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Old 07-01-2011, 12:06 AM
gdpawel gdpawel is offline
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Default The issue surrounding Avastin

In 2008, the FDA granted accelerated approval for Avastin to be used in combination with paclitaxel chemotherapy for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer. The approval was based on a phase III study (the E2100 study) of 722 patients with metastatic breast cancer randomly assigned to receive Avastin with paclitaxel chemotherapy or paclitaxel alone. A doubling in progression-free survival was observed in patients who received Avastin in combination with paclitaxel chemotherapy compared to patents who recieved paclitaxel alone (1).

Progression-free survival is the length of time during and after treatment in which a patient is living with a disease that does not get worse. Essentially, progression-free survival measures how long it takes for a tumor to start growing again. However, this result doesn’t mean that women taking Avastin lived longer. A doubling in progression-free survival simply means that it took twice as long for the tumor to progress. In fact, there was no increase in overall survival. Moreover, those women who received Avastin experienced a higher overall incidence of toxicities as well as more severe toxicities.

A second phase III trial, the (Avastin plus Docetaxel) AVADO trial, investigated the benefits of combining Avastin with a different chemotherapy, docetaxel, in over 700 previously untreated patients HER2-negative locally recurrent or metastatic breast cancer (2). In the primary analysis (data cut-off point: October 2007; median follow-up of 10.2 months), treatment with Avastin significantly increased progression-free survival compared to patients who received docetaxel chemotherapy alone (3). However, more recent analysis of the patient population evaluating overall survival (data cut off point: April 2009; median follow-up of 25 months) failed to define a statistically meaningful benefit (4).

A third phase III trial, the RIBBON-1 trial, evaluated chemotherapy (assigned at the discretion of a physician: either a taxane, an anthracycline or capecitabine) with or without Avastin for first-line treatment of stage IV HER2-negative locally recurrent or metastatic breast cancer (5). Avastin plus capecitabine compared with placebo plus capecitabine, and Avastin plus taxane or anthracycline versus placebo plus a taxane or anthracycline significantly improved progression-free survival but had no effect on overall survival.

In both the AVADO and RIBBON-1 trials, women receiving Avastin had an increased risk of death; 0.8% of women in AVADO and 1.2% of women in RIBBON-1 died from side effects thought to be related to Avastin (6).

A fourth phase III trial, the RIBBON-2 trial, which evaluated the efficacy and safety of Avastin in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer also significantly improved progression-free survival but failed to show statistically significant improvement of overall survival (4).

Thus, Avastin reproducibly increases progression-free survival but, on average, doesn’t keep women with metastatic breast cancer alive any longer than chemo alone.

The problem with Avastin is that doctors don’t know which patients will respond favorably in terms of overall survival. In the majority of patients, Avastin increases progression-free survival but has no effect on overall survival.

When the FDA started discussing the possibility of withdrawing the indication for Avastin, critics of the agency accused them of rationing healthcare, claiming that it was Avastin’s high cost (as much as $100,000 a year), not its limited benefit, that the FDA cared about.

Although the issue clearly revolves around Avastin’s survival benefit, the FDA should be concerned about costs. Healthcare costs endanger U.S. financial stability. Simply ignoring the skyrocketing costs of healthcare and focusing exclusively on the treatment benefits, however small — in this case the average survival benefit is zero — will have a devastating effect on the U.S. economy.

Avastin should be placed in a restricted-access program so that patents already on the drug and benefiting from it can maintain access to it. Pharmacogenomics should be used to identify the best candidate patient population and a subsequent study should then be undertaken to determine biomarkers that have clinical utility in measuring the efficacy of Avastin in those patients. Several candidate biomarkers have already been described, including tumor and plasma VEGF, circulating E-selectin, ICAM 1 and VCAM1 (7).

We consider this a realistic and rational approach to provide effective, personalized therapy while simultaneously managing healthcare costs. Indeed, patient advocacy organizations called for the use of personalized medicine stratetiges back in August to keep Avastin on the market for those who are most likely to benefit from the disease (8-9):

We recognize the benefits of Avastin overall are modest for women with metastatic breast cancer. However, we do know that for some women, Avastin offers a greater benefit, but we do not yet know how to determine which patients will experience greater benefits. We have much more to learn about the drug and how individual patients respond to the drug, such as why some women receive greater benefit while others do not. Moving into the world of personalized medicine, cancer treatments will be more tailored to the characteristics of patients’ individual tumors. Yet, due to the current state of the science, we don’t always know which patients will benefit most before a drug is made commercially available. As with all medicines, we encourage a thoughtful discussion between a woman and her doctor that carefully considers the benefits and the risks. FDA approval is not a requirement for a doctor to prescribe a drug. However, the panel’s decision could limit the so-called “off-label” use of Avastin for metastatic breast cancer, or ovarian cancer, for which Avastin is currently prescribed off label, if third party payers refuse to cover the cost of treatment.

