Bevacizumab (Avastin) has become an established component of combination chemotherapy for metastatic colorectal cancer, but several questions remain regarding use of this angiogenesis inhibitor, said James Abbruzzese, MD, The University of Texas MD Anderson Cancer Center, Houston. Speaking at the Chemotherapy Foundation Symposium, Dr. Abbruzzese said that studies are ongoing to identify potential mechanisms that drive resistance to bevacizumab. The hope is that identifying these mechanisms can help inform rational approaches to patients whose disease progresses on this drug.

Factors identified thus far as potentially predictive of progression include placental growth factor (PlGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor (HGF). These markers are increased in patients prior to progression on a bevacizumab-containing regimen.

"PlGF also increased just after exposure to single-agent bevacizumab and peaked prior to progression, so it may be a potential predictive factor," Dr. Abbruzzese told listeners. "There is considerable heterogeneity and variation in the magnitude of these changes [in the identified growth factors] between patients," he continued.

Myeloid lineage activators-recruitment of cells from the bone marrow and peripheral blood monocytes-are also increased prior to progression, as are mediators of these activators and chemotactic cytokines, he added.

The hope is that at least some, if not all, of these markers can be used for early detection of resistance to bevacizumab. The identification of these markers provides therapeutic targets for the development of agents that can reverse resistance to bevacizumab-containing regimens. Such markers may allow individualization of continued antiangiogenic therapy after progression, he explained.

Strategies for Combating Resistance

Potential approaches to resistance to bevacizumab might include inhibition of PlGF signaling by vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors and tyrosine kinase inhibition of bFGF, he explained.

"The absence of alternative angiogenic signaling at progression may represent an opportunity for continued benefit from bevacizumab," Dr. Abbruzzese stated.

Bevacizumab has been shown to improve progression-free survival, he continued, but the drug has variable effects on overall response rates and overall survival. The Bevacizumab Regimens Investigation of Treatment and Effects (BRITE) trial was a prospective observational study with "provocative" findings, he said.¹ Patients with metastatic colorectal cancer who continued on treatment with bevacizumab but switched the chemotherapy backbone had improved outcomes compared with those who did not continue bevacizumab.

"In both arms, patients eventually progressed on bevacizumab, suggesting that there are important mechanisms of resistance we can learn about to help develop therapies for patients whose disease progresses on antiangiogenic therapies," Dr. Abbruzzese commented.

Finding the Underlying Mechanisms

Increased numbers of proangiogenic substances have been identified, and these can exert secondary proangiogenic effects in the absence of VEGF, he continued. Placental growth factors and other factors that recruit macrophages and monocytes influence the endothelial milieu.

"Numerous mechanisms may come into play [in the development of resistance]. Studies are ongoing to identify these," he said.

To that end, Scott Kopetz, MD, Dr. Abbruzzese, and colleagues at MD Anderson Cancer Center conducted a phase II study of 40 patients in whom treatment with the combination of FOLFIRI (leucovorin, fluorouracil, irinotecan) plus bevacizumab failed. The investigators measured proangiogenic and primary cytokine levels after initiation of systemic FOLFIRI and bevacizumab, and again at distant time points when the disease progressed.² The factors measured included PlGF, bFGF, HGF, platelet-derived growth factor (PDGF), stem cell growth factor (SCGF), interleukin (IL)-1, IL-8, and eotaxin.

"After exposure to bevacizumab alone, a heterogeneous and perhaps interesting response was observed in terms of circulating growth factors," Dr. Abbruzzese said. PlGF and eotaxin increased after bevacizumab and FOLFIRI, whereas other factors decreased after initial exposure to bevacizumab and exposure to chemotherapy plus bevacizumab. No changes in PDGF were observed, for example.

"The hypothesis is that resistance mechanisms should precede clinical progression. We should be able to measure these changes just prior to emergence of clinical resistance. Indeed that is what we found," he continued.

Exploratory Analysis

PlGF showed a steady increase after exposure to chemotherapy plus bevacizumab; bFGF showed a marked increase after exposure to bevacizumab and chemotherapy just prior to progression. In some individuals, very substantial increases in both of these circulating cytokines were observed, suggesting that serial assays of these cytokines might be able to identify patients who are showing signs of progression during continual exposure to bevacizumab.
An exploratory analysis showed that other cytokines are increased that mediate myeloid cell activation as well as recruitment. These include IL-8 (a secondary proangiogenic factor), and patients with high levels of IL-8 had worse outcomes in this phase II study. Monocyte recruitment factors were also elevated as patients progressed clinically, he said.

"This small preliminary study opens the door to a number of possibilities and raises questions. After progression on CT, there may be a subset of patients who benefit from continuing bevacizumab or alternating therapies. Our greatest challenge would be to identify this subset and try to apply alternative strategies," he stated.

The phase II study had several limitations, including the fact that mechanisms associated with resistance are not necessarily causative. More study is needed to prove causality, Dr. Abbruzzese noted. Further, plasma levels of these factors may not reflect the tumor microenvironment. The investigators are continuing their studies to determine which of the changes in proangiogenic factors might be the most clinically relevant. ■

References

1. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer: Results from a large observational study (BRITE). J Clin Oncol 26:5326-5334, 2008.

2. Kopetz S, Hoff PM, Morris JS, 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 28:453-459, 2010.