukemia viral oncogene; BRK protein tyrosine kinase 6, c-Abl c-abl oncogene 1 receptor tyrosine kinase, c-Fms transmembrane glycoprotein receptor tyrosine kinase, c-Kit stem cell factor receptor, CSF-1R colony-stimulating factor-1 receptor, c-Src v-src sarcoma viral oncogene homolog, DDR2 discoidin domain receptor 2, EGFR epidermal growth factor receptor, Eph2A ephrin receptor 2A, FGFR fibroblast growth factor receptor, FLT3 fetal liver tyrosine kinase receptor 3, Lck leukocyte-specific protein tyrosine kinase, ltk interleukin-2 receptor inducible T cell kinase, PDGFR platelet-derived growth factor receptor, PIGF placental growth factor, PTK5 protein tyrosine kinase 5, Raf-1 v-raf-1 murine leukemia viral oncogene homolog 1, RET rearranged during transfection, SAPK2 stress-activated protein kinase 2, TIE2 tyrosine kinase with immunoglobulin-like and epidermal growth factor–like domains 2, Trk2A transforming tyrosine kinase protein 2A, VEGF vascular endothelial growth factor, VEGFR 13 vascular endothelial growth factor receptor 1–3

This review focuses on the role of these approved agents in cancer therapy and provides perspective on the use of anti-VEGF therapy in the era of personalized medicine.

Methods

We searched the PubMed database for prospective and retrospective clinical trials of FDA-approved anti-VEGF agents published through October 2012, reviewing response, survival and adverse events data. Other studies regarding mechanism of action of anti-VEGF therapies and preclinical studies were also reviewed.

Results

FDA-approved anti-VEGF drugs

Bevacizumab

Bevacizumab is a recombinant humanized monoclonal anti-VEGF antibody composed of a human immunoglobulin G1 platform upon which the six complementarity-determining regions of the murine monoclonal antibody (mAb) A4.6.1 are engrafted (93 % human/7 % murine sequences) [18, 19]. It binds to all biologically active isoforms of VEGF-A and neutralizes their activity by blocking the binding of VEGF to its receptors VEGFR 1 and 2 [18].

Bevacizumab was evaluated in phase II and III studies in combination with standard chemotherapy in patients with metastatic colorectal cancer (mCRC) [20, 21], metastatic breast cancer (mBC) [22], non-small cell lung cancer (NSCLC) [23, 24], recurrent glioblastoma (rGBM) [25, 26], and metastatic renal cell carcinoma (mRCC) [27]. In all of these studies, bevacizumab treatment resulted in improved OS and/or PFS compared to standard cytotoxic chemotherapy. These randomized trials led to this drug becoming the first FDA-approved anti-VEGF therapy in the United States for mCRC [21] in 2004, NSCLC [23] in 2006, and rGBM [25, 26] and mRCC [27] in 2009.

Bevacizumab received the FDA’s accelerated approval in February 2008 for the treatment for mBC, based on results of the E2100 study [28], which showed an improvement in PFS compared to paclitaxel alone when bevacizumab was combined with paclitaxel for first-line treatment, with no improvement in OS. However, in November 2011, that accelerated approval was revoked because two additional clinical trials, AVADO and RIBBON-1 [29, 30], revealed only a small effect of bevacizumab on tumor growth, without evidence of benefit in OS and with worsened quality of life and more grade 3–4 toxicities, compared to standard treatment.

Despite these results, bevacizumab, in combination with paclitaxel or capecitabine, is still approved in Europe for first-line treatment of mBC in patients for whom treatment with a taxane or anthracycline is not considered appropriate.

In ovarian cancer, bevacizumab was approved by the European Medicines Agency (EMA) on the basis of the results of two randomized clinical trials [31, 32] that showed improvement in PFS compared to standard treatment with carboplatin and paclitaxel, but minimum to no difference in OS. Because of this lack of benefit in OS, the manufacturer did not seek the approval of the FDA in the United States.

At present, bevacizumab is approved for the treatment for four cancers in the United States (mCRC, mRCC, NSCLC, and rGBM) and five cancers in Europe (mCRC, mRCC, NSCLC, mBC, and advanced ovarian cancer).

