The True Boundaries of VEGF Inhibitors in Colorectal Cancer

VEGF Inhibitors in Colorectal Cancer

Leonard Saltz, MD

Using antiangiogenic therapy to combat cancer was first proposed in the early 1970s by Judah Folkman, MD, professor, Harvard, director of the vascular biology program, Boston Children’s Hospital. Folkman believed that by creating an agent that attacked a patient's blood supply as opposed to the tumor itself, cancer cells would be nutrient deprived and rendered unable to sustain themselves.

Folkman’s theory led to the genesis of VEGF inhibitors bevacizumab (Avastin), ziv-aflibercept (Zaltrap), and ramucirumab (Cyramza) in treatment for colorectal cancer.However, these drugs are not true antiangiogenic therapies. Due to this, these drugs can only advance the treatment of colorectal cancer so far, says Leonard Saltz, MD, chief of Gastrointestinal Oncology, head of Colorectal Oncology, 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.”

Saltz says Folkman's work was based on the idea that cancer treatments would attack the blood supply and toxicities like nausea, neutropenia, and hair loss would be a thing of the past.

"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," said Saltz in an interview with Targeted Oncology.

"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."

Saltz said despite no "true" VEGF inhibitors being currently available, bevacizumab is the closest oncologists have at the moment. He added that the treatments that followed bevacizumab, those being aflibercept and ramucirumab, did not quite live up to the expectations held for them.

"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," he said. "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."

Saltz does add that in the second-line, either continuing bevacizumab is best, or switching to aflibercept or ramucirumab if an oncologist is also choosing to switch chemotherapies. He says the agents are likely to have a similar effect and that one is not "better" than the other, when switching.

Saltz also touches on times when a VEGF inhibitor would not function as a treatment.

"They don’t work in the adjuvant setting. That was a disappointment to all of us. We hope when we find a drug that we can add it to the treatment of metastatic disease and then further use it in earlier stage-disease to increase the cure rate in the adjuvant setting. Two extremely large studies were done adding bevacizumab to chemotherapy in stage II colon cancer and both were negative studies. One actually trended toward inferior results with bevacizumab. In the absence of data, I think it is fair to say all three should not be used in the adjuvant setting," he said.

In closing, Saltz says the he feels as though VEGF has been pushed as far as it can possibly be pushed when it comes to being a treatment.

"I think we’ve mined VEGF as far as we are going to be able to. Part of the problem in oncology is that people like to say we have a lot of drugs in development and there is a robust pipeline of new agents in clinical trials, but there is a big difference between a new drug that is a novel mechanism, first-in-class drug, versus a next-in-class drug that is just another VEGF inhibitor or another EGFR inhibitor," he said. "The likelihood that a next-in-class drug is going make a dramatic beneficial leap is unfortunately very small. I think that we are likely going to have to look in other areas to make meaningful advances."