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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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June 9, 2009

Avastin's Numbers

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Posted by Derek

Here's a fascinating (and alarming) look at the clinical data from the recent trial of Avastin (bevacizumab) in adjuvant colorectal cancer (that is, post-surgical therapy). This was an issue in the recent Roche/Genentech takeover, since it could significantly enlarge the market for the drug. According to the In Vivo Blog, the one-year interim look at the data (adding Avastin to the standard chemotherapy regimen) was nearly good enough to stop the trial early. There were 2,710 patients enrolled, and an additional six events would have pushed things over the top, statistically.

The trial went on, though, with two more years of standard therapy as follow-up. But by the (pre-set) three-year endpoint it turned out that there was no eventual real benefit to adding Avastin back in that first year. So what's the story? Is it that you need to keep giving the combination regime? Would those-one year results have held up? Or is this just a case of real long-term survival numbers wiping out what seems to be a promising short-term result?

It looks like Genentech may be gearing up to put that first theory to a test, and I wish them luck. Long-term tolerability will be an issue, and long-term cost will be a big one, too. They're going to have to show some pretty impressive numbers to overcome those two concerns. . .as impressive as, well, as those first-year interim ones they had. Will that effect dissipate or not?

Time and money will answer that little question. But for now, consider what would have happened if a few more patients had shown disease-free survival in time for that interim analysis. The trial would have been stopped early, all kinds of people would have gone on Avastin for their first year of adjuvant therapy. . .and this year we would have seen that it was apparently doing no good at all, at least in the take-it-for-a-year-and-stop mode. Clinical trial design: a real high-wire act.

Comments (9) + TrackBacks (0) | Category: Cancer | Clinical Trials


COMMENTS

1. Still Scared of Dinosuars on June 9, 2009 9:41 AM writes...

One of the biggest arguments in oncology trials concerns the validity of progression-free survival (PFS). I assume what Derek meant by disease-free survival though it might depend on the completeness of the resection in this case. Ton Fleming, a biostatistician who regularly sits on ODAC, strongly argues against the validity of PFS. You can expect him to throw a hissy fit if these data come up in front of ODAC and it looks like Roche's arguments are carrying the day.

And the 6 add'l events line assumes, among other things, that all 6 occur in the non-Avastin group. Or maybe 3 fewer in the Avastin arm would have done the same thing, but it didn't happen. A trial like this is supposed to be based in part on a certain clinically meaningful difference that is often dependent on the increased toxicity of the new treatment. You're paying a price clinically to avoid progression events and the interim analysis says that in the judgement of the sponnsor at the time the trial was designed that price was too high. The final results validated that conclusion.

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2. ex-Gtecher on June 9, 2009 10:40 AM writes...

Avastin has to have the worst cost-to-benefit ratio of any currently marketed drug.

Weeks to a couple of months of life extension at a cost of $10's of thousands?

We can and must do much, much better than this!

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3. qetzal on June 9, 2009 10:55 AM writes...

If we pretend that drug cost isn't an issue, I wonder how much value there might be in delaying disease recurrence.

Suppose that the patients in this trial had continued to receive Avastin for the full 3 years, but otherwise the results were the same. That is, they were significantly less likely to have recurrence during the first year, but just as likely to have recurrence after 3 years. Let's go further, and also assume that Avastin has no effect on mortality. All it does is increase the chance that you'll have at least one year without recurrence.

I wonder if patients (or doctors) would consider that a valuable benefit? It seems likely to me that quality of life is meaningfully better before recurrence than after, so delaying recurrence seems potentially valuable, even if your long term risk of recurrence and death is unchanged.

Of course, in the real world, drug cost is an issue. I guess I just wanted to question the implicit assumption that delayed recurrence by itself has no value.

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4. Still Scared of Dinosuars on June 9, 2009 1:50 PM writes...

quetzal - careful with the terminology. "Quality of life" is another controversial term in drug approval circles. "Symptom relief", which would seem to most of us to be almost synonymous, is in fact where the FDA is much more receptive as long as the system used to measure symptoms is validated. Delaying disease recurrence is of no real value, at least in the eyes of many, but if the return of disease can be shown to worsen symptoms then you have an angle.

