FDA Raises Questions About Benefits Of Avastin For Breast Cancer Patients

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Treating breast cancer with a combination of chemotherapy and the cancer drug Avastin "is not clinically meaningful," according to an FDA document published online on Friday, Dow Jones/Wall Street Journal reports. FDA said the level of improvement in women treated with chemotherapy and Avastin was not significantly better than in women who received chemotherapy alone...

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[gdpawel]

Treating breast cancer with a combination of chemotherapy and Avastin is not clinically meaningful, according a document published by the FDA. The FDA said the level of improvement in women treated with chemotherapy and Avastin was not significantly better than in women who received chemotherapy alone. In addition, women who took Avastin experienced more serious side effects, such as bleeding.

Avastin received "accelerated approval" in 2008 for the treatment of breast cancer in combination with Taxol. Accelerated approval is granted to drugs based on initial positive studies and drugmakers must submit additional data for full approval. The drug's manufacturer submitted two follow-up studies for full approval of Avastin. The FDA said the follow-up research failed to confirm the magnitude of the benefits observed in the initial study used for accelerated approval.

Investigators of a randomized, phase III trial of Avastin with Taxol in patients with metastatic breast cancer discussed the lack of an overall survival benefit in light of a significant and clinically meaningful improvement in progression free survival. The authors noted the possibility of accelerated tumor regrowth (tumor rebound) compared with chemotherapy alone. It was speculated whether increased in VEGF levels upon discontinuation of Avatin might have resulted in more aggressive disease (Miller K, Wang M, Gralow J, et al. Taxol plus bevacizumab versus Taxol alone for metastatic breast cancer. N Engl J Med 2007;357:2666-2676).

Serum from Avastin treated patients actually support endothelial cell growth in cell culture better than serum from control patients, without Avastin treatment. When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth/survival factors. It will take combination antivascular therapy to make a big difference, but this is definitely coming and it's the most promising thing on the near term therapeutic horizon.

However, there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen. Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry.

Actual results in patients count and theory doesn't matter as much as the evidence that it does what we want it to do. It would be more advantegeous to sort out what's the best profile in terms of which patients benefit from this drug.

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.

Clinical oncologists involved with functional tumor cell profiling analysis, can actually examine this. They have a method for testing anti-angiogenic/anti-microvascular agents, such as Avastin and testing for synergy between different anti-microvascular agents on an individual patient, individual tumor basis. Avastin appears to better deliver the effects of other classes of drugs.

Avastin facilitates vascular access of cytotoxics to tumors. It will take combination antivascular therapy to make a big difference, but this is definitely coming and it's the most promising thing on the near term therapeutic horizon.

As for Avastin's side effects. Evidence in the Journal of Clinical Oncology shows that many of the highly expensive targeted drugs like Avastin may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. Avastin is one example. The dose being used is 15 milligrams per kilogram of body weight, despite research showing it may work with 3 milligrams per kilogram.

In any case the issue with all these targeted drugs is we need better biomarkers to pick which patients are more likely to benefit from them to get the most for our buck. The new targeted drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased. Given the technical and conceptual advantages of cell-based functional profiling assays, together with their performance and modest efficacy of therapy prediction based on analysis of genome expression, there is reason for renewed interest in them for optimized use of medical treatment of malignant disease.

Cell culture assays are a "functional" biomarker. A functional biomarker providing information about the biomarker uptake rate in tumor cells or on tumor cell surfaces through fluorescence intensity changes. In vitro apoptosis for choosing drugs is not different than a marker like estrogen receptor or CD20 or a gene expression pattern. They are all markers. One is a structural marker, the other is a functional marker. There is no conceptual difference regarding the sort of study and data which is required to "validate" any of them.

Over the past few years, gene expression profiling has been suggested as the best way of determing ex vivo drug sensitivity. However due to most patients being treated with combination chemotherapy, this methodology cannot even be calibrated without the use of "functional profiling" cell culture assays, which can integrate all the gene expression into one convenient test result.

