FDA finds Avastin doesn't extend lives in BC patients... ?

[hutchibk]

http://news.yahoo.com/s/ap/20100717/...ncer_avastin_5

[chrisy]

Hmm. I'm not surprised about this as the studies have been out there showing no "survival advantage" even though there was progression-free survival advantage. I think the QOL aspect is another question. Intervals of progression free survival are important here. I'm also curious about the comment of "increased side effects" - compared to what? chemo? cancer symptoms?

[tricia keegan]

I saw this earlier and agree with Chrissy, I know a few people taking this and hoping it would help

[Rich66]

This seems to be the heart of the article:

Avastin's so-called "accelerated approval" was based on the condition that later studies would show a survival benefit.
But in briefing documents posted online,FDA reviewers said two follow-up studies recently submitted by Roche failed to show that Avastin significantly extended lives compared to chemotherapy alone.
Additionally, the FDA said that in follow-up studies the drug did not slow tumor growth to the same degree as in earlier studies.
Patients taking Avastin showed significantly more side effects, including high blood pressure, fatigue and abnormal white blood cell levels.

There has been some suggestion that it might be a drug that should be continued after progression to avoid rebound, kind of as a base to layer other chemos on top of. More frequent dosing could be beneficial as well.
Might do better with an Hif1 inhibitor.

Been tracking angiogenesis here:
http://her2support.org/vbulletin/sho...218#post221218

[Debbie L.]

Here's a link to the FDA website where you can see their documentation of the information that will be discussed at the ODAC meeting next week. http://tinyurl.com/3ys6hxb . Click on " Briefing Information for the July 20th . . ." in the first box. They have quite a detailed analysis of the two studies (AVADO and RIBBON1), some history of the drug, and a brief general discussion of treatment of metastatic breast cancer.

My sense is that Avastin is used a lot for 1st line HER2- metastatic treatment (and there are some adjuvant studies also), so a change in its (accelerated) approval status would be big.

But the bigger question here, as Crissy said, is about trial endpoints. Does a drug have to extend life to be worth using? What if it does not extend life, but by extending progression free survival it improves quality of life (fewer symptoms, fewer anxieties as progression happens and necessitates treatment changes, etc)? And then, what if it actually shortens life while improving quality (as some trends might indicate, in these studies)?

These end-point questions have not been answered by the FDA and those answers will have much longer-lasting impact than whether Avastin is approved for bc.

Another interesting part of this is that ODAC voted (5-4) AGAINST the accelerated approval, and the FDA granted approval anyway.

I don't know the answers. Frankly, depending upon who I'm talking to, I can be swayed either way. So wishy-washy. The argument against approval is that we must keep the bar high, so that drug companies will strive harder to offer better treatments, and so they do not think they can make fortunes with (very) marginally-effective products. The strongest argument for approval comes from those who say that quality of life is important too, and that at least for some, Avastin offers an improvement there. But even if we do agree that QOL should be part of the picture, these studies didn't measure quality of life. So can we infer it just because there was a little bit of PFS (plus lots more grade 3-5 SEs)? This dilemma makes it clear that if PFS is going to be an endpoint, QOL has to be included in the mix.

What a hard decision for ODAC and for the FDA.

[Jackie07]

Debbie,

What is PFS? Were you trying to say 'DFS' - Disease-free survival?

[Debbie L.]

Hi Jackie,

PFS is progression free survival. Crissy mentioned it and it was the primary endpoint of the studies. I should have spelled it out before using the abbreviation, just got lazy.

Some have thought that PFS would be a surrogate for overall survival (OS) - it seemed logical that it would be so. But that is clearly not true for Avastin (PFS is not a surrogate for OS) and so now more questions are raised. Is PFS still an important endpoint in itself, and if so, what other factors (QOL, toxicities, etc) should be considered in the evaluation?

Debbie

[Rich66]

This was from '08, when it was probably monotherapy, but seems relevant now:
http://www.cancerdecisions.com/conte.../lang,english/

[gdpawel]

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.

[Rich66]

http://www.pharmastrategyblog.com/20...rategy+Blog%29

[gdpawel]

Investigators of a randomized, phase III trial of Avastin with paclitaxel 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. Paclitaxel plus bevacizumab versus paclitaxel 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.

