Antiangiogenic Strategies for mCRC Need Further Exploration

Special ReportsGastrointestinal Cancers (Issue 3)
Volume 3
Issue 1

The number of therapies available for the treatment of metastatic colorectal cancer (mCRC) has increased dramatically since the mid-1990s, when the only option approved by the FDA was 5-fluorouracil (5-FU).

Muhammad Wasif Saif, MD

The number of therapies available for the treatment of metastatic colorectal cancer (mCRC) has increased dramatically since the mid-1990s, when the only option approved by the US Food and Drug Administration (FDA) was 5-fluorouracil (5-FU). Recent additions to the oncologist’s toolkit include new forms of systemic chemotherapy, as well as biologic agents targeting molecular drivers such as antiepithelial growth factor receptor (EGFR) drugs and antiangiogenic therapies.

The addition of either EGFR or angiogenesis inhibitors to cytotoxic chemotherapies can improve patient outcomes. One significant advantage of antiangiogenic drugs, however, is their potential efficacy in a wide range of patients. Anti-EGFR drugs are most effective in patients whose tumors haveRASmutations, but antiangiogenic therapies can be offered to patients regardless of mutational status. Pathogenesis Even today, 5-FU has remained the foundation of all chemotherapeutic schedules. The introduction of combinations with other cytotoxic agents such as oxaliplatin and irinotecan has improved outcomes in patients, however, the median overall survival (OS) in patients with mCRC has reached a plateau of 18 to 20 months.1As research has revealed a more complete picture of the biologic pathways that drive mCRC pathology, a greater understanding has emerged of the important role that angiogenic pathways play in oncogenic processes of proliferation, migration, invasion, and survival.

Antiangiogenic Agents

A recognition of the role of angiogenic processes in mCRC pathogenesis has led, in turn, to the development of targeted therapies that directly inhibit the angiogenic vascular endothelial growth factors (VEGFs) and their receptors (VEGFR). There are multiple ligands and receptors in the family, and although the interaction between VEGF-A and VEGFR-2 is thought to be the most important in the angiogenic process, other family members contribute to the process in ways that are still being elucidated.2Differences between antiangiogenic drugs in inhibiting multiple components of the VEGF family may therefore have important clinical consequences.Two antiangiogenic drugs have been approved by the FDA for use in second-line mCRC. Bevacizumab, an antibody targeting VEGF, was approved for that indication in 2006, while ziv-aflibercept, an anti-VEGF recombinant fusion protein, was approved for second-line treatment in 2012.

Bevacizumab is a humanized monoclonal antibody that inhibits angiogenesis by binding to all isoforms of VEGF-A and preventing it from binding to VEGFR-2 and other receptors. The efficacy of combining bevacizumab with cytotoxic chemotherapy as a second-line treatment for mCRC was first demonstrated by the phase III Eastern Cooperative Oncology Group (ECOG) E3200 trial. This study demonstrated that combining bevacizumab with a chemotherapeutic regimen of fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in previously treated patients significantly improved OS and response rates (RR) compared with either chemotherapy or bevacizumab alone.3A subsequent international phase III trial showed the benefit of continuing bevacizumab in the second-line setting even in patients who had progressed on a first-line bevacizumab/chemotherapy combination.4

Ziv-aflibercept is a humanized recombinant fusion of VEGFR-1 and VEGFR-2 extracellular domains with a portion of the human IgG1 protein. It binds VEGF-A, VEGF-B, and placental growth factor (PlGF) and prevents their interaction with VEGFRs.5The combination of ziv-aflibercept with a chemotherapeutic regimen of fluorouracil, leucovorin, and irinotecan (FOLFIRI) in patients who had previously treated mCRC improved OS, RR, and progression-free survival (PFS) over chemotherapy alone.6This benefit was demonstrated even in patients who had previously received bevacizumab.

Determining which antiangiogenic drug to use for second-line treatment depends on multiple factors, including which first-line agents were administered, patient age, performance status, and comorbidities. Although bevacizumab and ziv-aflibercept differ in their specificity for VEGF-family molecules, the clinical relevance of this difference is still unclear because there have been no clinical trials directly comparing these 2 drugs. In the phase III trials that have been conducted, bevacizumab was paired with FOLFOX while ziv-aflibercept was combined with FOLFIRI, making indirect comparisons problematic as well.