Sources:
J Clin Oncol 18:2245-2249
Current Treatment Options in Oncology 2006, 7:103-110 Current Science Inc. ISSN 1527-2729
Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms ASCO 2008 Breast Cancer Symposium Abstract No: 166

[gdpawel]

When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth/survival factors. A research article in The Journal of Clinical Investigation explains tumor vascular regrowth following withdrawal of an anti-VEGF agent.

Rapid vascular regrowth in tumors after reversal of VEGF inhibition.

http://www.jci.org/articles/view/24612

What may limit the effectiveness of Avastin is that there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.

Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry. The realization is that starving tumors by shutting off their blood flow requires that all three mechanisms be addressed.

Also, there are other proangiogenic factors that can affect whether Avastin works or not, FGF, PDGF, ephrin A1, angioprotein 1, IL8, etc. You need to attack these other targets as well. That is why we need combination anti-angioRX. If you can achieve this, then you don't really need the other drugs, which don't get into the tumor so well. Angiogenic attack provides true selective toxicity, something which is sorely lacking with all of the other treatments.

It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems' response to drug treatments, not just one or a few targets or pathways.

There are many pathways to the altered cellular (forest) function, hence all the different "trees" which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.

VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.

Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.

If you find one or more implicated proteins in a patient's tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won't tell you anything about protein interactions. Are you sure that you've identified every single protein that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you'll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell? You're not going to accomplish this using genetic tests.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

The major obstacle in controlling cancer drug prices is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. There is seldom a "standard" therapy which has been proven to be superior to any other therapy. What may work for one, may not work for another.

Literature Citation:
Eur J Clin Invest 37 (suppl. 1):60, 2007
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117
"Cure: Scientific, Social, and Organizational Requirements for the Specific Cure of Cancer" A. Glazier, et al. 2005

It is going to take combination antivascular therapy to make a difference, as Weisenthal, et al had shown at the 2008 ASCO Breast Cancer Symposium.

http://her2support.org/vbulletin/showthread.php?t=35591

[gdpawel]

An article appearing in the Journal of Internal Medicine reported that until the Microvascular Viability Assay (MVA) test, there have been the lack of a relevant and practical system for testing anti-microvascular drugs against human tumors in which to discover synergistic anti-microvascular drug combinations.

According to Dr. Larry Weisenthal, MD, PhD., developer of the test, it works by measuring drug effects upon endothelial cells which make up blood vessels. The MVA 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.

Dr. Weisenthal says he would like to see the test become available to patients worldwide through service agreements with larger laboratory companies or with a biotechnology company which might develop a testing kit for sale to hospitals and laboratories. He also would like to license the test to pharmaceutical companies for use in new drug development.

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

Source: J Intern Med 264:275-287, September 2008

Bibliography relevant to AngioRx/Microvascular Viability assay (MVVA)

1. Weisenthal, L. M. Patel,N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264(3): 275-287.

2. Weisenthal, L., Lee,DJ, and Patel,N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166. Slide presentation at: http://tinyurl.com/weisenthal-breast-lapatinib

3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)

4. Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. from http://hdl.handle.net/10101/npre.2010.4499.1

[gdpawel]

By Dr. Robert Nagourney

Nothing really. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman, MD, at Harvard University. Dr. Folkman reasoned that:

Cancers require oxygen and nutrients

These would need to be delivered by a blood supply

Tumors would avidly seek their own blood supply via humoral factors.

His groundbreaking work ultimately lead to the discovery of VEGF, as well as the FDA approval of Avastin, the monoclonal antibody that binds and inactivates circulating VEGF in patients. The problem isn’t with Avastin, it’s with the practice of oncology – the clinical trial process and the muddied waters that surround clinical utility of any drug, new or old.

There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. Our solution to this problem has been to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.

[Dr. Nagourney is medical and laboratory director at Rational Therapeutics, Inc., in Long Beach, California, and an instructor of Pharmacology at the University of California, Irvine School of Medicine. He is board-certified in Internal Medicine, Medical Oncology and Hematology.]