[Rich66]

http://www.wtsp.com/news/local/story...140009&catid=8

"I have always felt that Avastin benefits select patients to a great extent, and others not so much. I have had multiple patients who have responded very well to abraxane and Avastin for example, whereas some other did not derive as much response.

..we need better biomarkers to pick which patients are more likely to benefit

[gdpawel]

"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."

Couldn't have said it any better!

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 "functional tumor cell profiling" of cell culture assay, 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.

[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

[Debbie L.]

Another idea that could explain the Avastin thing(s) would be that there are some "super-responders" who benefit, but that we don't yet know how to identify them. Bryan Schneider at Indiana University, for example, is doing work on this. He's looking at host factors (vs. tumor factors) that may influence response (and perhaps also explain the association between side effect and response).

http://jco.ascopubs.org/content/26/28/4672.abstract

I heard that there are nearly 100 trials currently in progress on Avastin and breast cancer, so I doubt we've heard the last word on this topic yet. I hope they find a subgroup that benefits immensely, so we can give the Avastin to them and save everyone else the angst of denying it to them, the suffering of toxicities (for no benefit), and the enormous cost that drains our resources (again to no benefit).

Debbie Laxague

[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.]

[Debbie L.]

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.

I'm not sure what this is saying. It's the FDA's fault? I have my issues with the FDA but let's give them some credit. What they are using in their evaluations is the information submitted to them by the drug company's clinical trials. What about the drug companies? Shouldn't it be THEIR job (especially since they are making millions) to figure out who their drug works for, and who it does not work for? If we keep harassing the FDA to approve drugs that appear marginally effective but that probably work strongly in certain subgroups, we are encouraging drug companies to do what they've been doing -- spew out ridiculously expensive drugs, give them to broad populations of people, few of whom benefit and many of whom suffer -- but all of whom pay a lot of $$ for the privilege. I think it should be the drug company's responsibility to find the biomarkers or genetic traits that predict for response.

I don't think there has been any success in tying VEGF expression in breast cancer tumors to Avastin response. See my previous post about host factors -- maybe we will find the answer there (or not). But again, it frustrates me that WE are trying find the answer. The drug company should be looking for that answer, before asking to market ($$) their drug to untargeted populations.

Debbie Laxague

[schoonder]

Flip side, when company does go after a "targeted" drug, i.e. t-dm1 for Her2+ mbc treatment, FDA insists that "all" prior approved bc therapies, targeted or not, are included in the study. Is this a situation of having your cake and eating it too?

[Debbie L.]

when company does go after a "targeted" drug, i.e. t-dm1 for Her2+ mbc treatment, FDA insists that "all" prior approved bc therapies, targeted or not, are included in the study

Yes, I agree, that ruling made no sense to me either -- how could (on average) SEVEN prior therapies not be enough? But I've since learned that the above explanation is not the FDA's explanation, or at least not their full explanation. Because of proprietary licensing rules the FDA is not allowed to divulge their thinking. What we know of the FDA ruling on TDM-1 comes only from the drug company. Surely, part of the reason the FDA denied accelerated approval for TDM-1 sits upon the phase 2 non-randomized data that was submitted to obtain that approval. Yet Roche/ImmunoGen did not mention that reasoning in their press release. And their press release is the only information we are privy to.

It's frustrating. The FDA has this new "transparency" initiative, but they are bound by legistlation (that protects the drug companies) not to reveal their assessments, unless the issue is taken to ODAC, or the company voluntarily discloses the whole story.

[schoonder]

Well, one thing we do know about FDA's thinking is that they have no problems with fact that issuance of RTF could well delay access to an apparent effective drug by some two plus years to people so desperately in need of new options.
If FDA rated T-DM1 of sufficient critical stature, I believe even with RTF related shortcomings that were disclosed, agency's regulations provided them with an out so they could proceed with actual evaluation of the trial data.

"The agency may, for particularly critical drugs, not use the RTF procedure, even where it could be invoked or might review parts of a refused application if it believes that initiating the full review at the earliest possible time will better advance the public health."