Phase III clinical trial of Avastin abruptly halted

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BlankCOMPANY KILLS NEGATIVE CLINICAL TRIAL

In late June, the pharmaceutical company, Genentech, Inc., abruptly halted a

large phase III clinical trial of its drug Avastin. This trial was designed to

test whether Avastin (whose scientific name is bevacizumab) could prolong the

lives of patients with pancreatic cancer. The trial was halted at the

recommendation of an independent data monitoring board because the addition of

Avastin to an approved drug, Gemzar (gemcitabine), failed to improve overall

survival. Significant improvement in Avastin's performance was deemed unlikely

given the results that had already been seen.

Avastin is a so-called 'targeted' form of chemotherapy. It is a synthetic

antibody that is designed to seek out and inhibit a specific cell surface

protein called VEGF (vascular endothelial growth factor). VEGF is a signaling

protein that is crucial to the ability of tumors to generate and maintain new

blood vessels, a process called angiogenesis, which is essential for tumor

growth.

Paradoxically, the premature halting of the clinical trial is likely to work in

Genetech's - and Avastin's - favor. Genentech's losses have effectively been cut

before worse damage could be inflicted by all the negative publicity that would

follow publication of such mediocre results. The possibility that patients who

received Avastin plus Gemzar might actually have fared worse than those

receiving Gemzar alone has now been avoided. Genentech simply stated that

significant differences in overall survival were " highly unlikely " between the

two treatment arms.

But if such differences were so unlikely, why not let the trial play out? The

purpose of a clinical trial is supposed to be the generation of new knowledge,

even when that knowledge is detrimental to the financial interests of the

sponsor. The company promises that the results will eventually be published in a

medical journal, but this will probably receive next to no publicity when and if

it finally happens. Early closure of the trial precluded any new revelations

about Avastin's adverse effects. The company has asserted that the trial was not

halted for safety reasons and that no new safety concerns related to this

product were observed in the trial. However, a complete and thorough

peer-reviewed report might have also added new knowledge about the drug's

potential toxicity.

Despite this setback, Avastin remains a huge profit center for Genentech and its

majority stockholder, the Swiss pharmaceutical giant, Roche. US sales of Avastin

in the first quarter of 2006 jumped 96 percent to $398 million, from the $203

million mark for the corresponding period a year earlier. For Roche, Avastin

contributed $1.67 billion to its $27.27 billion 2005 revenue from prescription

drugs. This is not bad for a drug that, so far, has had only a minimal effect on

advanced cancers of any type, including its original approved indication,

colorectal cancer.

The cancelled trial was sponsored by the US National Cancer Institute (NCI) and

involved 602 patients at approximately 200 sites around the world. It was

initiated based on some hopeful results in a single-arm phase II study that

combined Avastin with Gemzar in pancreatic cancer. This study concluded that

" The 6-month survival rate was 77 percent and that " the combination of

bevacizumab [Avastin] plus gemcitabine is active in advanced pancreatic cancer

patients. Additional study is warranted " (Kindler 2005).

The larger phase III trial was carried out by a network of researchers organized

by the Cancer and Leukemia Group B (CALGB). Patients were randomized to receive

treatment with gemcitabine (Gemzar) plus Avastin or gemcitabine plus placebo as

their first-line therapy.

The U.S. Food and Drug Administration (FDA) had previously approved Avastin in

combination with intravenous 5-FU-based chemotherapy as a first-line treatment

for patients with metastatic colorectal cancer. In June 2006, the drug was also

approved as a second-line treatment of colorectal cancer (i.e., for use in

patients whose cancer has progressed despite having already received one course

of chemotherapy). The company has also requested licenses from the FDA for

Avastin for advanced non-small cell lung cancer and for the treatment of women

with advanced breast cancer.

In colorectal cancer trials, the drug has been shown to extend the lives of

patients by approximately 3.3 months (Kabbinavar 2005). In lung, breast and now

pancreatic cancer, however, there is not yet any proof of life extension from

rigorous trials.

Perhaps the most startling thing about Avastin is its price - around $100,000

per year for some indications. Genentech has staked much on the success of this

billion-dollar earner. The South San Francisco-based company is currently

funding 130 clinical trials in 25 different types of cancer. According to

MarketCancer.com, this decision to stop the pancreatic cancer trial will not

affect any existing filings or approvals in colorectal, lung and breast cancer.

For Roche-Genentech, the termination of this trial is only a minor setback,

according to Hernani de Faria, analyst at Zuercher Kantonalbank. " The Avastin

program is huge and broadly-based, as they're investigating more than 20 types

of cancer, " he said (RTT 2006). Wall Street analysts still estimate that the

drug could eventually reap revenue of up to $10 billion from these expanded

indications.

It seems extraordinary that a drug with such a weak general performance record

could earn so much money and garner such positive publicity. The two phenomena

are related, as patients and their doctors opt for specific treatments largely

because of favorable media coverage. Here are some typical headlines over the

past year. The first two come from the manufacturers of the drug, while other

equally adulatory statements come from influential journalistic sources, whose

ostensibly objective reporting adds weight to an essentially commercial agenda:

" Breakthrough cancer treatment Avastin receives first approval in the US "

–Roche.com

" Avastin is a breakthrough drug... " –Gene.com (Genentech's Web site)

" Avastin May be Cancer Wonder Drug for Pancreatic, Renal, Ovarian and Prostate

Cancers " –Medicalnewstoday.com.

" 90% of Cancer Patients Completely Unaware of New Breakthrough Cancer Therapy "

–antara.co.id

" Biotech Breakthrough for Colorectal Cancer. " —imshealth.com.

" Amazing Avastin. This innovative colorectal cancer drug has the potential to

revolutionize cancer therapy. " —PharmaLive.com.

Meanwhile, this abruptly halted clinical trial, with its unequivocally negative

results, has received little publicity, and certainly nothing like the intensely

positive attention that surrounded the drug's approval last year. This kind of

selective reporting helps to foster the illusion that targeted drugs such as

Avastin are steadily improving the treatment and outcome of cancer. The truth,

as revealed by the curtailed Genentech study, is very much less rosy. With a few

notable exceptions, so-called 'targeted' drugs are still not targeted enough to

make much of a difference to the outcome of the most common forms of cancer.

Ralph W. Moss, Ph.D.

References:

Kabbinavar FF, Hambleton J, Mass RD, Hurwitz HI, Bergsland E, Sarkar S. Combined

analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin

improves survival for patients with metastatic colorectal cancer. J Clin Oncol.

2005 Jun 1;23(16):3706-12. Epub 2005 May 2.

Kindler HL, Friberg G, Singh DA, Locker G, Nattam S, Kozloff M, Taber DA,

Karrison T, Dachman A, Stadler WM, Vokes EE. Phase II trial of bevacizumab plus

gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2005 Nov

1;23(31):8033-40.

RTTNews. Genentech Stops Avastin Pancreatic Cancer Trial As Results Fail To Meet

Endpoint – Update., June 27, 2006. Available at:

http://www.tradingmarkets.com/.site/news/TOP%20STORY/290927/