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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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April 7, 2014

Is Palbociclib Promising? Or Not?

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Posted by Derek

Here's a good test for whatever news outlets you might be using for biotech information. How are they handling Pfizer's release of palbociclib information from the AACR meeting over the weekend?

Do a news search for the drug's name, and you'll see headline after headline. Many of them include the phrase "Promising Results". And from one standpoint, those words are justified. The drug showed a near-doubling in progression-free survival (PFS) when added to the standard of care, and you'd think that that has to be good. But a first analysis of overall survival (OS) shows no statistically significant improvement.

Now, how can that be? One possibility is that the drug helps hold advanced breast cancer back, until a population of cells breaks through - and when they do, it's a very fast-moving bunch indeed. Pfizer, for its part, is certainly hoping that further collection of data will start to show a real OS effect. They're going to need to - Avastin's provisional approval for breast cancer was based on earlier PFS numbers, which did not hold up when OS data came in. And that approval was revoked, as it should have been. Now, Avastin also had side effect issues, and quality-of-life issues, so these cases aren't directly comparable. But the FDA really wants to see a survival benefit, and that's what a new cancer drug really should offer. "You'll die at the same time, but with fewer tumors, and out more money" is not an appealing sales pitch. This issue has come up several times before, with other drugs, and it will come up again.

You'd think that a PFS effect like palbociclib's should translate into a real survival benefit, and as more data are added, it may well. But it's surely not going to be as impressive as people had hoped for, or it would have been apparent in the data we have. So take a look at the stories you're reading on the drug: if they mention this issue, good. If they just talk about what a promising drug for breast cancer palbociclib is, then that reporter (and that news outlet) is not providing the full story. (Here's one that does).

Update: there is an ongoing Phase III that's more specifically looking at overall survival. Its results will be awaited with great interest. . .

Comments (30) + TrackBacks (0) | Category: Cancer | Press Coverage


COMMENTS

1. Wise Bio on April 7, 2014 9:44 AM writes...

1- All drugs for ER+ metastatic breast cancer have been approved on the basis of a PFS primary endpoint.

2- See Femara label. Very hard to hit OS here given the post-progression crossover to other treatment options

"Overall logrank P=0.5136 (i.e., there was no significant difference between treatment arms in overall
survival). The median overall survival was 35 months for the Femara group and 32 months for the tamoxifen group, with a P-value 0.5136 , 57% of events / n=453 per arm

Study design allowed patients to cross over upon progression to the other therapy. Approximately 50% of patients crossed over to the opposite treatment arm and almost all patients who crossed over had done so by 36 months. The median time to cross over was 17 months (Femara to tamoxifen) and 13 months (tamoxifen to Femara). "

http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020726s014lbl.pdf

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2. fluorogrol on April 7, 2014 10:31 AM writes...

Very true.

I read the Fierce Biotech story first. On seeing stories in other outlets, I initially thought I'd mixed up the names and was reading about a different drug.

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3. interested reader on April 7, 2014 11:38 AM writes...

If it is true that the compound has a large effect on PFS but no effect on OS- perhaps due to some sort of complex mechanism as postulated in the blog post- this would not be a reason to give up on the drug, but rather would be an indication that the drug needs to be combined with another agent that has a complementary mechanism of action. Of course, picking which one to combine it with is a non-trivial undertaking.

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4. Chrispy on April 7, 2014 12:10 PM writes...

The New York Times ran an article on this, too, noting:

"But Dr. Baselga, the physician in chief at the Memorial Sloan-Kettering Cancer Center, said the results might have been biased because the study investigators, who determined whether tumors had progressed, knew which patients were getting palbociclib."

An unblind clinical trial? Don't we know better than this?

And won't this just be yet another nonspecific antiproliferative, hitting cells that divide quickly?

Well, I hope the hype is deserved because breast cancer patients sure need more options.

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5. Am I Lloyd peptide on April 7, 2014 12:17 PM writes...

I am skeptical. The drug hits CDK4 and 6 for crying out loud. Non-specific side effects may well show up in larger trials. Let's hope not.

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6. Bernard Munos on April 7, 2014 1:05 PM writes...