Bevacizumab and colorectal cancer (CRC)

Because of its modest responses, bevacizumab is not used alone in CRC but is used in combination with all the basic chemotherapeutic regimens [33]. Also, it is only used in the metastatic setting [34], without anti-epidermal growth factor receptor (EGFR) agents [35, 36], as studies have demonstrated no benefit when anti-VEGF agents are combined with anti-EGFR agents. In fact, this combination may be associated with poorer survival in CRC.

A pivotal phase III trial compared irinotecan plus weekly bolus of 5-fluorouracil (5-FU)/leucovorin (IFL) plus bevacizumab versus IFL alone; the addition of bevacizumab resulted in no serious adverse events and superior overall survival [20]. Simultaneously, the ECOG-3200 trial [33] evaluated the use of bevacizumab in combination with the FOLFOX-4 regimen (oxaliplatin and infused 5-FU/leucovorin) in the second-line setting for patients who were naïve to bevacizumab treatment and for whom irinotecan and fluorouracil had failed. OS, PFS, and objective response rates were higher for FOLFOX-4 plus bevacizumab than for FOLFOX-4 alone.

This trial was the first to provide safety data for the combination of bevacizumab and FOLFOX; therefore, this regimen became highly acceptable as a first-line option in the United States. Subsequently, the NO16966 trial [37] randomly assigned chemotherapy- and bevacizumab-naïve patients (n = 1,400) to oxaliplatin-based regimens [FOLFOX-4 or capecitabine plus oxaliplatin (XELOX)] and then to either placebo or bevacizumab (5 mg/kg every 2 weeks for FOLFOX-4 and 7.5 mg/kg every 3 weeks for XELOX). There was a statistically significant PFS advantage with the addition of bevacizumab, but the OS was not statistically different between the two groups.

Bevacizumab has been shown to improve survival in patients with mCRC, as a first- or second-line therapy, and it works with irinotecan- and oxaliplatin-based therapy, as well as with fluorouracil-based therapy for patients who are not able to receive irinotecan or oxaliplatin.

Bevacizumab and NSCLC

Bevacizumab is FDA approved for the treatment for locally advanced, unresectable, recurrent or metastatic non-squamous non-small cell lung cancer as a first-line therapy in combination with carboplatin and paclitaxel.

A randomized phase II study demonstrated that bevacizumab was active when combined with carboplatin and paclitaxel [23] and suggested an improvement in PFS in patients with NSCLC; however, central squamous cell carcinomas tended to form cavitation, and fatal hemoptysis developed in 4 of 6 patients. Those results led to the design of a pivotal phase III E4599 open-label, multicenter, randomized trial (n = 878) [24] in which chemotherapy-naïve patients with locally advanced, metastatic, or recurrent non-squamous NSCLC were randomized to treatment with carboplatin, paclitaxel, and bevacizumab vs. carboplatin and paclitaxel alone. This study excluded patients with squamous cell histology, significant hemoptysis, brain metastases, ECOG performance status >1, or inadequate organ function. The results showed that OS was higher in the bevacizumab arm.

Bevacizumab and renal cell carcinoma (RCC)

Hypervascular histology is characteristic of RCC because of the large proportion of cases in which the von Hippel Lindau (VHL) gene is lost in this type of cancer. VHL is a tumor-suppressor gene whose inactivation contributes to tumor development, and in up to 97 % of RCC tumors, one VHL allele has been lost, with additional point mutations or transcriptional hypermethylation of the remaining allele in up to 60 % of cases [3840].

When VHL is lost, the gene product that regulates the degradation of hypoxia-inducible factor-alpha (HIF-α) does not develop. Therefore, HIF-α accumulates and binds to other HIF-α, forming a transcriptional complex that upregulates the expression of VEGF and PDGF, which bind to endothelial cells and pericytes, promoting cell migration, proliferation, and survival [3843].

Bevacizumab in combination with interferon alpha in previously untreated mRCC patients, compared with interferon alpha alone, has been studied in two multicenter, randomized phase III trials (AVOREN trial [n = 649] [44] and CALGB 90206 trial [n = 732] [45]). PFS (primary endpoint) was higher in the bevacizumab arm in both trials, which led to approval by the FDA in 2009 of bevacizumab for patients with previously untreated mRCC. Neither trial showed an improvement in OS (secondary endpoint).

Bevacizumab and rGBM

Glioblastoma multiforme (GBM) is the most common form of malignant glial tumor and has the worst prognosis. The median survival duration is 8–15 months from diagnosis [46]. Standard treatment consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide.

