Another Angiogenesis Inhibitor Shows Benefit in Metastatic Colorectal Cancer, but Where Do We Go Next?

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Weijing Sun, MD, FACP

Translational study is required to improve cost-to-benefit ratios in choosing antiangiogenic-based combination treatment for an appropriate subpopulation of patients. Hopefully, the pending translational research of prespecified potential biomarkers from the RAISE trial (and other studies) will assist us in patient selection.

—Weijing Sun, MD, FACP

The phase III RAISE trial—reported by Tabernero and colleagues in The Lancet Oncology1 and reviewed in this issue of The ASCO Post—demonstrated that ramucirumab ­(Cyramza), a fully human IgG1 monoclonal antibody to the vascular endothelial growth factor receptor 2 (VEGFR2) extracellular domain, in combination with FOLFIRI (leucovorin, fluorouracil [5-FU], irinotecan) significantly prolonged overall survival (13.3 vs 11.7 months, hazard ratio [HR] = 0.844, 95% confidence interval [CI] = 0.730–0.976, P = .0219, difference = 1.6 months) and progression-free survival (5.7 vs 4.5 months, HR = 0.793, 95% CI = 0.697–0.903, P < .0005, difference = 1.2 months) in patients with metastatic colorectal cancer whose disease progressed during or after first-line treatment with bevacizumab (Avastin), oxaliplatin, and a fluoropyrimidine.

With the U.S. Food and Drug Administration approval of ramucirumab as second-line treatment of metastatic colorectal cancer in combination with FOLFIRI, there are now three agents—monoclonal antibodies or IgG1 Fc-based angiogenesis inhibitors (bevacizumab, ziv-aflibercept ­[Zaltrap], and ramucirumab)—that act via selective targeting of the VEGF-A/VEGFR2 pathway available for treatment of metastatic colorectal cancer as part of a second-line combination.

Three Key Studies

Three randomized phase III studies—ML18147 (continuation of bevacizumab after first progression in metastatic colorectal cancer),2 VELOUR (combination of ziv-aflibercept with FOLFIRI in previously oxaliplatin and fluoropyrimidine–treated metastatic colorectal cancer),3 and RAISE—confirmed that inhibition of tumor angiogenesis after first-line chemotherapy (including previous exposure to antiangiogenic regimen) is effective, despite differences among these studies in study design and variations in patient selection and treatment regimens.

In ML18147, all patients were treated with bevacizumab; however, about 60% of patients received an irinotecan-based regimen as their first-line therapy, and the rest received oxaliplatin-based regimens. In the VELOUR and RAISE studies, all patients were treated with oxaliplatin and fluoropyrimidine–based regimens as first-line treatment. However, only about 30% of patients had bevacizumab during their first-line therapy in the VELOUR trial.

Strengths of the RAISE study are that (1) all patients had the same second-line chemotherapy (FOLFIRI) and had previous exposure to an antiangiogenic agent (bevacizumab), and (2) the study populations were closer to the patients seen in our clinical practice who are candidates for continuing antiangiogenesis therapy after disease progression with first-line antiangiogenesis therapy, including those whose disease progressed at various times during or after first-line treatment.

From these three large randomized studies, clinical benefits of these three agents (bevacizumab, ziv-aflibercept, and ramucirumab) have been demonstrated in combination with ­FOLFIRI. Interestingly, the increments of survival benefits from three different antiangiogenic agents are almost the same (difference in median overall survival of around 1.4 to 1.6 months and difference in median progression-free survival of around 1.6 months). Stratified hazard ratios are similar in the RAISE (0.84), ML18147 (0.83), and ­VELOUR trials (0.82, in the total population and 0.86 in the subpopulation of patients who had received first-line bevacizumab). The toxicity profiles from the three agents are similar as well, with increased overall toxicities and likely antiangiogenic agent–related specific adverse events (eg, hypertension and proteinuria) in the antiangiogenesis agent arms that are all manageable with appropriate treatment. Thus, there are no major differences among these three antiangiogenic agents.

However, with the approval of ramucirumab and the results of the RAISE trial, more issues have been raised, including (1) the mechanistic differences among these three antiangiogenic agents, (2) whether colorectal cancer may develop crossover tolerability/resistance to these different agents, (3) potential opportunities to maximize the benefit from these three agents in the treatment of metastatic colorectal cancer, (4) potential predictive markers for these VEGF-A/VEGFR2 pathway inhibitors, (5) possibilities of using these antiangiogenic agents in combination with other biologic targeted agents, especially immune checkpoint inhibitors, and last but not least, (6) what are the cost-benefit ratios of all these agents?