Doesn't the longer PFS suggest a higher quality of life while the patient is alive? It would seem that that itself is valuable.

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7. Derek Lowe on April 7, 2014 1:59 PM writes...

#6

It may well. But I'll bet that Pfizer wasn't planning on making its case to the FDA based on quality of life. . .!

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8. NoDrugsNoJobs on April 7, 2014 2:02 PM writes...

Much too early to determine survival benefit, especially with the numbers involved.....

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9. newnickname on April 7, 2014 4:03 PM writes...

@6 Bernard Munos "Doesn't the longer PFS suggest a higher quality of life while the patient is alive? It would seem that that itself is valuable." - Quality of life for self, family and descendants is negatively impacted by financial stress, bankruptcy or other drastic measures needed to pay for the new drugs. Hospice is sometimes a better, higher quality choice. (Emphasis: as long as there are options available from which to make a choice.)

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10. Analytical Scientist on April 7, 2014 4:17 PM writes...

OS takes a lot longer and much more statistical powering to get a statistically significant result. You'll always get PFS data first. Complicating matters, when patients progress on palbociclib, they will be given other therapies in later lines of treatment, and overall survival will have built in noise from these later non-palbociclip treatments. OS is really hard to demonstrate, even if the drug is great. In front line ER+ MBC, getting approval based on OS (rather than PFS) is seen as well nigh impossible. The statistical powering of your phase III trial would make the study just too expensive and time consuming to be worth it.

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11. matt on April 7, 2014 9:20 PM writes...

@Bernard Munos #6, newnickname #9: I wondered about quality of life, too, but recall that during that average of ten months, patients are still going to the hospital, taking harsh chemo drugs--it's not like they are exactly enjoying themselves and taking a holiday from illness. Any illusion that they have beaten the cancer is just false hope, with no statistical difference in OS (as yet). I'm with newnickname, hospice care and/or a round of medical marijuana at home if pain intrudes might be far, far preferrable for quality of life (for many; of course each patient is different). And a heckuva lot cheaper for all involved.

@Analytical Scientist #10 (or anybody else who thinks PFS is enough): PFS, unblinded, is to my mind tainted and most likely worthless. PFS, even blinded, seems to me likely to be too crude and subjective a measure for something you are saying requires extreme statistical power. You can't build statistical strength on eyeballing judgments. What are the error bars on those individual measurements?

And, given no difference on OS, how confident are you that there was, indeed, no progression during that time? Maybe it's just "no progression in the types of cancerous cells we know how to look for, but extra fast progression of hidden cancer"--is that worth $100,000 a year? I guess that's a pretty good gig for the drug company and cancer treatment center if they can find takers, but it sucks for the patient and the taxpayers.

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12. Casual Observer on April 7, 2014 11:20 PM writes...

Assuming the palbociclib study was a crossover design, it would be surprising to see a big OS effect.

The big disadvantage of crossover is the lack of a clean OS comparison. When patients progress, they're able to "cross over" to the other therapy. So, in a simple case, you're comparing first-drug-then-comparator against first-comparator-then-drug. Even if the drug is great, might not see a big difference. Nice thing about PFS is that it offers a (relatively) clear comparison of drug vs comparator.

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13. Nimbo on April 8, 2014 10:14 AM writes...

@Matt -- "PFS, unblinded, is to my mind tainted and most likely worthless" I'm guessing you were a poly sci major.... did you even take an introductory course in stat?

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14. Imaging guy on April 8, 2014 11:38 AM writes...

It seems that the measuring PFS itself is quite problematic. This is what the author said in an article about the reasons for rejection of Avastin for breast cancer in NEJM.
"Fourth, the use of progression-free survival presents substantial problems: it requires that
clinical trials be blinded and randomized;
it necessitates blinded assessment by independent radiologists; it poses difficulties for the
categorization of patients without measurable disease; its results depend on the times at which
progression is assessed; and its analysis can be contaminated by missed assessments, incomplete
baseline assessments, or uneven assessment in different treatment groups."
"Changing End Points in Breast-Cancer Drug Approval —The Avastin Story"

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15. matt on April 8, 2014 9:36 PM writes...