When GBM recurs (median time to recurrence after standard therapy is 6.9 months [46]), the median survival duration is only 3–9 months [47]. In this setting, various treatments, such as radiotherapy, chemotherapy, or biologic or experimental therapies, are employed, resulting in short-term responses [48, 49].

Bevacizumab was studied in GBM because this tumor is highly vascular [50] and has high levels of VEGF [51]. It received accelerated approval by the FDA in 2009, as a single agent for the treatment for recurrent disease, on the basis of the results of a randomized, non-comparative, phase II trial (n = 167), wherein patients received bevacizumab ± irinotecan [25]. The estimated PFS rate at 6 months was 42.6 % (97.5 % CI 29.6–55.5 %) with bevacizumab alone and 50.3 % (97.5 % CI 36.8–63.9 %) with bevacizumab plus irinotecan, which significantly surpassed the historical 15 % rate for salvage chemotherapy and irinotecan-only therapy.

Even though it was approved in the United States on the basis of this phase II trial, there have been no phase III randomized trials evaluating bevacizumab in the recurrent disease setting, and there are no data indicating an improvement in disease-related symptoms or increased overall survival in this and other small phase II trials. For this reason, it has not received the approval of the EMA.

Sunitinib

Sunitinib (Sutent®) is an oral anti-VEGF small molecule tyrosine kinase inhibitor (TKI) that acts on the receptors for VEGF and on several other signaling pathways, leading to impaired angiogenic sprouting and impaired vessel stabilization through the inhibition of pericyte recruitment and development [52].

At present, sunitinib is approved for the treatment for gastrointestinal stromal tumor (GIST), mRCC, and pancreatic neuroendocrine tumor (pNET) in both the United States and Europe.

Sunitinib and GIST

Approved in January 2006 for the treatment for GIST, sunitinib is indicated after disease progression on or intolerance to imatinib mesylate (Gleevec®, Novartis Pharmaceuticals). In an international, randomized, double-blind, placebo-controlled trial (n = 312), sunitinib improved the primary endpoint of time to tumor progression, with additional improvement in progression-free survival, compared to placebo [53].

Sunitinib and mRCC

Sunitinib was approved in February 2007 for the treatment of mRCC on the basis of a multicenter, randomized, phase III trial (n = 750) that compared sunitinib with interferon alfa-2a in patients with previously untreated mRCC. The PFS rate, which was the primary endpoint, was higher in the sunitinib arm [54].

In an adjusted updated analysis [55], the median OS duration was significantly improved in the sunitinib arm when adjusted for the stratification factors of lactate dehydrogenase level greater than or less than 1.5 times the upper limit of normal, Eastern Cooperative Oncology Group performance status 0 or 1, and absence or presence of a prior nephrectomy [stratified log rank test: hazard ratio (HR) 0.818 (95 % CI 0.669–0.999); P = .049].

Sunitinib and pNET

Approved in May 2011, sunitinib is indicated for the treatment for progressive, well-differentiated pNET in patients with unresectable, locally advanced, or metastatic disease. PFS and objective response rate were significantly improved with sunitinib compared with placebo in a randomized, double-blind, multinational study (n = 171) [56].

Sorafenib

Sorafenib (Nexavar®) is a small molecule TKI that acts on multiple intracellular and surface kinases, specifically C-type Raf kinase (CRAF) and B-type Raf kinase (BRAF), which regulate endothelial apoptosis [57]. It also blocks other angiogenesis pathways, resulting in the interruption of VEGF and basic fibroblast growth factor–signaling cascades, thereby leading to a robust pro-apoptotic effect on endothelial cells [58] and the inhibition of tumor neovascularization.

At present, sorafenib is approved for the treatment for mRCC and unresectable hepatocellular carcinoma in both the United States and Europe.

Sorafenib and mRCC

Sorafenib was approved in December 2005 as a second-line therapy when treatment with interferon alfa or interleukin 2 had failed or could not be used. This approval was based on the results of a phase III, randomized, double-blind, placebo-controlled trial known as TARGET [59] (n = 903), in which sorafenib showed prolonged PFS but no improved OS, which was the primary endpoint. However, when post-cross-over placebo survival data were censored, the difference became significant (17.8 vs. 14.3 months, respectively; HR = 0.78; P = .029) [60].