References

1. Miller et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76.

2. D. Miles et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. J. Clin. Oncol. 2008;26(155)(Suppl): LBA1011.

3. Avastin improves survival in advanced breast cancer. Pharma Strategy Blog. 2008 Jun 2.

4. Avastin for breast cancer shines in PFS but not overall survival. Pharma Times. 2009 Dec 4.

5. Robert et al. RIBBON-1: Randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J. Clin. Oncol. 2009;27(155)(Suppl): 1005.

6. FDA Advisory Committee Recommends against Bevacizumab for Metastatic Breast Cancer. NCI Cancer Bulletin. 2010 Jul 27.

7. Yang SX. Bevacizumab and breast cancer: current therapeutic progress and future perspectives. Expert Rev Anticancer Ther. 2009 Dec;9(12):1715-25.

8. Statement on Avastin. Susan G. Komen for the Cure. 2010 Aug 17.

9. Ovarian Cancer National Alliance and Susan G. Komen for the Cure Appeal to FDA and Key Lawmakers on Avastin Issue. Ovarian Cancer National Alliance. 2010 Aug 12.

Source: Highlight HEALTH
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Old 07-01-2011, 12:07 AM
gdpawel gdpawel is offline
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Default FDA looks to a more stringent path for accelerated drug approval?

The FDA’s Oncologic Drugs Advisory Committee (ODAC) met to debate the value of the FDA's accelerated approval program for cancer drugs. The goal of the accelerated program is to provide novel and promising treatments to patients faster than through the traditional, longer route to FDA approval.

Accelerated approval is granted based on a surrogate endpoint study rather than the gold standard of overall survival, bona fide clinical efficacy, or quality of life improvement. Surrogate endpoint trials are generally faster than the traditional efficacy trials that are required for full drug approval because the surrogate endpoints are typically laboratory readouts that are available before direct measure of effectiveness.

Subsequent to an accelerated approval, drug makers are required to confirm clinical efficacy and demonstrate drug safety with post-marketing trials called Phase 4 confirmatory trials. If the drug does not live up to its anticipated clinical benefit, the FDA can use an expedited procedure to withdraw the drug from the market. The meeting was prompted by the recent decision to remove the breast cancer indication from Roche's cancer drug, Avastin, from the market.

Accelerated approval is based on likely, but not yet proven clinical benefit. Therefore, the right surrogate marker study is crucial, as is the post-marketing effectiveness trial. The panel discussed both the design of trials required for accelerated approval as well as post-marketing studies. The committee debated whether a randomized, two-arm trial rather than a single-arm trial should be required in certain accelerated approval cases.

The committee also discussed whether a minimum of two post-marketing trials is necessary and whether accelerated approval should be delayed until the confirmatory trials are actually underway. Ideally, the FDA Office of Oncology would like drug makers’ to have confirmatory trials underway, with set completion dates, at the time of accelerated approval.

Two years ago, the breast cancer indication for Avastin was approved under the accelerated program, however the FDA officially announced its recommendation to remove the breast cancer indication from Avastin’s label in December 2010, following an independent advisory committee’s 12-1 vote for indication removal.

The greatest benefit that breast cancer patients have seen on Avastin is improvement in progression-free survival by a few months when the drug is combined with chemotherapy. Genentech responded to the FDA in January 2011 with evidence the company says demonstrate why the label should stay in place and has requested an FDA hearing. The company is still awaiting a response.

The goal of the ODAC is not to remove the accelerated program but to improve the regulation, design, and conduct of the trials required for accelerated approval and for confirmatory trials. If the FDA is able to put forth more stringent rules about accelerated approval trial design and enforce the timely execution of Phase 4 trials, this should, at least in theory, allow necessary access to promising medication while decreasing the time an ineffective treatment stays on the market.