@Nimbo, #13: Imaging Guy, #14 wasn't even me, but that's the relevant reference...

I'm curious...rather than ad hominem, how do you see statistics "curing" the human tendencies toward self-interest or even wishful thinking unprotected by blinding? Did your statistics course indicate blinded trials aren't necessary in these enlightened times? Is there some routine in R which deconvolves input data which was tainted by conflicts of interest or wishful thinking? That would be worth a Nobel prize, I think.

Going back to the Feynman quote: "The first principle is that you must not fool yourself, and you are the easiest person to fool." It sounds like a fair number of people need to unfool themselves: PFS generates really clear, sharp results; but do those results actually reflect anything clinically useful?

Screw clinical...would those results mean anything to you personally, should you or someone you love be given that treatment? Would they be distinguishable from (in this data) an average of ten extra months of false hope and cheerfulness from your doctor? In other words, your doctor could achieve the same result for free by simply saying "your cancer is doing very well, it hasn't gotten any worse" (but you'll still die in the same amount of time, after it "rapidly progresses" at the end). What if your doctor was not being dishonest, but was simply ignorant...would that make it better?

Unless and until there's an OS difference, PFS is problematic. If the treatment has negligible cost and inconvenience (ie, pop it like a statin at home) to match its negligible result, it may still be worth it. But too often these days, the cost is the extreme opposite of negligible. And for some oncology treatments, the same is true for inconvenience and impact on quality of life.

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16. matt on April 8, 2014 9:50 PM writes...

And by the way, speaking of poly sci fi, where's Ray Kurzweil and the Singularity? Aren't we getting closer to having cured cancer by now? Why are we fiddling around with proxy endpoints...seems like at this late date we should be crossing off major categories of cancer as completely curable. That should be a measurable difference in overall survival, I think.

I think the same thing about Life Extension...if they are planning to live forever, they'd better get on things like arthritis and Alzheimer's pretty quickly.

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17. Mac patient on April 9, 2014 10:27 PM writes...

It is clear that none of you are or know women with MBC. Quality of life is everything and this drug is far far preferable to chemo. Nobody is sitting around on hospice at early stages of MBC when palbociclib is being used. You need to compare the benefit of longer pfs on a drug like palbociclib which has mild side effects to what it would be like to be on chemo that entire time. I for one am glad the FDA does not insist on using OS alone for approvals.

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18. David Young MD on April 9, 2014 10:46 PM writes...

I was at the lecture and it was pointed out that the study was an open study... the physicians who determined when the patients began to relapse were aware of which patients were on Palbociclib and which patients were not. The presenter was well aware of the that drawback. The study was not a phase III registration study and the determinants of progression were not made by a central, unbiased radiology group. Palbociclib is a cell cycle inhibitor, first-in-class and the results were quite provocative. Keep in mind that with this data the combination might be most effective in the neoadjuvant setting and I expect that Pfizer will run a study on this. Palbociclib causes neutropenia but there were no incidents of neutropenic sepsis or even fever.... still..... it might not be a good drug for long term use, but if the combination of Letrazole and Palbociclib shrinks a 3 cm tumor to 1/2 cm in 2 months, it could have a really good use in the neoadjuvant setting. Yes, there were some encouraging papers presented at this year's AACR meeting, this being one of them.

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19. MCarter on April 11, 2014 9:24 AM writes...

#18: There is a phase III study now enrolling in the adjuvant setting. The name of the trial is Penelope. It is being conducted by the German Study Group. 1:1 randomization to Placebo+SOC vs Palbo+SOC of 800 patients with HER2-/ER+ disease who did not achieve pathological CR in the neoadjuvent setting. There are also large randomized phase 3 1L (Paloma 2, study 1008) and 2L (Paloma 3, Study 1023) studies in the space that are enrolling for Palbo in combo with letrozole and fulvestrant, respectively. I just hope that we dont see positive phase II data and sucky phase III results like the parp inhibitor BSI-201/iniparib in her2-...hoping for the best for breast cancer patients!!

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20. Nimbo on April 12, 2014 8:31 PM writes...