Sorafenib and hepatocellular carcinoma (HCC)

Sorafenib was approved in November 2007 for the treatment for unresectable HCC. The approval was based on a phase III, international, multicenter, randomized, double-blind, placebo-controlled trial known as SHARP (n = 602), wherein sorafenib significantly prolonged median OS (primary endpoint) and delayed time to radiologic progression [61].

Other drugs

Pazopanib (Votrient®)

Pazopanib is another TKI of multiple angiogenesis signaling pathways [62]. It was approved in October 2009, by both the FDA and the EMA, for the treatment for advanced RCC in patients who had not received any previous treatment or who had already been treated with cytokine therapies. Its approval was based on a randomized, double-blind, placebo-controlled, phase III trial (n = 435), which showed improved PFS in treatment-naïve and cytokine-pretreated patients [63].

In April 2012, pazopanib also received approval for the treatment for advanced soft tissue sarcoma in patients who had received prior chemotherapy, when a randomized, double-blind, placebo-controlled, multicenter, phase III trial (PALETTE [n = 369]) [64] showed improved PFS, but not improved OS.

Vandetanib (Caprelsa®)

Vandetanib is a kinase inhibitor that inhibits RET and members of the EGFR, VEGF, and other angiogenesis-activating pathways [65]. This inhibitory activity leads to reduced angiogenesis, vessel permeability, tumor growth, and invasiveness.

In April 2006, vandetanib was approved by the FDA and EMA for the treatment for patients with symptomatic, unresectable, locally advanced or metastatic medullary thyroid carcinoma on the basis of the results of an international, multicenter, randomized, double-blind phase III trial (n = 331) that demonstrated improved PFS with vandetanib treatment compared to placebo [66].

Axitinib (Inlyta®)

Axitinib is a kinase inhibitor shown to block receptors 1 to 3 of VEGF, thereby reducing angiogenesis and tumor growth [67]. It was FDA and EMA approved for the treatment of advanced renal cell carcinoma after the failure of one prior systemic therapy. The approval was based on a phase III, randomized, open-label, multicenter trial [AXIS (n = 723)], wherein axitinib was demonstrated to improve PFS compared to sorafenib [68].

Aflibercept (Zaltrap®)

This drug, also known as a VEGF trap, is a fusion protein that contains portions of the extracellular domain of VEGF receptor 1–2 fused to the crystallizable fragment (Fc) portion of immunoglobulin G1. It acts as a high-affinity ligand trap to VEGFA, VEGFB, and placental growth factor, preventing them from binding to their respective receptors and, therefore, blocking their activity and thus reducing neoangiogenesis and vessel permeability [69].

Approved by the FDA in August 2012, aflibercept is indicated for the treatment of metastatic colorectal cancer in combination with irinotecan plus 5-fluorouracil and leucovorin (FOLFIRI) in patients whose disease is resistant to or has progressed following an oxaliplatin-based regimen. The approval was based on a randomized, double-blind, placebo-controlled study (n = 1,226), wherein OS was significantly improved with the addition of aflibercept to FOLFIRI compared to FOLFIRI plus placebo [70].

Regorafenib (Stivarga®)

Regorafenib is structurally similar to sorafenib, but differs by the addition of a fluorine atom, which gives regorafenib a wider spectrum of activity and more potent action, specifically by inhibiting VEGFR 1–3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2), and platelet-derived growth factor receptor (PDGFR) –β, which promote angiogenesis, vessel stabilization, and lymphatic vessel formation [71].

TIE2 is an important angiogenesis regulator expressed almost exclusively in endothelial cells, which acts via ligands angiopoetin (Ang)1, Ang2, VEGF, and fibroblast growth factor (FGF), to promote the growth of immature vessels. Ang2 is upregulated in a variety of tumor samples, mediated by the also upregulated fibroblast growth factor receptor (FGFR) [71].

Regorafenib confers a combined blockade of VEGFR, FGFR, and TIE2, exerting a more effective antiangiogenic impact than VEGF signaling alone (e.g., VEGFR 2–3 inhibited by sorafenib). This antitumor activity was demonstrated in vivo, on murine xenograft models of colorectal cancer, breast cancer, and renal cell carcinoma [71].

This preclinical antitumor activity, and subsequent clinical trials, led to the approval of regorafenib by the FDA, in September 2012, for the treatment for patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, or if they have KRAS wild-type disease, an anti-EGFR therapy. The approval was based on a small, but significant, increase in OS duration observed in a multicenter, phase III, double-blind, randomized, placebo-controlled trial (n = 760) [72].