Source: cancernetwork.com
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Old 07-01-2011, 12:13 AM
gdpawel gdpawel is offline
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Default More on Avastin

A meta-analysis focusing on cardiovascular events in randomized studies of chemotherapy with or without Avastin (bevacizumab) in the metastatic disease setting demonstrated the expected risk of hypertension but also a modest but statistically significant increase in left ventricular dysfunction. Rates of arteriothrombotic events were not statistically different.

A Meta Analysis of Risk of Cardiovascular Events in Patients with Metastatic Breast Cancer (MBC) Treated with Anti Vascular Endothelial Growth Factor (VEGF) Therapy – Bevacizumab.

Nasim S, Sousa BA, Dent RA, Pritchard KI. Sunnybrook Health Sciences Centre, Toronto, ON, Canada; University of Toronto, ON, Canada

Background and objectives:

Bevacizumab, used in combination with chemotherapy has demonstrated efficacy in randomized trials in MBC. Hypertension, congestive heart failure and cardiomyopathy have been reported in trials of bevacizumab in breast cancer. The aim of this systematic review and meta analysis is to determine the overall risk of grade 3-4 hypertension (HTN), left ventricular dysfunction (LVD) and venous (VT) and arterial thromboembolic events (ATE) related to Bevacizumab in patients with MBC.

Methods:

We selected randomized phase III trials which compared chemotherapy with or without bevacizumab in MBC as first or second line therapy. Data extraction was carried out from results published in the literature or from conference proceedings of the selected studies. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. We collected all grade 3-4 events reported in these trials in relation to cardiovascular events: HTN, LVD, congestive heart failure, cardiomyopathy, VT and ATE.

Results:

Five trials were included in the meta-analysis: E2100, AVADO, RIBBON-1, RIBBON-2 and Miller et al study (capecitabine alone or plus bevacizumab in previously treated MBC). In total 2126 patients received chemotherapy in combination with bevacizumab and 1444 chemotherapy alone. When there was tendency for heterogeneity, random-effects models were used. Thromboembolic events were pooled together as VT and ATE as information was not clear in some of the reported studies. CHF and cardiomyopathy were considered for LVD events in the Miller study as LVD was not reported. Patients treated with bevacizumab-containing regimens had a RR for HTN of 10.32 (95% CI, 4.23- 24.79; p<.0001), RR for LVD 2.58 (95% CI, 1.06 - 6.32; p=0.04) and RR for VT and ATE of 1.71 (95% CI, 0.81- 3.60; p=0.16) as shown in figure 1.

Conclusion:

HTN is a recognized side effect of bevacizumab therapy. The risk of LVD is also significantly higher with bevacizumab therapy (RR 2.58) as shown in this pooled analysis, but the risk of thrombotic events is not increased.

Another Phase II study demonstrated good tolerability and encouraging efficacy when docetaxel 75 mg/m2 was combined with Avastin (bevacizumab) in HER2-negative disease, as well as when Herceptin (trastuzumab) was added to the regimen in patients with HER2-positive tumors.

Phase II Multicenter Study of Docetaxel and Bevacizumab (Bev) +/- Trastuzumab as First-Line Treatment of Patients with Metastatic Breast Cancer (MBC).

Schwartzberg LS, Hermann R, Blakely J, Richey SS, Tauer KW, Childs BH. West Clinic, Memphis, TN; Northwest Georgia Oncology Center, Marietta; Sanofi-Aventis, Bridgewater, NJ

Background:

The addition of Bev to the taxanes docetaxel and paclitaxel has resulted in improved progression-free survival (PFS) in the first line setting of HER2- MBC. The majority of data with docetaxel is from the AVADO study, which used a dose of 100 mg/m2 of docetaxel. No data exists that combines Bev with docetaxel at the current U.S. standard dose of 75 mg/m2 in HER2- MBC, or at any dose in the HER2+ setting. We report here the results of the feasibility, safety, and efficacy data of the combination of 75 mg/m2 of docetaxel and bevacizumab in HER2- MBC, and the first reported results of docetaxel, Bev, and trastuzumab in HER2+ MBC.