@matt
Unlike most of the folks posting, I know a little bit about the drug, as my wife had been on it for almost 9 months.

Given that PD0332991 is shrinking her liver lesions & 1/2 a year of taxanes & herceptin did not, I'm guessing it's not the placebo effect.
And frankly, most metastatic patients are pretty jaded ... Having your onc tell you that you are doing great isn't going to blow wind up your skirt if you feel like crap 99% of the time.

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21. David Young on April 14, 2014 2:32 PM writes...

@Nimbo

So, what you are saying is that you wife has considerably less side effects with Palbociclib than what she had with the Taxanes. Could you tell me..... how does she fair with the neutropenia? Is it a bother?... or just a laboratory finding that does not influence how she feels?

I am glad that she has had regression of her tumors.

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22. Nimbo on April 15, 2014 9:22 AM writes...

@David Young

Pablociclib's side effects are nowhere near those of taxanes. That said, myelosuppression is still a problem and my wife was dose reduced accordingly. She is definitely fatigued by the 3rd week in her cycle.

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23. Cari on May 21, 2014 1:16 PM writes...

Hello Nimbo,
How is your wife doing? I am on the sixth day of Paloma 3 trial and can't yet tell if I go the placebo or the palbo. I would love to hear that she continues to improve.

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24. Nimbo on June 16, 2014 3:16 PM writes...

@Cari

My wife's latest RECIST looked great....thank you for asking. I'm throwing good thoughts your way :)

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25. Patriotic on June 19, 2014 12:54 AM writes...

@Cari and Nimbo. Hope you are both doing well. I just began the trial about 2 weeks ago and am doing very well. I just received the first blood work results indicating the WBC is down and some other signals. I have slight fatigue but otherwise doing great. Nimbo, do you mind sharing approximately how much tumor regression your wife experienced? We know there's no magic bullet. Just looking forward to some positive news!

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26. Nimbo on June 24, 2014 12:18 PM writes...

@Patriotic
RECIST shows a 72% decline (linear) since starting the trial ...which means the tumor mass is a tiny fraction of what it was.

I'm sending good thoughts your way as well :)
I'll check back in periodically to see how you & Cari are doing.

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27. Patriotic on August 20, 2014 12:20 AM writes...

Hi Nimbo and Cari,

Just checking in. Been on the trial 7 weeks now. A little tired in week 3 but otherwise okay. I have the 1st CT Scan soon. I have a lesion in my hip area that no longer bothers me. So, it's hard to tell if the Letrozole and/or Palbociclib is responsible. But, I am thinking of you both and hoping you are doing okay. My healthcare facility has approximately 20 in the study and only 3 have exited the study (presumably, for progression). So, statistically, I think that is positive.

I am hoping that both of you are experiencing positive results, too.

Xo

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28. Patriotic on August 20, 2014 12:23 AM writes...

Hi Nimbo and Cari,

Just checking in. Been on the trial 7 weeks now. A little tired in week 3 but otherwise okay. I have the 1st CT Scan soon. I have a lesion in my hip area that no longer bothers me. So, it's hard to tell if the Letrozole and/or Palbociclib is responsible. But, I am thinking of you both and hoping you are doing okay. My healthcare facility has approximately 20 in the study and only 3 have exited the study (presumably, for progression). So, statistically, I think that is positive.

I am hoping that both of you are experiencing positive results, too.

Xo

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29. Patriotic on August 20, 2014 12:26 AM writes...

Hi Nimbo and Cari,

Just checking in. Been on the trial 7 weeks now. A little tired in week 3 but otherwise okay. I have the 1st CT Scan soon. I have a lesion in my hip area that no longer bothers me. So, it's hard to tell if the Letrozole and/or Palbociclib is responsible. But, I am thinking of you both and hoping you are doing okay. My healthcare facility has approximately 20 in the study and only 3 have exited the study (presumably, for progression). So, statistically, I think that is positive.

I am hoping that both of you are experiencing positive results, too.

Xo

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30. Nimbo on August 21, 2014 10:37 AM writes...

Hi Patriotic.... sounds like you are probably a responder :) :) :) Let me know how your scans go.

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