[gdpawel]

Published online 21 November 2010 | Nature | doi:10.1038/news.2010.623

http://www.nature.com/news/2010/1011....2010.623.html

About the most key statement in the article (when it comes to treatment) is, "most people agree that a single pathway is not going to do it." When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth/survival factors.

The problem with Avastin is the same thing that was a problem with AZT for HIV/AIDS. Early results, then rapid resistance. Solution was combination therapy to attack different targets. With cancer, it's going to take combination antivascular therapy to make a difference.

Tumor vasculature needs VEGF to survive. Avastin removes VEGF, killing blood vessels. But other proangiogenic factors can substitute: FGF, PDGF, ephrin A1, angioprotein 1, IL-8 etc. We need to attack these other targets, as well.

If you can achieve this, then you may not even need the other drugs, which don't get into the tumor so well. But angiogenic attack provides true selective toxicity, something which is sorely lacking with all of the other treatments.

Perhaps Avastin "sensitive" tumors secrete relatively low levels of VEGF. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent which works by blocking VEGF.

As the article mentions "vascular mimicry," something I've written about on the board previously, there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis.

Tumors can acquire a blood supply by angiogenesis, co-option of existing blood vessels and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.

While vasculogenic mimicry - some types of cancers form channels that carry blood, but are not actual blood vessels - with co-option, instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process cannot be stopped with drugs that inhibit new blood vessel formation.

The consistent and specific cure or control of cancer will require developing and using a set of drugs, given in combination, targeted to patterns of normal cellular machinery related to proliferation and invasiveness.

A sufficient number of independent methods of cell killing must be employed so that it is too improbable for a cancer cell to evolve that can escape death or inactivation. It must examine every cell in the body and must do so for a prolonged period of time.

Given the current state of the art, cell-based in vitro drug sensitivity testing (with functional profiling) could be of significant clinical value. One aspect of a functional profiling assay is that microvascular viability can measure dead microvascular cells in tissue, fluid and peripheral blood specimens to identify potential responders to anti-angiogenic drugs (Avastin, Nexavar, Sutent) and to assess direct and potentiating anti-angiogenic effects of tyrosine kinase targeted therapy drugs (Tarceva, Iressa).

[gdpawel]

The UK’s National Institute for Health and Clinical Excellence has rejected the use of Roche’s Avastin for treating breast cancer on the grounds that the med offers “limited and uncertain benefit” for patients compared with existing treatments. Roche had calcuated the total average cost of treating a patient with Avastin plus chemotherapy is more than $52,000.

“Unfortunately, we did not receive any evidence from the manufacturer to show that (Avastin) can significantly lengthen a patient’s life or, importantly, offer a better quality of life than existing treatments. Although the data seemed to show that the drug may slow the growth and spread of the cancer, the size of this effect varied between studies. Furthermore, it was extremely unclear that the benefits in terms of slowing tumour growth translated into benefits on overall survival, which is what really matters for patients,” NICE chief executive Andrew Dillon says in a statement.

Nonetheless, the decision casts an ominous shadow over an upcoming decision by the FDA. Last July, you may recall, an FDA advisory committee dealt Roche a blow by voting 12 to 1 to recommend the agency withdraw approval for the multibillion-dollar cancer drug for treating breast cancer. The FDA approved Avastin two years ago to fight breast cancer, but two studies - which were undertaken as a condition of approval - found patients given Avastin and chemotherpay didn’t survive longer than those given chemo alone. Avastin patients also suffered more serious side effects.

The Avastin decision has stirred controversy over the yardsticks used to approve Avastin for breast cancer treatment and the FDA’s accelerated approval program. For instance, one advocacy group, Breast Cancer Action, maintains the FDA placed too much emphasis on surrogate markers, specifically, progression-free survival. Meanwhile, some cancer patients worry the agency will yank the med, which in some cases has been proven helfpul.

Source: Pharmalot

http://www.nice.org.uk/newsroom/pres...eastCancer.jsp

http://www.pharmalot.com/2010/07/fda...breast-cancer/

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