In Table 2, we highlight selected anti-VEGF trials with their respective differences in PFS and OS.
Table 2

Selected trials of anti-VEGF therapy

Angiogenesis

inhibitors

Tumor

Study

Phase

End point

Treatment ±

anti-angiogenic

Change in PFS (months)

P

Change in OS (months)

P

Bevacizumab

mCRC

AVF2107 [20]

III

OS

IFL

4.4

.004

4.7

<.001

NO16966 [37]

III

PFS

XELOX/FOLFOX-4

1.4

.002

1.4

0.077

NSCLC

E4599 [24]

III

OS

Carboplatin/paclitaxel

1.7

<.001

2

0.003

mRCC

AVOREN [44]

III

OS

IFN

4.8

<.0001

2

0.129

CALGB 90206 [45]

III

OS

IFN-alpha

3.5

<.0001

0.9

0.069

rGBM

Friedman et al. [25]

II

PFS

Irinotecan

1.4

N/A

−0.5

N/A

mBC

E2100 [28]

III

PFS

Paclitaxel

5.9

<.001

1.5

0.16

AVADO [29]

III

PFS

Docetaxel

1.9

<.001

−1.7

0.85

RIBBON-1 [30]

III

PFS

Capecitabine/taxane/anthracycline

2.9/1.2/1.2

<.001

N/A

N/A

Ovarian

GOG-0218 [31]

III

PFS

Carboplatin/paclitaxel

3.8

<.001

0.4

0.76

 

ICON7 [32]

III

PFS

Carboplatin/paclitaxel

1.7

0.04

N/A

N/A

Sunitinib

GIST

Demetri et al. [53]

III

TTP

Placebo

18.1*

<.0001

N/A

N/A

mRCC

Motzer et al. [54]

III

PFS

IFN-alpha

6

<.001

4.6

0.051

pNET

SUN 1111 [56]

III

PFS

Placebo

5.9

<.001

N/A

Sorafenib

mRCC

TARGET [59]

III

OS

Placebo

2.7

<.01

2.6

0.146

HCC

SHARP [61]

III

OS

Placebo

N/D

N/D

2.8

<.001

Pazopanib

mRCC

Sternberg et al. [63]

III

PFS

Placebo

5

<.0001

N/A

STS

PALETTE [64]

III

PFS

Placebo

3

<.0001

1.8

0.25

Vandetanib

MTC

ZETA [66]

III

PFS

Placebo

N/A (HR 0.47)

<.001

N/A

Axitinib

mRCC

AXIS [68]

III

PFS

Sorafenib

2

<.0001

N/A

Aflibercept

mCRC

van Cutsem et al. [70]

III

OS

FOLFIRI

2.23

<.0001

1.44

0.003

Regorafenib

mCRC

CORRECT [72]

III

OS

Placebo

0.2

<.000001

1.4

0.005

FOLFIRI irinotecan, 5-fluorouracil and leucovorin, FOLFOX-4 oxaliplatin, 5-fluorouracil and leucovorin, GIST gastrointestinal stromal tumor, HCC hepatocellular carcinoma, HR hazard ratio, IFL irinotecan, 5-fluorouracil and leucovorin, IFN interferon, mBC metastatic breast cancer, mCRC metastatic colorectal cancer, mRCC metastatic renal cell carcinoma, MTC medullary thyroid carcinoma, N/A not available, N/D not done, NSCLC non-small cell lung cancer, OS overall survival, PFS progression-free survival, pNET pancreatic neuroendocrine tumor, rGBM recurrent glioblastoma multiforme, STS soft tissue sarcoma, TTP time to tumor progression, XELOX capecitabine and oxaliplatin

* Change in TTP [90]: 20.9 (P ≤ .0001)

Challenges

Adverse events

Even though the production and use of anti-VEGF therapies is increasing, there have been adverse events associated with their use (Table 3). These include cardiovascular complications such as hypertension, cardiomyopathy, and thromboembolic events that could be life threatening in patients with pre-existing cardiovascular conditions.
Table 3

Adverse events of anti-VEGF therapies

Adverse event

Frequency

Hypertension

15–60 %

Bleeding (minor)

26–60 %

Thromboembolic events

5–15 %

Proteinuria/edema

Up to 30 %

Hypothyroidism

Up to 36 %

Fatigue

5–10 %

Leukopenia/immune modulation

Unknown

Skin toxicity/hand-foot syndrome

Up to 42 % for sorafenib

Perforation

<1 %

A meta-analysis of 10 randomized clinical trials (n = 4,679) of patients treated with sorafenib, sunitinib, or pazopanib found that the incidence of fatal adverse events, including hemorrhage, myocardial infarction, and thromboembolism, related to VEGFR TKIs was 1.5 % (95 % CI 0.8–2.4 %), with a relative risk of 2.23 (95 % CI 1.12–4.44; P = .023) compared to control patients [73].