Methods:

Phase II, nonrandomized, parallel arm study, stratified by HER2 status, conducted in a large community practice network. Eligibility: Histologically-proven breast adenocarcinoma, stage IV disease with at least one measurable lesion per RECIST criteria, ECOG PS 0-1, no prior chemotherapy for metastatic disease, no evidence or history of brain or leptomeningeal metastases. Stratum 1 (HER2-) treatment: Bev (15mg/kg) followed by docetaxel (75 mg/m2) q 3 weeks. Stratum 2 (HER2+) treatment included in addition trastuzumab (8 mg/kg loading dose on day 2 of cycle 1, and 6 mg/kg on day 1 of all subsequent cycles). All subjects received G-CSF as primary prophylaxis. Treatment continued until unacceptable toxicity, disease progression, or death. Docetaxel could be discontinued after 8 cycles if a complete response (CR) was obtained with continuation of Bev (and trastuzumab in her-2+ pts) until disease progression. Primary endpoint: Progress-free survival (PFS) in each stratum. Secondary endpoints: overall response rate (ORR), clinical benefit rate (CBR), overall survival, safety.

Results:

The trial accrued 73 patients (Stratum 1/2, 52/21) pts from August 2006 to March 2009. Seventy two pts (Stratum 1/2 52/20) were treated. As of April 5, 2010, two pts (both stratum 1) remained on treatment. The most common grade 3-4 adverse event in each stratum was fatigue (Stratum 1/2 11.5%/10%). Incidence of grade 3 hypertension (Stratum 1/2) was 3.8%/5.0%. No treatment-related deaths, colonic perforations or clinical CHF events occurred. The median number of cycles of docetaxel delivered was 8 in both strata. The median number of cycles of Bev delivered was 8 in stratum 1 and 12.5 in stratum 2. The median number of cycles of trastuzumab delivered in stratum 2 was 13. The ORRs were 57.7% (5.8% CR, 51.9% PR) in stratum 1, and 81.0% (28.6% CR, 52.4% PR) in stratum 2. The CBRs were 67.3% (95% C.I., 52.9%-79.7%) in stratum 1, and 81.0% (95% C.I., 58.1%-94.6%) in stratum 2. The median (95% CI) PFS was 8.5 (5.33-10.77) months in stratum 1 and 13.43 (12.10-N.A.) months in stratum 2.

Conclusion:

In first-line MBC, docetaxel of 75 mg/m2 plus Bev administered Q3W in HER2- and of docetaxel and trastuzumab plus Bev in HER2+ disease is feasible and safe in the community practice setting, with high response rates and promising PFS compared to historical controls not treated with Bev. The tolerability of docetaxel 75 mg/m2 with Bev may be better than higher dose docetaxel. These results support the use of these regimens in the clinical practice setting.

Note:

Clinical Benefit Rate (CBR) and Disease Control Rate (DCR) are defined as the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents. CBR and DCR are commonly reported in many clinical trials in abstracts, papers, meeting presentations and media releases. The frequent use of these measures of drug activity presents the question of whether CBR and DCR are useful additional endpoints in early clinical trials, and if they can reasonably predict the success of an agent in subsequent, adequately powered, randomized trials. There are no comprehensive analyses to demonstrate that CBR or DCR add to the value of traditional response/activity endpoints in early clinical trials. Data from phase II clinical trials in which the CBR or DCR are reported suggest that CBR or DCR provides ambiguous information that likely exaggerates the anticancer activity of the therapy. The terms 'disease control' and 'clinical benefit' in the context of non-randomized trials are themselves disingenuous because neither tumor regression nor stable disease, defined without any consideration of duration of effect or reduction of symptoms appropriate for the specific patient population, are evidence of these endpoints in an individual patient (Curr Opin Investig Drugs. 2010 Dec;11(12):1340-1).

Reporting disease control rates or clinical benefit rates in early clinical trials of anticancer agents: useful endpoint or hype?

[url]http://www.ncbi.nlm.nih.gov/pubmed/21268434
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Old 07-01-2011, 12:38 AM
gdpawel gdpawel is offline
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Default FDA's Decision to Remove Approval for Avastin in MBC Caught Between Data and Emotion

Dr. Len Lichtenfeld of the American Cancer Society, blogged about his experience at the hearing, on June 28th and 29th, held by the FDA on the question of whether or not Avastin should retain approval for the treatment of metastatic breast cancer.

