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As Roche Looks on, Genentech's Big Avastin Study Attracts Critics

cancercell.jpgA handful of scientists are skeptical that Genentech's C-08 trial of its Avastin anti-cancer drug will show any benefit in preventing the recurrence of colorectal cancer following surgery, reports PharmaWire (via the Financial Times).

Avastin is one of Genentech's most valuable products, and currently rakes in sales of $650 million a quarter. But the drug faces criticism that it is overpriced and less effective than Genentech wants it to be.

If these boffins turn out to be right, it adds an interesting wrinkle to the Roche-Genentech takeover, as part of Genentech's value hinges on whether Avastin can kill off free-floating cancer cells -- or at least prevent them from growing into new tumors.

Genentech is hoping that Avastin can be extended for use in treating post-surgical patients -- the so-called "adjuvant setting." Although surgery can remove tumors from the colon, it can't stop tiny clumps of cancer cells from floating off in the bloodstream. If these cells take root elsewhere in the body, the cancer returns. Genentech's C-08 trial, which has 2,700 patients in it, is designed to see whether Avastin can prevent that recurrence.

But here's what cancer docs are telling PharmaWire's Klara Czobor about the trial:

Dr Alberto Sobrero, the director of medical oncology at the San Martino Hospital in Genoa, Italy, said the scientific rationale behind Avastin's use in the adjuvant setting is not very strong, and he considers it unlikely the drug's anti-angiogenic effects will work in this setting.
Dr Axel Grothey, a colon cancer expert at the Mayo Clinic College of Medicine in Rochester, Minn., said, "I don't think that it is safe to be used in this setting. I have a hard time seeing how Avastin would work in the adjuvant setting. We see that it works in colorectal cancer, but the presumed mechanism of action doesn't lend itself to believe that it works in the adjuvant."
Their argument is that Avastin works by screwing up the blood vessels that tumors develop to feed themselves. Free-floating cancer cells don't have blood vessels attached, so there's no apparent logic for the C-08 test.

Avastin seems to be a bit of a pinata for some doctors. Last May, some cancer scientists suggested that Genentech was looking at the wrong endpoint in C-08. They believe the goal should be to see if Avastin helps the overall survival of the patients, but C-08 primary endpoint is disease-free survival -- i.e. the length of time in which cancer appears to be absent. (Overall survival is the secondary endpoint.)

The FT reported in July that Sue Hellmann, president of product development at Genentech, defended Avastin's safety profile in an earnings call, saying the interim safety data "looked encouraging and we expect the final analysis of this study to be in 2009." Here's Genentech's latest update on C-08, in which it touts the fact that no safety issues have arisen that would derail the test. That's an important issue for Genentech, because Avastin is associated with a laundry list of serious side effects, including heart failure and hemorrhage. Obviously, it's more difficult to persuade doctors to put patients who have had tumors removed and are ostensibly cancer-free on drugs with those risks.

And then there's the price of the drug itself. The NYT launched a lengthy broadside at Avastin earlier this year, in which it noted that the price of treatment can reach $100,000 a year. That would be fine if Avastin was a cure for cancer. But it's not. Avastin's performance on metastatic colorectal cancer is summed up in the fine print of the company's website. It gives you only about two more months to live when combined with the most up-to-date chemotherapy:

Median survival for patients receiving Avastin plus FOLFOX4 was 13.0 months, compared to 10.8 months for those receiving FOLFOX4 alone.
As I noted earlier, if the price of Genentech rises, the value of the company potentially falls as Genentech's senior staff cash in their stock and leave. Roche can only guess about the outcome of C-08, so it will be interesting to see if the uncertainty will give Roche an extra argument for keeping the price of the deal down.

(Disclosure: Czobor was a former student of mine in an NYU journalism class. She got good grades, if memory serves.)