IMPORTANT For Avastin Sutent Trial participants!!!!!

[RandyW]

WASHINGTON (Reuters) - Genentech Inc has warned doctors about a type of anemia seen in patients treated with the company's blockbuster cancer drug Avastin in combination with Pfizer Inc's Sutent in a clinical trial, U.S. regulators said in a notice issued on Monday.

The cases of microangiopathic hemolytic anemia seen in a Phase 1 kidney cancer study led to the closure of a mid-stage trial of Avastin plus Sutent, Genentech said in a letter to doctors that was posted on the Food and Drug Administration's website.

The combination of Avastin plus Sutent is not approved or recommended, the company's letter said.

Avastin, which is approved to treat colon, lung and breast cancer, is widely considered to be Genentech's most important product. Analysts are looking for second-quarter U.S. Avastin sales of more than $640 million when Genentech announces its quarterly results later on Monday.

The medicine, which works by cutting off the blood supply to tumors, is being tested in combination with numerous other drugs in scores of clinical trials.

Sutent is one of the most widely used medicines for the treatment of advanced kidney cancer.

The letter to doctors noted that five of 12 patients who received the highest dose of Sutent in the study had laboratory findings consistent with microangiopathic hemolytic anemia .

Two of the cases were considered severe with evidence of several adverse side effects, including severe high blood pressure, the letter said. Both cases were reversible within three weeks of discontinuation of the two medicines without additional medical intervention, Genentech said.

Genentech spokeswoman Kimberly O'Campo said other studies combining lower doses of Sutent with Avastin are ongoing. Continued...

However, two other mid-stage studies of Avastin in combination with Sutent and chemotherapy were halted due to poor tolerability involving fatigue, gastrointestinal complications and myelosuppression -- a condition in which production of blood cells and platelets is reduced.

Those trials involved patients with breast and lung cancer, O'Campo said.

The letter asks doctors to report cases of microangiopathic hemolytic anemia or any serious adverse events suspected to be associated with Avastin use.

Genentech shares were down $2.36, or 3 percent, to $75.39 on the New York Stock Exchange.

(Additional reporting by Bill Berkrot in New York)

(Reporting by Lisa Richwine; Editing by Andre Grenon, Gary Hill

[gpawelski]

True synergy is rather uncommon in most adult solid tumors. Most drug combinations in diseases such as cancer are merely additive, where the whole equals the sum of its parts, and not synergistic.

In cases where drugs are only additive and not synergistic, nothing is learned by testing the drugs in combination over what is learned by testing them separately. So drugs in combination are only tested in cases where there is the realistic possiblity of seeing true synergy.

The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.

The theory behind combination chemotherapy is that you can't give full doses of all drugs when you give them together. They have overlapping toxicity, which means you need to cut the doses when you give them together, so you get down to "homeopathic" dose levels.

Pharmaceutical companies have been attracted to studies looking at the maximum tolerated dose of any treatments. Cancer sufferers have been taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need.

Many of the highly expensive targeted cancer drugs may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The search for minimum effective doses of treatments should be one of the key goals of cancer research.

Molecular testing methods detect the presence or absence of selected gene mutations which theoretically correlate with single agent drug activity (either Avastin or Sutent). Tests are performed using material from dead, fixed or frozen cancer cells, and are never exposed to anti-cancer agents.

Cell culture methods assess the net effect of all inter-cellular and intra-cellular processes occurring in real-time when cells are exposed to anti-cancer agents. Tests are performed using intact, living cancer cells plated in microclusters.

Cell culture methods allow for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007

Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 31e-32

[jaminkw]

"Many of the highly expensive targeted cancer drugs may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The search for minimum effective doses of treatments should be one of the key goals of cancer research."

gpawelski, Much of your post is over my head but I really zeroed in on the above paragraph. As someone on a maintenance chemo that is causing side effects I would rather avoid, I would certainly appreciate this kind of research. Problem is, drug companies want to sell more not less so how do we get this kind of research?

Judy in Key West

[gpawelski]

Judy. That paragraph is precisely what should be zeroed in on. Over the past couple of years, if you watched TV with any regularity, it would have been difficult to miss the direct to consumer advertising that touted the benefits of some drugs over others, especially for patients undergoing treatment for cancer. Even to the point that buses covered with "shrink wrapped" advertising being strategically placed outside major cancer centers for patients and their families to see (EPO anyone?).

Drugmakers are going directly to the consumer at a time when their products are indeed at the margins of evidence-based medicine. More must be spent on analyzing drug data, and the need for larger and more detailed studies to figure out why there is an association between pharmaceutical involvement and positive results.

In the meantime, cancer sufferers are taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need, Dr. Ian Haines reported in the Journal of Clinical Oncology. Emerging evidence shows that many of the highly expensive "targeted" cancer drugs (Herceptin, Avastin and Rituximab) may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses.

He stated in the Journal that "it would seem that pharmaceutical companies are attracted to studies looking at the maximum tolerated dose of any treatments." He gave as an example, Avastin, used to fight colon and lung cancers, the dose being tested is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram.

http://jco.ascopubs.org/cgi/content/full/25/25/e31

It's not a case of throwing "targeted" drugs at the problem. It's knowing "what" targeted drugs and how to use them in "individual" patients (not average populations). The problem is that few drugs work the way oncologists think they do and few of them take the time to think through what it is they are using them for.

[CaroleHammett]

Added to that is the fact that the pharmaceutical's search for "synergy" translates into fewer clinical trials of "stand alone" drugs. Instead, they are concentrating on combinations, which also means that the number of those eligible for the trials is a much smaller number.

I am thinking, of course, of CP751,871 (http://lungevity.org/l_community/viewtopic.php?t=37534), which is only being tested in conjunction with other chemos, even though earlier trials show it can be as much as 78% effective as a "stand alone" for squamous cell carcinoma.

Arrrggghhh.

Affectionately,

Carole