[url]http://www.cancer.org/AboutUs/DrLensBlog/post/2011/06/28/The-FDAs-Decision-to-Remove-Approval-for-Avastin-in-Metastatic-Breast-Cancer-is-Caught-Between-Data-and-Emotion.aspx

When the votes were in, the FDA Advisory Committee voted 6-0 that the risks, being substantial, outweighed the benefits associated with a slight slowing of the pace at which metastatic breast tumors progress. Thus, for the Avastin indication granted accelerated approval in 2008 — metastatic breast cancer — Avastin is considered unsafe, according to ODAC.said unanimously that the approval of Avastin for the treatment of metastatic breast cancer should be withdrawn.

[url]http://www.cancer.org/AboutUs/DrLensBlog/post/2011/06/29/FDA-Advisors-Vote-Unanimously-That-Avastin-Approval-Should-Be-Withdrawn-And-You-Could-Hear-The-Pain.aspx

Avastin combined with chemotherapy has improved the survival of some lung cancer patients. Avastin plus folfox has improved survival for some 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 cancer patients.

Roche has reported that women with breast cancer who were treated with Avastin in combination with chemotherapy followed by the continued use of single-agent Avastin demonstrated a significant improvement in progression-free survival. It’s unclear if Avastin can help increase the overall survival rate in this indication.

I remember a clinical oncologist involved with real-time studies under real-world conditions of drugs like Avastin, telling me 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 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.

The solution to this problem is 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.

In regards to Avastin side effects, any chemotherapeutic has its range of side effects. With Avastin though (and probably most other agents), it was reported in JCO that emerging evidence shows many of the drugs like Avastin may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The dose being used for Avastin is 15 milligrams per kilogram of body weight, despite research showing it may work with 3 milligrams per kilogram.

There are selected groups who will benefit from Avastin, if they knew who they were. Genentech/Roch (or whatever flavor of the month they are) researchers have been looking for tests to help predict how patients will respond to Avastin. Some have suggested that they should use the cell-based functional profiling platform (AngioRx Assay) to identify a potential targeted population of cancer patients that it thinks will benefit from Avastin, and then conduct a randomized clinical trial among this group.

However, unlike some genetic assays that look whether an individual has a particular mutation or amplification, and therefore tests for “theoretical” candidates for a particular targeted drug, the functional profiling technique may find Avastin not synergistic (cooperative) and finds some other VEGF-targeted (or multiple VEGF-targeted) drug may work better in an individual cancer patient and then put that individual into the clinical trial. I can understand they may not want some other drug tested on their dime.

There are a number of new classes of drugs that target VEGF, at the protein level (Avastin, Zaltrap), at the tyrosine kinase level (Iressa, Nexavar, Tarceva, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel). However, responses to any individual mechanism occurs in the miniority of patients. It is unclear why some patients repond to these interventions while others fail. In cell function analysis, it has found unexpectedly good response to conventional cytotoxic drugs following a failure to respond to these targeted agents.

This reinforces the need for cancer therapies to be individualized. It remines us that it is the good outcome of the patient not the therapy applied that constitute successful therapy. There is really nothing wrong with Avastin. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman. There are not perfect drugs. There are simply drugs that work for certain patients. But that’s not what pharmaceutical companys like to hear. They like to produce drugs that apply to a broad base of patients. To make the most out of a drug, not just some subsets of patients.
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Last edited by gdpawel : 02-08-2013 at 10:59 AM. Reason: corrected url address
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Old 07-06-2011, 01:41 PM
gdpawel gdpawel is offline
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Default Angiogenesis and the role of VEGF

Angiogenesis is the formation of new blood vessels. Although this process is normal in the growth of development of children, it happens rarely in adults. For example, angiogenesis occurs during the healing of a deep cut. Otherwise, angiogenesis in adults is usually part of a disease process such as cancer.

Angiogenesis is essential for the growth and metastasis (spread) 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.

The role of VEGF

Vascular endothelial growth factor (VEGF) is an important activator of angiogenesis. Like the name indicates, VEGF causes endothelial cells to grow. Research has shown that oncogenes (genes that help cancer cells grow), cytokines (substances produced by the immune system), and hypoxia (a low-oxygen environment, which is common in tissues around solid tumors) can all directly or indirectly activate VEGF, thereby starting angiogenesis.

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 reactions inside the cell. Because VEGF is so important to angiogenesis, it is a target of new cancer treatments. For example, the drug bevacizumab (Avastin) blocks a receptor for VEGF.

In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF. There are multiple ways by which tumors can evolve that are independent of VEGF. 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.