Commenting on important factors for choosing between antiangiogenic drugs, Muhammad Wasif Saif, MD, of the Tufts University School of Medicine, Boston, Massachusetts, wrote, “Safety considerations are of course a key aspect of antiangiogenesis therapy, but comparative data can only be gleaned in the context of randomized controlled trials and the approved labeling of these agents when used in mCRC.”

Patient Subgroups

He added that, “Because adverse events are also impacted by the concomitant regimen and patient population studied, these factors must also be considered, and as such, no directly comparative data exist among the approved biologic agents, bevacizumab and ziv-aflibercept.”The main advantage of antiangiogenic drugs compared with anti-EGFR agents is that they do not depend onRASmutational status for efficacy. However, a disadvantage of bevacizumab and ziv-aflibercept is there are no biomarkers available that can predict a positive patient response to these treatments. A way to stratify patients who progress on first-line bevacizumab to those who are most likely to benefit from continuing treatment versus those who would benefit from a switch to ziv-aflibercept would be particularly useful.

Clinical Pearls

  • Pathogenic signaling through the angiogenic VEGF pathway contributes to oncogenic processes in mCRC including proliferation, migration, invasion, and survival.
  • In contrast to EGFR inhibitors, the efficacy of antiangiogenic drugs does not depend on the mutational status of the tumor.
  • There are 2 antiangiogenic agents currently approved for second-line therapy in mCRC: bevacizumab has narrow specificity for VEGF-2, and ziv-aflibercept more broadly inhibits VEGF signaling through VEGF-1, VEGF-2, and PlGF.
  • Safety profiles and prior treatment regimens are key considerations in choosing an antiangiogenic drug for second-line therapy, especially since trial data directly comparing the efficacy of bevacizumab and ziv-aflibercept is not available.
  • Biomarkers to identify patients likely to respond to antiangiogenic therapy are not currently available, although candidates, such as VEGF-1 and CEA expression levels, are being investigated.

“Unfortunately, no data or biomarkers are present at the moment. However, the inclusion criteria of the bevacizumab and aflibercept trials can give some clues for patient selection, such as duration on bevacizumab, prior adjuvant FOLFOX, etc,” noted Saif.


There is evidence that VEGF family members in addition to VEGF-A contribute to angiogenesis, and that some of those other factors, such as PlGF, may play a role in the development of resistance to bevacizumab.7These data, combined with the results showing a response to ziv-aflibercept in patients with mCRC who had progressed on prior bevacizumab,6suggest that agents targeting a more broad range of angiogenic targets may be more effective following patient progression, but rigorous trials are needed.Antiangiogenic agents used as second-line therapy for mCRC have been shown to improve the response rates and increase survival times in patients. These drugs do not depend on the mutational status of the tumor to be effective, as is the case with EGFR inhibitors andRASmutations. Furthermore, these drugs have been shown to have efficacy even in patients who have progressed on first-line antiangiogenic therapy with bevacizumab.

However, there is still much to be learned about these drugs.

“We need to answer many questions urgently, such as how to determine which patients and which tumors are the best candidates for these therapies. Clearly, identifying antiangiogenesis biomarkers will be an essential component of the safer, more efficient, and cost-effective application of these therapies in mCRC and other cancers. The availability of such markers would favor a more personalized approach to the treatment of mCRC, which considers both patient- and tumor-specific factors,” Saif stated.


  1. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line.J Clin Oncol. 2005;23(36):9441-9442.
  2. Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity.Nat Rev Cancer. 2008;8(8):579-591.
  3. Giantonio BJ, Catalano PJ, Meropol NJ, O’Dwyer PJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.J Clin Oncol. 2007;25(12):1539-1544.
  4. Bennouna J, Sastre J, Arnold D, Österlund P, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.Lancet Oncol. 2013;14(1):29-37.
  5. Saif MW. Anti-VEGF agents in metastatic colorectal cancer (mCRC): are they all alike?Cancer Manag Res. 2013;5:103-115.
  6. Van Cutsem E, Tabernero J, Lakomy R, Prenen H, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen.J Clin Oncol. 2012;30(28):3499-3506.
  7. Kopetz S, Hoff PM, Morris JS, Wolff RA, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance.J Clin Oncol. 2010;28(3):453-459.

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