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

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.”

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