[gdpawel]

We are reminded that the FDA advisory committee, made up of academic experts without ties to the drug industry, voted 12-1 to withdraw the agency's previous approval of Avastin for breast cancer. That previous approval was based on a single clinical trial that showed the drug, when added to chemotherapy in women with far-advanced disease, delayed tumor progression for an additional five and one half months compared to women who got chemotherapy alone.

However, that single clinical trial didn't last long enough to show whether women on Avastin lived any longer. But the FDA gave the drug "accelerated approval" which is a process so companies can begin marketing the drug, but they must conduct new trials to confirm that the surrogate marker of clinical benefit - postponement of tumor growth - actually postponed death.

Recent evidence came in the form of two confirmatory clinical trials submitted to the FDA. Avastin delayed tumor progression for three months but the average length of time to death stayed the same. The delay of tumor progression dropped to less than a month and the patients on Avastin actually fared worse in terms of time until death than those on chemotherapy alone. According to the chairman of the committee, Wyndham Wilson of NCI, Avastin hasn't been shown that it has a clinical benefit.

Maybe this is not only a drawback to the "accelerated approval" process but a drawback to the clinical trial system, a scientifically bankrupt paradigm which has not fostered either efficient or humane progress in cancer chemotherapy. The problem is not with using the prospective, randomized trial as a research instrument, the problem comes from applying this time and resource-consuming instrument to address hypotheses of trivial importance: do cancers prefer Coke or Pepsi?

It is recognized that the benefits of Avastin overall are modest for women with metastatic breast cancer, and that it is known that for some women, Avastin offers a greater than modest benefit. Just who are those who benefit?

The VEGF (vascular endothelial growth factor) system is a target for a number of anti-microvascular cancer drugs. Avastin (bevacizumab) can block VEGF and cause existing microcapillaries to die. A Microvessel Viability Assay (MVA), with functional profiling, can measure death of existing endothelial (and associated) cells.

Avastin directly binds to VEGF to directly inhibit angiogenesis. If Avastin works, within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apopotosis. 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.

Direct anti-tumor and anti-vascular effects were studied of Avastin in fresh biopsy specimens of breast cancer and presented at the ASCO Breast Cancer Symposium on September 5, 2008. The system utilized for the study was MVV with functional profiling, which may be used to "individualize" antivascular therapy. It can be adapted for simple, inexpensive and sensitive/specific detection of tissue and circulating microvascular cells in a variety of neoplastic diseases.

Avastin showed striking anti-microvascular effects but minimal anti-tumor effects. The testing can accurately sort drugs into categories of above average probability of providing clinical benefit on one hand and below average probability of providing clinical benefit on the other hand, based both on tumor response and patient survival.

But, Avastin as a single agent is relatively ineffective in virtually all tumor types other than Renal cancer because it is known to be driven by the VEGF pathway. Some scientists are not sure whether Avastin or any other anti-angiogenic agents are working primarily by pruning new blood vessels, increasing the delivery of another anti-cancer therapy, or potentially another mechanism.

Until this test, there have been the lack of a relevant and practical system for testing anti-microvascular drugs against human tumors in whick to discover synergistic anti-microvascular drug combinations. The MVV test is both relevant and practical for use in discovering synergistic drug combinations and identifying which patients are most likely to benefit from which drug combinations.

Many patients are treated not only with a targeted therapy drug like Avastin, but with a combination of chemotherapy drugs. Therefore, existing DNA or RNA sequences or expression of individual pathways often examine only one compenent of a much larger, interactive process. The oncologist might need to administer several chemotherapy drugs at varying doses because tumor cells express survival factors with a wide degree of individual cell variability.

It is suggested that Genentech should use assays like MVV to identify a potential target population of breast cancer patients that it thinks will benefit from the drug and then conduct a randomized clinical trial among this group. I couldn't agree more.