The problem with Avastin is the same thing that was a problem with AZT for HIV/AIDS. Early results, then rapid resistance. The solution is "combination therapy" to attack all the different targets.

We need to attack these other targets as well. If you can achieve this, then you really don't need the other drugs, which really 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.

There are a number of new classes of drugs that target VEGF, at the protein level (Avastin), at the tyrosine kinase level (Nexavar, Sutent) and at the intracellular metabolic pathway mTOR (Afinitor, Torisel).

It's going to take "combination" antivascular therapy to make the big difference, but this is definitely coming and it's the most promising thing on the therapeutic horizon.

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). The AngioRx Assay can be of significant clinical value.

Source: Cell Function Analysis
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Old 07-07-2011, 04:36 PM
gdpawel gdpawel is offline
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Default The Avastin Saga Continues

[Dr. Robert A. Nagourney is medical director at Rational Therapeutics and instructor in Pharmacology at the University of California, Irvine School of Medicine. He posted on his blog about the issue surrounding Avastin.]

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.
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Old 08-02-2011, 09:52 PM
gdpawel gdpawel is offline
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Default With Low-dose Chemotherapy - You Wouldn't Need Avastin

Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. However, the anti-angiogenic effects of dose-dense therapy may be masked and marginalized by the way it is usually administered. The main targets of high-dose chemotherapy are presumed to be proliferating tumor cells. The main targets of low-dose chemotherapy are the endothelial cells of the growing vasculature of a tumor. In other words, chemotherapeutics are used as anti-angiogenic agents.

The process of angiogenesis is controlled by two distinct types of proteins, referred to as "angiogenic growth factors" and "angiogenesis inhibitors." Medical researchers have identified 19 angiogenic growth factors in the human body and 31 angiogenesis inhibitors. In a healthy body, a perfect balance of factors that promote and prevent angiogenesis is maintained. After cells become cancerous, the regulation of this balance is disturbed, stimulating the production of new blood vessels.

Targeted therapies, such as Avastin, were originally designed with the goal of replacing chemotherapy, to reduce the serious morbidities associated with standard high-dose chemotherapy. Although targeted therapies may be somewhat less toxic, most of them have been found to have very modest efficacy, at least when used as single agents in treating patients with advanced disease. They have therefore mainly been used in combination with standard chemotherapy or radiation protocols.

It is becoming more apparent to administer drugs to patients with certain types of cancer on a weekly schedule. The advantage of low-dose chemotherapy is the possibility of combining it with anti-angiogenic drugs as well as other types of targeted therapies, such as those that target specific signal-transduction molecules or with antitumor vaccines.

Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply. When administering both anti-tumor and anti-angiogenesis drugs, the endothelial cells (involved iin angiogenesis) are the first in the tumor to undergo cell death (apoptosis).

Adding Avastin, which only goes after VEGF-sensitive cancer cells, you need to go after other pro-angiogenic factors which can substitute for VEGF: FGF, PDGF, ephrin A1, angioprotein 1, IL-8, etc. And with Taxol promoting an increase of IL-8, how effective is it with Avastin? With the low-dose protocol having an anti-angiogenic effect, you really wouldn't need to add a drug like Avastin into the mix.

Source: Cell Function Analysis
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  #8  
Old 11-18-2011, 11:35 AM
gdpawel gdpawel is offline
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Default FDA Withdraws Avastin's Breast Cancer Indication

According to Merriall Goozner (who occasionaly writes for the Journal of the National Cancer Institute), two clinical trials showed no improvement in mortality among women with metastatic breast cancer. Those trials didn’t even replicate the delay in progression of disease that had been shown in the original trial that led to accelerated approval in 2007. Now comes the firestorm from patient advocacy groups, who will use anecdotal stories to claim the drug works for some women.

Here’s the truth of those matters: Anecdotes are not science. Those who insist their use of the drug is the reason why they are remaining alive longer than average will still have access to the drug since most insurance companies and Medicare will continue to follow the National Comprehensive Cancer Network guidelines.

NCCN’s guideline writing committee, a third of whom have financial ties to Roche/Genentech, has said it will not withdraw Avastin’s use in metastatic patients. A few years ago, CMS passed a rule that said it would reimburse any use of a cancer drug, even if the FDA had not approved it for that use, if it was included in the NCCN guidelines and accompanying formulary.

