The issue surrounding Avastin
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according to ODAC.said unanimously that the approval of Avastin for the treatment of metastatic breast cancer should be withdrawn.
http://www.cancer.org/AboutUs/DrLensBlog/post/2011/06/29/FDA-Advisors-Vote-Unanimously-That-Avastin-Approval-Should-Be-Withdrawn-And-You-Could-Hear-The-Pain.aspx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), at the tyrosine kinase level (Nexavar, 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.
Comments
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OK, Avastin is not for everyone
Dear Greg
Thanks for posting this along with your insights. I read somewhere that the people who had elevated blood pressure from Avastin also had the best results.
In the clinical trials, no one is controlling for diet, exercise and stress management--so these "confounding variables" may have some synergistic effects on the outcome of the trials along with the genetic uniquenesses of the subjects.
take care and be well,
Carolen0 -
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 Analysis0 -
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.0 -
With Low-dose Chemotherapy - You Wouldn't Need Avastingdpawel said: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.
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 Analysis0 -
Biomarker for Avastingdpawel said: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
This is starting to sound very much like the situation with Herceptin years ago. Herceptin drew fire from the FDA and other groups, including ASCO, because of its expense and the fact that it helped only 11-20% of patients who received it.
There were tons of data showing that pathologists were "over-calling" the cases of HER2-positive via IHC and manual microscopy. There were tons of data showing that use of automated image analysis virtually eliminated "over-calls" and very reliably normalized IHC scoring among pathologists of all levels of experience.
Even Dennis Slamon (one of the inventors of Herceptin) had told Genentech, they had a drug that is even better than they knew. It only has to be administered to the right patients. The disinterest on the part of Genentech was palpable.
In the end, the FDA did force them to work with someone to develop a reliable pharmacodiagnostic test. Genentech put their muscle behind FISH.
However, in the end, they couldn't completely supplant low-tech IHC and both received FDA approval. Herceptin is now approved for patients who are positive via FISH or IHC, even though patients considered Her2-negative using both tests benefited from Herceptin. In other words, the problem was never solved. It's an inconvenient truth which everyone involved conveniently chooses to ignore. Sheesh!
The way that you get responses to Avastin is by (temporarily) destroying the vasculature, not by normalizing blood vessels in tumors (or "pruning" the vasculature). The problem is that the vessels grow back (quickly). The most vulnerable vessels (to Avastin) are the most newly formed, which are at the vanguard of the advancing tumor.
It is possible to correctly administer Avastin by measuring the vasculature of a tumor with an anti-angiogenesis microvascular viability assay called AngioRx. The test works by measuring drug effects upon endothelial cells which make up blood vessels. Its use could prolong lives, save money, and spare patients exposure to the harmful side-effects of ineffective chemotherapy treatments.
For some time, clinicians have been grumbling about not having a biomarker for Avastin or any other anti-angiogenesis compound to better help choose which patients would be most likely to respond, thereby avoiding the need to treat everyone to gain a benefit in a few.
Suppose there was a biomarker that was relative to Avastin and could be helpful for predictive purposes? Then you could actually make better use of the drug based on the biomarker. You would be able to predetermine and monitor therapy for specific subtypes and avoid exposing patients to the effects and costs of a drug that may not work for them.
A private cell-based assay lab came along with a smart idea, a rational approach to the problem and some creative thinking to develop a biomarker for anti-angiogenesis compounds.
http://cancerfocus.org/biomarker_for_avastin/467080
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