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The Limitations of VEGF Inhibition in Colorectal Cancer

Laura Panjwani
Published: Wednesday, Oct 14, 2015

Leonard Saltz, MD

Leonard Saltz, MD

The idea of using antiangiogenic therapy to fight cancer was first proposed in the early 1970s by Judah Folkman, MD, a professor at Harvard and director of the vascular biology program at Boston Children’s Hospital. Folkman, who died in 2004, believed that by creating an agent that attacked the blood supply instead of the tumor itself, cancer cells would be deprived of the nutrients they needed to grow and thereby unable to sustain themselves.

Folkman’s theory eventually led to the approval of VEGF inhibitors bevacizumab (Avastin), ziv-aflibercept (Zaltrap), and ramucirumab (Cyramza) in colorectal cancer.

However, these drugs are not true antiangiogenic therapies, and because of that they can only advance the treatment of colorectal cancer so far, says Leonard Saltz, MD, chief of gastrointestinal oncology and head of colorectal oncology at Memorial Sloan Kettering.

“My politically incorrect opinion is that we haven’t come out with any real antiangiogenic therapies,” says Saltz. “We need to be honest with ourselves and each other in admitting what these drugs are and what they are not. They are small steps forward, much smaller than any of us wanted them to be, and we need to keep that in perspective, especially when we look at the cost of them, which is very significant.”

Below, Saltz explains his definition of an antiangiogenic agent, how VEGF inhibitors can best be optimized in colorectal cancer, and what their limitations are, via a series of questions and answers.

OncLive: Why don’t you consider VEGF inhibitors like bevacizumab, aflibercept, and ramucirumab to be true antiangiogenic agents?

Dr Saltz: The work of Folkman was based on the idea that we would no longer be attacking the tumor, but rather the blood supply. It was thought that by now we’d look back with disbelief that we used to give people agents that had toxicities like nausea, neutropenia, hair loss, and so on. It has not worked out that way. What we clearly have is agents that are anti-VEGF. If something was truly antiangiogenic, we would expect that it would work as a single agent—it wouldn’t need to be given with cytotoxics, and it might even interfere with cytotoxics by blocking the blood supply in order to decrease delivery of the drug to the tumor.

What we see with VEGF inhibitors is just the opposite. They don’t work as single agents, and they modestly enhance the effectiveness of cytotoxic regimens. We don’t spare patients the toxicity of those regimens, we just add the toxicities of the VEGF inhibitors on top of it. What happens when you give an anti-VEGF agent with chemotherapy is that it appears to improve the delivery of that chemotherapy to the tumor. That is its major benefit. I think that antiangiogenic is a somewhat wishful marketing term, and it is more accurate to define these drugs as anti-VEGF.

Are true antiangiogenic agents possible?

I don’t believe we have succeeded in creating clinically available antiangiogenic agents, certainty not in the context in which the word was initially used in the discussion of the development of these drugs. No one ever set out to develop bevacizumab, aflibercept, ramucirumab, or any of these agents, for the purpose of combining them with chemotherapy to get a little bit of benefit. The hope was that these would replace chemotherapy, and they have not been able to do that.

Are there VEGF inhibitors that you feel have shown the most patient benefit?

Bevacizumab has been on the market for more than a decade now and it has become our standard anti-VEGF agent. Everyone hoped that the two agents that came after it, aflibercept and ramucirumab, would be better. Unfortunately, the data suggest that these drugs are not better. The problem that we’ve had with both of them is that they’ve cost more than double what bevacizumab costs and without adding any apparent benefit. It is hard to see a role for them.

As a result, perhaps of the awareness of the cost differences, aflibercept dropped its price by more than half and now is priced very comparably to bevacizumab. There are no data supporting aflibercept as a first-line agent, and there are no data supporting aflibercept without FOLFIRI. In first-line, if one is going to use a VEGF agent, bevacizumab is the only one with data that proves it to be effective.

In second-line, the data suggest that either continuing bevacizumab is best, or switching to aflibercept or ramucirumab if you are also switching chemotherapies. These agents are likely to have similar effectiveness, but there is no reason that one is better than the other and no reason that one would rescue the other. There is no rational for example, to use FOLFIRI and bevacizumab and then try FOLFIRI and aflibercept or FOLFIRI and ramucirumab after that. It would be an inappropriate exposure of toxicity for the patient with no real chance of benefit.




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