[url]http://www.fda.gov/NewsEvents/Newsroom/UCM279485

The limitations of progression-free survival as an endpoint

We are being told that dedicated physicians, empowered to scrutinize the best data, could not prove beyond any doubt that Avastin improved survival. The progression-free survival data was favorable and the survival data also “trended” in a favorable direction. But, the final arbiter of clinical approval – the survival advantage for the Avastin-based therapies in breast cancer – has not met statistical significance.

The progression-free survial in the confirmatory trials were less, there were more treatment-related deaths and the overall survival was less. Progression-free survival does not address the patient’s quality of life during those additional months of some serious side effects a number of women experience.

The FDA’s “intent” was that in first-line therapy, it wants to see an overall survival benefit. The reason that Avastin was approved without showing overall survival was the progression-free survival benefit was great. The confirmatory trials found that not to be.

In regards to the few patients with MBC that do well with Avastin, the problem is that doctors don’t know which patients will respond favorably in terms of overall survival, and you do not want to give it to every patient with MBC. 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 biology, we will confront one Avastin after another. There should be an inclusive effort to study and utilize technologies which are based on both the sub-cellular (molecular) level and at the cellular (cell function) level. Because what may benefit one individual cancer patient may not benefit another.

The solution to this problem is 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.

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials.
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Old 11-18-2011, 07:16 PM
gdpawel gdpawel is offline
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Default FDA Yanks Breast Cancer Indication For Avastin

Ed Silverman
Pharmalot.com

After more than a year of controversy and anticipation, the FDA has decided to formally yank the breast cancer indication for Avastin after deciding the widely used medication is not safe and effective for that purpose. However, the drug - which is sold by Genentech - will remain on the market to treat cancers that affect the colon, lung, kidney and brain.

The decision marks a trying stretch for the agency as debate broke out over the wisdom of using progression free survival as a surrogate - instead of quality of life - for conferring approval, while breast cancer patients and their families lobbied hard to maintain the status quo. The episode also highlighted ongoing concerns about the FDA accelerated approval - or fast track - program that first greenlighted Avastin for treating breast cancer.

“This was a difficult decision. FDA recognizes how hard it is for patients and their families to cope with metastatic breast cancer and how great a need there is for more effective treatments. But patients must have confidence that the drugs they take are both safe and effective for their intended use,” FDA commish Margaret Hamburg says in a statement.

“After reviewing the available studies it is clear that women who take Avastin for metastatic breast cancer risk potentially life-threatening side effects without proof that the use of Avastin will provide a benefit, in terms of delay in tumor growth, that would justify those risks. Nor is there evidence that use of Avastin will either help them live longer or improve their quality of life.”

The move comes nearly a year after the FDA initially announced plans to revoke the indication, citing study results showing Avastin does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh such risks as severe high blood pressure; hemorrhage; swelling of the brain, and heart attack or heart failure. The agency had reviewed two additional studies that Genentech submitted in hopes of maintaining the indication.

After the agency gave its initial thumbs down, Genentech appealed, setting up an unusual two-day meeting last summer to review trial data, where the panelists voted 6-to-0 nothing to pull the breast cancer indication. The drugmaker recently offered a compromise that would have modified the Avastin usage and labeling.

The decision to revoke the breast cancer indication was seen as an important test for Hamburg, who has emphasized drug safety as a hallmark of her tenure, which began in the lingering aftermath of the corrosive Vioxx scandal. And for the past several months, Avastin has come to symbolize a willingness to brook extensive pressure to allow a drug to remain on the market amid safety issues.

“This decision sets an important precedent: accumulated science has trumped politicized argument,” says Daniel Carpenter, the Allie S. Freed professor of government at Harvard University and author of ‘Reputation and Power: Organizational Image and Pharmaceutical Regulation at the FDA.’ “The agency faced enormous political pressure from the company and from organized interest groups, and yet rendered a strong decision based upon a searching reading of the available evidence.

Whether this move will put to rest some of the issues raised during the Avastin episode is unclear. In particular, critics say more data should be required before accelerated approval is employed. The FDA has also been criticized for not forcing drugmakers to provide required follow-up data more quickly. Last year, Pfizer withdrew a drug used to treat acute myeloid leukemia after a study found a lack of clinical benefit and an unexpected number of deaths, but the study began four years after approval.

