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New England Journal of Medicine Avastin in Lung Cancer

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Genentech, Inc. announced the publication of data from a pivotal Phase III clinical trial in the New England Journal of Medicine showing that Avastin (bevacizumab) in combination with paclitaxel and carboplatin chemotherapy significantly improved overall survival in patients with unresectable, locally advanced, recurrent or metastatic non-squamous, non- small cell lung cancer (NSCLC), the most common type of lung cancer.


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  • 4 months later...

Maybe, for these reasons.

Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. The "targets" that the new "smart drugs" go after can be located on the "inside" or "outside" of a cancer cell. The most common targets on the outside are receptors, proteins that help relay chemical messages. And many targets on the inside are enzymes, proteins that help speed up chemical reactions in the body.

Monoclonal antibodies are "large" molecules that attach to specific proteins on the "outside" of cancer cells but not having a convenient way of getting access to a large majority of the targeted cells. There is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth. "Small" molecules act on multiple receptors in the cancerous cells.

Angiogenesis is essential for the growth and metastasis of cancer. A growing tumor requires nutrients and oxygen, which helps it grow, invade nearby tissue, and metastasize. To reach these nutrients, the tumor builds new blood vessels. In fact, growing tumors can become inactive if they can't find a new supply of nutrients.

Angiogenesis starts when cancer cells produce a variety of growth factors and other activators (biologic molecules that begin a process). Growth factors cause endothelial cells (the cells that line blood vessels) to produce chemicals that break down the nearby tissue and the extracellular matrix (the spaces between cells). Then, the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide structural support for the new blood vessels.

Because angiogenesis is necessary in the growth and spread of cancer, each part of the angiogenesis process is a potential target for new cancer therapies. The assumption is that if a drug can stop the tumor from receiving the supply of nutrients, the tumor will "starve" and die.

Anti-angiogenesis drugs work by blocking the activity of vascular endothelial growth factor (VEGF) to prevent the growth of new capillaries into the tumor and thereby sustain tumor growth. VEGF causes angiogenesis by attaching to special receptors (proteins on the outside of cancer cells that act like doorways), and this action starts a series of chemical reactons inside the cell.

Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent like Avastin which works by blocking VEGF (Avastin "sensitive" tumors). It potently inhibits the formation of new blood vessels.

Avastin (bevacizumab) is a monoclonal antibody, a type of genetically engineered protein. Monoclonal antibodies are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside which are protected from the drug. The cells may pass small molecules back and forth.

Vatalanib (PTK/ZK) is a "small" molecule tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth factor receptor, and c-KIT. It is a multi-VEGFR inhibitor designed to block angiogenesis and lymphangiogenesis by binding the intracellular kinase domain of all three VEGFRs, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Vatalanib is a targeted drug that inhibits the activity of all known receptors that bind VEGF. The drug potently inhibits the formation of new blood vessels (angiogenesis).

However, do the drugs even enter the cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In some cases, these and other drugs, kill tumor cells without killing microvascular cells in the same time frame. In other cases they kill microvascular cells without killing tumor cells. In yet other cases they kill both types of cells or neither type of cells. The ability of these agents to kill tumor and/or microvascular cells in the same tumor specimen is highly variable among the different agents.

A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar and vatalanib. The Microvascularity Viability Assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect.

The principles and methods used in the Microvascularity Viability Assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.

It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro. Photomicrographs in the assay can show that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The Assay measures the net effect of everything which goes on (Whole Cell Profiling). Are the cells ultimately killed, or aren't they?

Each of these new targeted drugs are not for everybody. According to the National Cancer Institute, those who benefit substantially from "targeted" drugs is approximately 10% to 20%. What if you are one of those few? This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first.

Source: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007

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  • 4 weeks later...

Research has shown that controlling production of new blood vessels can restrict tumor growth, often prolonging the life of the cancer patient. Perhaps the most widely-used anti-angiogenic agent to emerge to date is a drug called Avastin. Avastin was approved by the FDA for use in combination with intravenous 5-fluorouracil-based chemotherapy for first-line treatment of patients with metastatic colorectal cancer. However, Avastin has also shown activity in many other solid tumor types such as breast, lung, and ovarian cancers. As with most targeted-therapy drugs, Avastin does not necessarily benefit every patient and it is expensive. Further, no test currently exists that shows reliably who will benefit from it.