Bevacizumab and aflibercept are also known to be associated with a higher incidence of hypertension. In addition, a meta-analysis of 15 randomized clinical trials of patients treated with chemotherapy with or without bevacizumab (n = 7,956) verified that patients treated with bevacizumab had a significantly increased risk of venous thromboembolism, with a relative risk of 1.33 (95 % CI 1.13–1.56; P < .001) compared with controls [74].

Therefore, although these drugs are very promising, we should closely monitor our patients and ensure their safety, discontinuing the treatment as soon as we realize that the risks outweigh the benefits.

Resistance

Unfortunately, some patients have disease with intrinsic resistance to VEGF inhibitors and do not respond to therapy; for those who do respond, the improvement is transitory and followed by adaptive resistance [75], with the recurrent tumor having greater malignancy and invasiveness and increased risk of metastasis.

Experimental studies have shown that this adaptive resistance to VEGF blockade and the transformation to a more invasive phenotype are therapeutically induced by anti-VEGF inhibitors [76], as these drugs disrupt the tumor vasculature and pericyte coverage and diminish the oxygen supply (increased hypoxia), leading to an upregulation of extracellular proteases, latent signaling pathways (e.g., c-Met), and epithelial-to-mesenchymal transition that increases invasiveness and metastatic dissemination [77].

The same effect was observed with sunitinib and sorafenib, with even more aggressively invasive tumors being observed. These are more potent inhibitors than anti-VEGF-only drugs, as they block other receptors involved in angiogenesis. Thus, the more effective the VEGF/angiogenesis inhibition, the more pronounced the adaptive resistance.

Therefore, an important implication for the development of new anti-VEGF therapies is the realization that suppression of tumor angiogenesis can aggravate the invasion and the metastatic potential of a tumor.

Cost

New drug development is costly, owing to the increased complexity of technology, preclinical testing, clinical trials, and other regulatory requirements. As a result, the cost of cancer drugs today is several times higher than the equivalent cost 20 years ago.

For example, at our institution, treatment for a 60-kg patient with a 7.5 mg/kg dose of bevacizumab for 10 months (13 doses) costs $115,011.00 [$19.66/mg; 7.5 mg × 60 kg = 450 mg × 19.66 = $8,847.00 (per dose) × 13 doses]. Some investigators suggest that economic studies are needed to assess the cost-effectiveness of this approach for the treatment for cancer and to address whether the cost of bevacizumab is justified, as several studies have not demonstrated a survival benefit. This is particularly relevant, as the prices of cancer drugs are rising faster than the benefits observed with them, making them not cost-effective [78]. However, such studies are complicated and difficult to conduct because they are lengthy and multiple factors need to be taken into consideration in the assessment of cost and benefit. These factors include but are not limited to clinical outcomes, adverse events and their therapeutic management, and the impact of subsequent therapy on survival.

Role of anti-VEGF therapy in personalized medicine

Since imatinib was approved for the treatment for Philadelphia chromosome-positive chronic myeloid leukemia [79], researchers have undertaken the task of identifying molecular abnormalities in solid tumors that are involved in the pathophysiology of carcinogenesis, metastasis, and drug resistance, as well as developing agents targeted against those abnormalities [8083].

Even though anti-VEGF therapy does not involve directing the drug to a specific molecular abnormality, it is considered a type of targeted therapy because it is not cytotoxic and it affects downstream signaling pathways through the three VEGF receptors and two co-receptors. Unfortunately, there is no biomarker to predict which patients will benefit from anti-VEGF drugs.

