Staff Writer

The failure of Roche AG's Phase III AVANT trial of Avastin (bevacizumab) in adjuvant colon cancer wasn't a surprise, but it does raise questions about the VEGF-inhibitor's potential in earlier-stage cancer.

Avastin is currently approved for late-stage colorectal, lung, kidney and breast cancer, as well as for brain cancer that has progressed after prior treatment. Expanding into the adjuvant setting – usually following surgery in earlier-stage cancer patients – could significantly expand the drug's already massive sales, which totaled $3.4 billion in the first half of this year.

Yet Avastin has yet to succeed in a Phase III adjuvant trial, according to Amy Berry, a spokeswoman at Roche's Genentech Inc. subsidiary.

Last year, Avastin failed in a highly anticipated Phase III adjuvant colon cancer trial dubbed C-08. The drug plus FOLFOX (oxaliplatin, 5-FU and leucovorin) chemotherapy failed to improve disease-free survival over FOLFOX alone in 2,710 patients with surgically resected Stage II or Stage III colon cancer. (See BioWorld Today, April 23, 2009.)

The disappointing data came barely a month after Roche paid $46.8 billion to acquire Avastin-maker Genentech Inc., and speculation over the outcome of C-08 drove much debate over whether the takeout price was a fair one. At the time, analysts predicted the adjuvant market for Avastin could reach $5 billion and viewed C-08 as somewhat of a predictor of the drug's potential in other adjuvant settings like lung and breast. (See BioWorld Today, March 13, 2009.)

Once C-08 failed, analysts didn't have high hopes for the Phase III AVANT study, which compared Avastin plus either FOLFOX or XELOX (capecitabine and oxaliplatin) to FOLFOX alone in 3,451 patients with surgically resected Stage II or Stage III colon cancer.

Indeed, Roche said Monday that the trial did not meet its primary endpoint of improving disease-free survival. In fact, the data numerically favored the control arm, an outcome not seen in the C-08 trial.

Despite the C-08 and AVANT failures, Roche is still conducting two other Phase III trials of Avastin for adjuvant colon cancer, one in the U.S. focusing on Stage II patients and one outside of the U.S.

The pharma also has Phase III trials ongoing for Avastin in adjuvant lung and breast cancer.

But Berry said the company is "definitely evaluating our next steps with the adjuvant development program." She added that the "biology of the tumors is different based on the stage of cancer" and that Roche is looking into the specific results of its studies to try to determine whether Avastin's benefit translates to earlier-stage disease.

Importantly, the early stage colon cancer failures have "absolutely" no bearing on Avastin's existing full approval for late-stage colorectal cancer, Berry noted.

That approval, granted in 2004, was based on strong benefits in both progression-free and overall survival. The drug has since gone on to revolutionize the standard of care for advanced colorectal cancer. (See BioWorld Today, Feb. 27, 2004.)

So there's no danger the FDA will yank Avastin off the market for colorectal, meaning the current controversy regarding rescinded approvals will remain limited to breast cancer.

The FDA previously granted accelerated approval for Avastin plus paclitaxel in first-line treatment of HER2-negative metastatic breast cancer. The decision was controversial for many reasons: It marked the first time progression-free survival had been used alone to approve a first-line breast cancer drug; it was based on an open-label study not originally intended to support approval; and it ran contrary to an advisory committee's recommendations. (See BioWorld Insight, March 3, 2008.)

Data from two subsequent Phase III trials – AVADO and RIBBON-1 – were intended to confirm the progression-free survival benefit and lay the controversy to rest. In November 2009, Roche submitted two supplemental biologics license applications based on the studies, aiming to convert the accelerated approval to a full approval and expand the chemotherapy combination options.

But in July 2010, an FDA advisory panel said it was unimpressed with the data from the two newer trials and recommended revoking the accelerated approval and removing the breast cancer indication from Avastin's label. (See BioWorld Today, July 21, 2010.)

The FDA has not yet moved to act on the advisory committee's recommendations, although Genentech spokespersons said the agency could do so at any time and there is no set timeline for such a decision.

However, the FDA was scheduled to make a decision on the two sBLAs last Friday. Instead it extended its review by three months, until Dec. 17.

Genentech said the extension was due to its submission of information during the review cycle, which was deemed a major amendment.