QOL itself is often mired in a lot of psychological benefits that many dismiss rather casually. A drug I worked on had very clear efficacy which was associated with QOL benefits. When the (non-oncology) AC voted on whether QOL benefits (which were pre-specified secondary endpoints in both Phase 3 trials) should go in the label it was an almost univeral "No". One panel member thought it would be "prejudicial".

What-ever...

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5. qetzal on June 9, 2009 6:58 PM writes...

SSoD,

Yeah, I didn't necessarily mean QOL the way some have tried to use it as a possible endpoint. More the general point that if your disease hasn't recurred yet, then you maybe you aren't yet having to undergo further unpleasant procedures, or take more debilitating drugs, or whatever. Plus as long as the disease hasn't recurred, you probably have a better mental outlook. Once it does recur, I imagine that triggers a number of things that make life less pleasant than it was.

I don't really expect you could win approval based only on reducing 1 yr recurrence. I just thought it was worth noting that regardless of what FDA or docs think, patients might indeed appreciate a drug that postpones recurrence.

Or maybe not.

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6. David Young MD on June 9, 2009 9:26 PM writes...

As a medical oncologist, the primary outcome of an adjuvant trial is curing patients. That is, preventing relapse. If a treatment just delays relapse, then save it for those who do relapse and put them into remission. If adding Avastin to FOLFOX only delays relapse then forget it. Just give FOLFOX the best you can.

And everyone knows that if you prevent the relapse of cancer by giving adjuvant chemotherapy, you are doing so with only 4 to 6 months of chemotherapy. That is why we no longer give 12 months of adjuvant CMF for breast cancer. Don't try to put a spin on it by saying that one needs more than 6 months of Avastin.

There seems to be more and more data that tells us that Avastin is not "just" an antiangiogensis drug and the benefit of Avastin is much more complex than just the ability to shut down growth of blood vessels and that, in fact, it may do a poor job of shutting down blood vessels. Avastin seems to help, but perhaps in ways that we do not know and perhaps those ways limit the use of the drug.


Permalink to Comment

7. qetzal on June 10, 2009 10:59 AM writes...

If adding Avastin to FOLFOX only delays relapse then forget it.

So in your opinion, delaying recurrence has no value at all? Note that I'm not asking whether it's worth giving Avastin to delay recurrence, since that brings in issues of cost, side effects, etc. I'm just curious whether you as an oncologist, who deals directly with cancer, think there is ever any value to delaying recurrence, even if the ultimate risk of recurrence and death is unchanged?

It seems to me there could be value, but I'm not a medical professional.

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8. D-avid Young, M on June 16, 2009 4:56 PM writes...

For the most part, delaying recurrance has very little value, unless, perhaps, the intervention is totally non-toxic, readily available and comes cheap.

Think of it this way. You have 4 interventions (single drugs or combinations of drugs) that have activity against metastatic cancer, let's pick breast cancer. You can choose to give, say two, of these interventions to women who have had surgery to remove a breast cancer. Perhaps only 35 percent of these women are going to relapse, but you give the treatment anyway to every woman (who meets the criteria) because you have reason to believe that some of those women who would have relapsed (and die) will not relapse (and live.) If all you do is delay relapse, you have not gained anythng (or very little). The reason is, is that once they relapse you have already used up two of your interventions and your ability to control the cancer is limited. If you do not treat them, you will have more interventions at hand and will be able to contol the cancer longer. In other words, if all you have are interventions that delay therapy, you will not extend the life of anyone. Rather, you are just giving unnecessary chemotherapy to many who don't need it (at expesne, risk and side effects) when you could have waited and just treated those who relapse, and therefore just treated those who needed it.

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9. marlyn on September 24, 2009 12:22 PM writes...

I have your article as I look for information on the cost of avastin. I have been given this drug for 18 months, initially, for 6 months alongside paclitaxel. This is part of a trial involving women with metastatic breast cancer. For me, this has meant almost a year of almost pain free remission with few side effects. I have in fact been given my life back for a while. The cancer will progress, but it hasn't so far. So, as one of your writers comments; understanding how avstin works is not simple, and for some of us, it does work miracles.

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