VEGF Inhibitor Mechanisms

As we know, pathologic angiogenesis is a key component of cancer growth and a necessary process for tumor metastasis, including in colorectal cancer. The VEGF-A/VEGFR-2 pathway is thought to be the dominant promoter of angiogenesis. Targeting VEGF signaling is classified into three approaches: (1) VEGF-A ligand sequestering, such as with the monoclonal antibody bevacizumab and the IgG1 Fc-VEGF receptor construct, as with ziv-aflibercept; (2) antibody or antibody-like molecules that bind to VEGFR-2 and prevent receptor activation by VEGF-A, as with ramucirumab; and (3) low-molecular-mass tyrosine kinase inhibitors such as sunitinib, sorafenib (Nexavar), regorafenib (Stivarga), and others.

Although VEGF inhibitors are generically viewed as a class of therapeutics, each inhibitor is unique by virtue of its mode of action, interaction with a binding target, selectivity profile, and pharmacokinetic properties. Bevacizumab and ziv-aflibercept neutralize VEGF-A signaling by sequestrating the ligand and selectively blocking the VEGF signaling axis. However, efficacy may be affected by the local concentration of targeted ligand(s), which may explain the debate/controversy over appropriate bevacizumab dosage in combination with chemotherapy regimen(s). In addition, expression of VEGF-A and other ligands may increase after the loop blockade as a physiologic response to rebalance the pathway, which may partially explain the lesser benefit of ziv-aflibercept in patients with previous exposure to bevacizumab (VELOUR data).

With binding to the VEGFR-2 extracellular domain, biologic efficacy of ramucirumab may be less influenced by the local concentration of VEGF-A. On the other hand, small-molecule tyrosine kinase inhibitors (eg, sorafenib, sunitinib, and regorafenib) are not exclusively selective for VEGFR-2, with most inhibiting VEGFR-1, -2, and -3 and often other kinases (eg, PDGFR, Ras/Raf, c-kit, CSF1R, and Flt-3). It is unknown whether antiangiogenic effects could be maximized with the combination of these monoclonal antibody or IgG Fc-reconstructed agents with small-molecule tyrosine kinase inhibitors.

Predictive Markers

A limited benefit of this class of antiangiogenic agents may be partly due to the fact that no selection criteria have been used to enrich for patients who may be likely to derive a durable benefit from treatment. The identification of biomarkers of sensitivity or resistance to VEGF signaling inhibitors may potentially broaden the clinical impact of these agents and might even distinguish the clinical application of each agent.

Some preliminary studies have shown that a low VEGF(165)b:VEGF(total) ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer4 (ie, individuals with relatively high levels may not benefit from bevacizumab); low serum angiopoietin-2 (Ang-2), an inhibitory ligand of the endothelial Tie-2 receptor, may be a predictive marker5; and low serum neuropilin-1 (NRP-1) may predict a better response and overall outcome of tivozanib, an oral VEGF tyrosine kinase inhibitor, or bevacizumab in combination with mFOLFOX6 (modified leucovorin, 5-FU, and oxaliplatin).6

Such translational study is required to improve cost-to-benefit ratios in choosing antiangiogenic-based combination treatment for an appropriate subpopulation of patients. Hopefully, the pending translational research of prespecified potential biomarkers from the RAISE trial (and other studies) will assist us in patient selection. ■

Disclosure: Dr. Sun reported no potential conflicts of interest.


1. Tabernero J, Yoshino T, Cohn AL, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499-508, 2015.

2. Bennouna J, Sastre J, Arnold D, et al: ML18147 Study Investigators: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 14:29-37, 2013.

3. Van Cutsem E, Tabernero J, Lakomy R, 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 30:3499-3506, 2012.

4. Bates DO, Catalano PJ, Symonds KE, et al: Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab. Clin Cancer Res 18:6384-6389, 2012.

5. Goede V, Coutelle O, Neuneier J, et al: Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy. Br J Cancer 103:1407-1414, 2010.

6. Benson AB, Krivoshik A, Van Sant C, et al: Neuropilin-1 as a potential biomarker of progression-free survival benefit for tivozanib plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 in metastatic colorectal cancer: Post-hoc biomarker analysis of BATON-CRC phase II trial. AACR Angiogeneis Meeting. Abstract 24. Presented March 6, 2015.

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