“In an ironic way, this decision actually allows the FDA to expand the accelerated approval program, as there is now a strong, visible and clear precedent for withdrawing an approval when postmarket experiments for an approved drug produce disconfirming efficacy evidence and perhaps problematic new safety signals,” Carpenter says. “This is not an anti-innovation decision and could, in fact, assist pharmaceutical innovation in the years ahead…I predict its longer-term impact will be to help rebuild the agency’s reputation for science-based decisionmaking and for independence from emotionally charged lobbying.”

Some patient advocates hailed the FDA move, having argued that the FDA moved too quickly to endorse the breast cancer indication in the first place. “If we are to continue to speed up the rate at which treatments reach patients we must be able to take back approval when the evidence shows that a drug doesn’t work. Although some individual women believe that Avastin worked for them, there are many women who are not here to tell their story about how Avastin didn’t work. We all want better treatment for women with this disease. Unfortunately, Avastin is not that treatment,” Karuna Jaggar, who is executive director of Breast Cancer Action, writes us.

As for Genentech, the drugmaker now stands to lose an estimated $1 billion in sales. “We are disappointed with this outcome,” the Roche unit says in a statement. “Despite today’s action, we will start a new Phase III study of Avastin in combination with paclitaxel in previously untreated metastatic breast cancer and will evaluate a potential biomarker that may help identify which people might derive a more substantial benefit from Avastin.”

Indeed, Genentech does have an option to resubmit an application to the FDA for a breast cancer indication for Avastin if additional studies prove successful. The drugmaker also has the option of a legal challenge to the agency decision to yank the indication.

The decision is certain to have significant implications for patients, doctors and payers. A recent survey found doctors were largely split over whether they would continue to use Avastin to treat breast cancer. Nearly 45 percent would use Avastin in a first-line setting and nearly 52 percent would use the drug in combination with paclitaxel, otherwise known as Taxol, regardless of an FDA decision.

Meanwhile, the National Comprehensive Cancer Network, an organization of major cancer hospitals, reaffirmed last summer that Avastin was “an appropriate therapeutic option for metastatic breast cancer.” This decision is significant because the NCCN panel of oncologists carries great weight with other specialists and its guidelines are widely used as a reference by the Centers for Medicare & Medicaid Services and insurers for making coverage decisions.

In fact, CMS earlier this year indicated it would continue to provide coverage, even if treatment amounts to off-label use. But one big insurer recently eliminated coverage. Blue Cross of California last month decided to no longer pay for Avastin to treat breast cancer. Whether other insurers follow suit will become a closely watched sport.

For the record, the formal indication that the FDA is now revoking involves Avastin used in combination with the cancer drug paclitaxel (Taxol) for those patients who have not been treated with chemotherapy for their form of metastatic breast cancer known as HER2 negative.
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Old 11-20-2011, 11:28 PM
gdpawel gdpawel is offline
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Default Risks of Fatal Events with VEGFR Tyrosine Kinase Inhibitors

Cary A. Presant, MD, FACP

The use of VEGFR tyrosine kinase inhibitors has increased. The VEGFR TKIs are usually regarded as relatively safe drugs with manageable side effects. However, a report by F. Schutz, et. al. (J. Clin Oncol 2012; 30:871-877) puts a new spin on these impressions. In their metaanalysis, looking at over 4,600 patients in ten randomized trials, the overall incidence of fatal adverse events due to VEGFR TKIs was 1.5%. The results were discordant, with no fatal adverse events in three trials and the remaining fatal adverse events distributed among the other seven trials.

The fatal adverse events which were observed were most commonly hemorrhage (about half of all fatal adverse events) followed by myocardial infarction, liver failure, septicemia, heart failure, cerebrovascular accident, and pulmonary embolism. These fatal adverse events seemed to be evenly distributed among sorafenib, sunitinib, and pazopanib. The highest incidence was 3% risk of fatal adverse events in one trial.

Since more of our patients are being treated with VEGFR TKIs, it is important for us to be aware of these problems, and to discuss them with our patients while they are receiving any of these drugs to be certain that they report any symptoms or signs that would suggest the occurrence of these events. Needless to say, the discussion with patients and the continued monitoring for these adverse events constitutes evidence for using comprehensive visit codes in the follow up of these patients.

Being aware of these unusual reactions gives us added responsibilities in caring for our patients, and added opportunities to help our patients with safer oncologic treatment.

[url]http://jco.ascopubs.org/content/30/8/871.abstract
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