The Weisenthal Cancer Group has developed an assay for microvasacular viability (M.V.V.) to identify potential responders to Avastin, Nexavar, Sutent, and other anti-angiogenic drugs and to assess previously unanticipated direct and potentiating anti-angiogenic effects of targeted therapy drugs such as Tarceva and Iressa. Prior to development of the M.V.V. assay it was thought that the lack of an intact tumor micro-vasculature would prevent in vitro drug studies in disaggregated tissues. However, it was discovered that endothelial cells are present in tumor microclusters and it appears that drug effect upon these cells can be assessed in the M.V.V. assay.

The M.V.V. assay is being offered currently to selected Weisenthal Cancer Group clients on a research basis and as an adjunct to either a Weisenthal Cancer Group standard CytoRxTM assay or an EGFRx™ tyrosine kinase assay.

http://weisenthalcancer.com/Professiona ... sional.htm

http://weisenthalcancer.com/Patient%20P ... kFacts.htm

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  • 1 year later...

Targeted Cancer Therapy Improved with Ex-Vivo Chemosensitivity Analysis

The Todd Cancer Institute at Long Beach Memorial Medical Center is the first cancer program in the nation to apply assay-directed therapy as the first-line treatment for advanced solid tumors. The Center is currently hosting clinical trials for cancers of the lung, colon, stomach, pancreas and prostate.

One of those has been Phase II assay-directed therapy in previously untreated, measurable, Stage IV NSCLC. Patients who had high activity for erlotinib in vitro and received first line single agent erlotinib had a 100% response rate (Genetic Engineering and Biotechnology News, June 1, 2007).

PET scans were not approved because they saved lives in a controlled clinical trial that compared the outcome of patients who received care with or without the benefit of a PET scan. They were approved because their performance characteristics (sensitivity/specificity) are reporducible, favorable and provide useful information to treating physicians.

Chemosensitivity analyses have performance characteristics that are reproducible, favorable and provide useful information to treating physicians. What's more, this information is a result of a clinical trial in which NSCLC patients underwent an assay as part of a Phase II assay-directed trial (IRB-approved). It so happens that these patients were found more sensitive to Tarceva than to other forms of chemotherapy, all of which were tested for the same $3,500 price.

If costs well in excess of $1,000 to do EGFR mutation and FISH for amplification. All of which tells you whether or not to give Tarceva (one drug). Chemosensitivity analyses more often find NSCLC patients sensitive to other compounds and combinations and can recommend these all from one assay. It costs a lot more to give a single cycle of chemotherapy than it does to test all of the possible options.

The evidence supporting a doctor's use of therapy may be far less solid than the evidence supporting chemosensitivity analysis. If a physician uses chemotherapy for NSCLC, does he/she give second-line chemotherapy to patients with good performance status who fail first-line therapy? If so, there is only one study to support it, Docetaxel. There is also one non-inferiority trial for Alimta. If the physician does anything other, he/she is not adhering to the evidence. I'm sure there are dozens of practices that fail to meet these lofty evidence standards.

As increasing numbers and types of anti-cancer drugs are developed, oncologists become increasingly likely to misuse them in their practice. There is seldom a "standard" therapy which has been proven to be superior to any other therapy. When all studies are compared by meta-analysis, there is no difference. What may work for one, may not work for another.

Cancer chemotherapy could save more lives if pre-testing were incorporated into clinical medicine. The respected cancer journals are publishing articles that identify safer and more effective treatment regimens, yet few community oncologists are incorporating these synergistic methods into their clinical practice. Cancer patients suffer through chemotherapy sessions that do not integrate all possibilities.

The current clinical applications of in vitro chemosensitivity testing is ever more important with the influx of new "targeted" therapies. Given the technical and conceptual advantages of "functional profiling" of cell culture assays together with their performance and the modest efficacy for therapy prediction on analysis of genome expression, there is reason for renewed interest in these assays for optimized use of medical treatment of malignant disease.

The chemotherapy regimen chosen by most community oncologists is based on the type of cancer being treated. However, there are factors other than the type of cancer that can be used to determine the ideal chemotherapy drugs that should be used to treat an individual patient.

It is highly desirable to know what drugs are effective against particular cancer cells before these toxic agents are systemically administered. Pre-testing on "fresh" specimens of cancer cells to determine the optimal combination of chemotherapy drugs could be highly beneficial.


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