A recent trial, the phase II Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study, has shed some light on this matter and demonstrated the importance of assigning treatment according to the patient’s tumor abnormalities [84]. In this study, 255 heavily pre-treated patients with metastatic NSCLC had prospective tumor biopsies and, based on their tumor markers, were adaptively randomized to receive treatment with the greatest potential to benefit based on cumulative data and highest scientific and clinical interest. The treatment options were EGFR (erlotinib), KRAS/BRAF (sorafenib), retinoid-EGFR (bexarotene and erlotinib), and VEGFR (vandetanib). Note that two of the drugs used are anti-VEGF therapy (i.e., sorafenib and vandetanib), on the basis that these drugs inhibit pathways abnormally activated when the molecular alteration is present. With this approach, the overall 8-week disease control rate (primary endpoint) in 244 patients was 46 %; median PFS was 1.9 months (95 % CI 1.8–2.4); median OS was 8.8 months (95 % CI 6.3–10.6); and the 1-year survival rate was 35 %. This was the first biopsy-mandated, biomarker-based, adaptively randomized study, and it demonstrated an improvement in the probability of a positive outcome when patients were treated according to their molecular abnormalities, which were determined via real-time prospective biopsy and not tissue samples taken at initial diagnosis [84].

Based on the encouraging results of the BATTLE study, in 2007, we initiated a personalized medicine program for patients referred to the Phase I Clinic at The University of Texas MD Anderson Cancer Center. The goal of this study was to explore whether targeted therapy based on the molecular analysis of advanced cancer would counteract the effects of specific aberrations and be associated with improved clinical outcomes [85]. In this program, we accrued 1,283 patient samples for molecular analysis, with 1,144 (89.2 %) having adequate tissue available for examination. Of those examined, 379 patients had a single aberration, 73 had two aberrations, and 8 had three aberrations. Because the majority of patients had one aberration, we focused on those and conducted a non-randomized study (n = 291), wherein we treated 175 patients with matched therapy and 116 with non-matched therapy.

The overall response rate was 27 % (CR, 2 %; PR, 25 %) in the 175 patients treated with matched therapy and 5 % (all PRs) in the 116 patients treated with non-matched therapy (P < .0001). Stable disease lasting ≥6 months was noted in 23 and 10 % of patients in each group, respectively. The median time to treatment failure in patients treated with matched-targeted therapy was 5.2 months (95 % CI 4.3–6.2) versus 2.2 months (95 % CI 2.0–2.7) in patients treated without matching (P < .0001). The median survival duration of 175 patients treated with matched therapy was 13.4 months (95 % CI 9.5–18.5), compared with 9.0 months (95 % CI 5.9–11.7) for 116 patients treated without matching (P = .017). Even though there were limitations to this study, these encouraging results confirm the need to further investigate study designs that incorporate novel technologies for molecular profiling into the process of making treatment decisions based on the genetic aberrations found [85].

Personalized medicine, that is, the implementation of advances in technology, optimizing tumor molecular profiling, and the discovery of new targeted agents, is expected to expedite drug development and to improve patient care. Until targeted agents with high antitumor activity and favorable toxicity profiles become available for every patient, the use of anti-VEGF agents is important in treating selected patients with tumor types that are known to benefit from this type of therapy.

Conclusions

As new discoveries about the biology of cancer are made, strategies for the treatment for cancer are heading toward a more “individualized” or “personalized” approach that considers the molecular abnormalities and/or driving mutations present in the tumor cells.

Inhibition of angiogenesis pathways (especially VEGF and its receptors) in most of the clinical trials was related to improvements in response rates and PFS. However, OS was significantly improved only in a very few trials in colorectal cancer and lung cancer. Subsequently, selected patients treated with anti-VEGF therapy may develop a more invasive phenotype, with augmented probability of metastasis, and may have an increased risk of severe cardiovascular adverse events. Anti-VEGF therapy is also associated with high cost.

New anti-VEGF therapeutic strategies are emerging, including targeting the Notch signaling pathway (essential for vessel sprouting and development) [86]; using vascular-disrupting agents that cause already-existent vascular structure inside a tumor to collapse, increasing hypoxia and tumor necrosis [87]; introducing short-interfering RNA (siRNA) that silences the VEGF gene [88]; or even maintaining anti-VEGF therapy beyond progression [89], which has shown promising results in clinical trials.

To optimize the use of anti-VEGF therapies, we need to develop models to help us understand the biology of patients’ tumors that respond and those that do not respond to anti-VEGF treatment, design studies that combine anti-VEGF therapies with other targeted therapies, and treat the right patients with the right targeted drugs.

Acknowledgments

The authors would like to thank Christine Eberle for assistance with manuscript submission.

Copyright information

© Springer-Verlag Berlin Heidelberg 2013