NSABP chair admits ‘failure’ in C-08 trial, denies defeat

ABSTRACT: Experts, including Louis Weiner, MD, and Paulo Hoff, MD, discuss whether the results mark the beginning of the end for adjuvant bevacizumab in early-stage colon cancer.

ORLANDO-The headlines declaring bevacizumab’s inability to deliver in colorectal cancer did right by the nattering nabobs of negativity:

• “Genentech’s Avastin falls short in colon cancer trial” (New York Times)
• “Roche drug fails in early colon cancer” (Wall Street Journal)
• “Is Avastin living up to the hype?” (Forbes)

You won’t hear NSABP Chair Norman Wolmark, MD, claim that the headlines were inaccurate. “We failed, and nobody likes to fail,” said Dr. Wolmark during an ASCO 2009 plenary session. “The prespecified and hoped-for endpoint-increases in the cure rate of early-stage colon cancer-was simply not met. But did we fail abominably, or did we fail with distinction cum laude, with no hope for redemption?”

No, according to Dr. Wolmark. “Let’s cut to the chase. There was an interesting pattern to these curves (see Figure below). They separated early in favor of bevacizumab then converged. Actually, it wasn’t bevacizumab that failed. If anything, we failed to provide our patients with a novel intervention that would increase cures.”

‘Transient but robust’
The results in brief: NSABP randomized 2,710 stage II and III colorectal cancer patients to two treatment arms (see Table on page 2). At a median follow-up of 36 months, disease-free survival (DFS) was 75.5% in the control arm and 77.4% in the bevacizumab (Avastin) arm (HR 0.89; P = .05), Dr. Wolmark reported.

Post-hoc analysis showed a significant benefit for bevacizumab for the one year that patients were actually on drug. DFS at one year was 94.3% with bevacizumab and 90.7% with modified FOLFOX6 alone, for a 3.6% absolute improvement, translating into a 40% reduction in events (P = .0004). There was no evidence of a “flare phenomenon,” or a later detrimental effect from bevacizumab in encouraging tumor growth, reported Dr. Wolmark, who is also chair of oncology at Allegheny General Hospital in Pittsburgh (abstract LBA4).

“We found there was a transient but robust benefit in DFS during the one year that bevacizumab was utilized,” he noted. “The magnitude is similar to that seen with trastuzumab (Herceptin) in breast cancer in NSABP B-31. As a matter of fact, we came close to reaching the early stopping boundary for efficacy. So bevacizumab was effective, but this efficacy disappeared after bevacizumab was stopped. The challenge is to learn how to use bevacizumab to its maximum potential in the adjuvant setting.”

Is long-term anti-VEGF therapy reasonable?
The idea of long-term treatment with bevacizumab is cause for concern, said Lee Ellis, MD, professor of surgical oncology and cancer biology at Houston’s M.D. Anderson Cancer Center. Issues that need to be addressed are:

• Optimal duration of treatment.
• Risks and inconvenience of treating every three weeks for three years to life.
• Clinical meaningfulness of a 3% to 5% improvement in DFS.

Of course, there are the ever-present financial hurdles. “Will insurers be willing to pay the cost for perhaps a significant but relatively small benefit, with no increase in cure, and one that requires continuous treatment indefinitely to see the benefit?” Dr. Ellis asked (see Vantage Point).

Other clinicians weighed in on the results to Oncology News International.

Alan Venook, MD, professor of clinical medicine at the University of California, San Francisco, questioned the notion that bevacizumab actually did have a biological effect.

“There is a suggestion that Avastin delayed progression or delayed recurrence,” he said. But “this study did not mandate any CT scans, and this is very relevant, because if you look at DFS, it’s defined as the absence of recurrence. For the most part, in colon cancer, you don’t know if disease has recurred if you don’t do the scans. So it may be that the DFS is an absolutely true finding, but it’s possible that there was a bias in when the scans were done.”

Dr. Venook pointed out that patients undergoing conventional treatment generally receive more follow-up scans than those in the experimental arm. “(Trial investigators) have to get us the data. It may be that the scans were symmetrical and it doesn’t matter.”

For Jordan Berlin, MD, the results of the trial signal the end of the line: That bevacizumab should not be used in a patient with completely resected colorectal cancer.

“No further trials needed,” said Dr. Berlin, who is clinical director of GI oncology and an associate professor of medicine at Nashville’s Vanderbilt University. “We can await the long-term outcomes evaluation, but this was a negative trial. The question is whether or not other issues in trial design may have resulted in a short-term separation of the DFS curves.”

Given that there was “at least some hint” that bevacizumab did have a positive impact on DFS, Paulo Hoff, MD, isn’t quite ready to write off anti-VEGF therapy in this setting. But while long-term results from C-08 filter in, other agents may become available for testing and prove more successful, added Dr. Hoff, who is executive director of the Centro de Oncologia, Hospital Srio-Libans and the University of So Paulo, Brazil. “Nothing really changes,” he said. “Bevacizumab was not indicated before, and based on this trial, it still should not be used in the adjuvant setting.”

Louis Weiner, MD, agreed that the results should discourage oncologists from using adjuvant bevacizumab in their early-stage colon cancer patients. “I think many oncologists hoped that the addition of Avastin would enhance the effects of chemotherapy to the extent that it further improved the odds for cure,” he said.

For Dr. Weiner, the nuts and bolts of bevacizumab may offer the answer to the question: What makes bevacizumab useful in metastatic col

on cancer but not in the adjuvant setting?

“The original hypothesis was that the antibody, by blocking VEGF, would block the formation of new blood vessels,” he said. “One would predict that when used in the adjuvant setting, blocking the formation of new blood vessels would have been critically important and would have led to an improved treatment outcome.”

Perhaps bevacizumab’s dominant mechanism of action in this setting isn’t angiogenesis inhibition at all, added Dr. Weiner, who is director of the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center in Washington, DC. “There’s evidence that VEGF antibodies can change permeability of blood vessels and may act primarily by enhancing the delivery of chemotherapy to relatively poorly vascularized tumors. That may be the true advantage of VEGF inhibitors.”

Watchful waiting
Meanwhile, the results raise the stakes even higher for the AVANT trial, which is also evaluating bevacizumab in the adjuvant setting. Dr. Venook is not necessarily convinced that AVANT will change the standard of care anymore than C-08 did. “If AVANT is strongly positive, then you have to square it with a negative study. My suspicion is that AVANT will have similar findings.”

If results of the AVANT study are not outright positive, then further trials of long-term anti-VEGF for the adjuvant treatment of colorectal cancer should not be conducted, Dr. Ellis said.

Dr. Berlin concurred, recommending that attention should be focused instead on reducing toxicity of current regimens, examining duration of therapy, and “most important, evaluating other new agents that show promise.”

But Dr. Wolmark is not willing to count out adjuvant bevacizumab in early-stage colorectal cancer just yet, stating that trials using the agent well beyond one year should receive strong consideration. “We hope to start a trial in the near future using bevacizumab for two years,” he said.