T DM-1 Approved !!

[phil]

the recommended tx schedule will probably be 3 weeks, dosing starting at 3.6. but whats exciting is that now all that can be flexed per pt response. should ameliorate some s/e 's like plats.
i have an issue ( u can tell i have alot of issues !! lol) , with This FDA 20th century trial system in the 21st century , with 21st century drugs. how long will we wait for trials comparing taxanes to t dm-1 ? yrs ?? ridiculous . we know those drugs inside and out , as if taxanes were any where near as good as t dm-1 . they are not. most of the t dm-1 success stories i talk with are not posting, and probably fewer than 2,000 pts have even got to try the drug , many , like Lorraine, after yrs of tough chemos, lots of mets. it is not 100 % , somewhere in mid-range 50-60 % , now more can get it w/ flexiblity , not get kicked off trials for lung irritation or liver irritation, etc. more will get it after around of taxane only, so rate of successs will go up. it may very well be acure for more and more, and now u can add other chemos to it , off protocol.
but how many yrs until adjuvant studies are completed in his System, Dr. pazdur and his team are know it alls, pushing OS , longer trials , NO SENSE OF URGENCY WITH TDM-1 ! some estimate 45,000 Stage iv's could have tried this drug during that time. when will perjeta get to Stage IV ?? Investigate This FDA !

[Joan M]

Phil,

I would agree that the clinical trial system has to come out of the Dark Ages, and I think we'll be seeing more neoadjuvant trials, which will help shorten the process. The FDA recently issued draft guidance on using pCR as an endpoint in such trials, in order to accelerate approval.

As to t-dm1 and EMILIA, I have a lot of concerns. The capecitabine and lapatinib combo is the pip-squeak on the block. They couldn't have picked a better weakling for comparison. For several years now, oncs have known that patients who stay on herceptin even after they've progressed do better than those taken off of it. When my cancer progressed to my lung, my onc offered to give me capecitabine and lapatinib to ADD to herceptin, not in place of herceptin. And that was in spring 2007, almost 6 YEARS AGO. So, is it any wonder that T-DM1 beat out capecitabine and lapatinib?

OS, or overall survival, is very important to me. PFS is nice ... but what I want to know is whether a drug is going to make me LIVE LONGER. Often PFS doesn't pan out, and patients end up not surviving longer. Twenty years after doing bone marrow transplants, it's now known that there was no survival difference between the women who got them and those that didn't. Yet in the early days of this elixir women were suing their insurance companies for denying coverage!

Here's a very interesting piece written in September. It clearly spells out the problem.

http://www.clinicaloncology.com/View...887&a_id=21703

Please don't misunderstand me. I have metastatic disease and speak from the heart. I just wish that the trial design had been more compelling. It worries me. What a waste of money … and time. Yes, Paul, precious time. I cry over it. It's very upsetting to me.

And now I worry about adjuvant and neoadjuvant trials of t-dm1 going forward, and the suggestions that the NBBC made about trial design that are being ignored.

Joan

[Joan M]

Here's the article from the link above, if you can't access it online. Joan

TDM-1 Is a Good Drug, But Better Than WHAT?
Steven Vogl, M.D.

American Society of Clinical Oncology (ASCO) 2012 saw the plenary presentation of the EMILIA trial comparing a new targeted therapy consisting of a HER2 antibody (trastuzumab; Herceptin, Genentech) conjugated to a very toxic chemotherapy drug (a maytansine analog called DM-1) with an “approved” (by the FDA) chemotherapy regimen of lapatinib and capecitabine. The results appeared quite favorable for the antibody conjugate, called TDM-1, which was tested in women whose tumor had worsened on prior therapy including trastuzumab (Table 1).

TDM-1 seems to be a “nice” drug. It causes no alopecia, little neutropenia and only moderate thrombocytopenia. It requires only a short infusion every three weeks, lacks cumulative toxicity and has a response rate as first-line chemotherapy that is about the same as that of docetaxel and trastuzumab with apparently longer remissions—median duration 14.2 versus 9.2 months as cited by Kimberly Blackwell, MD, in her ASCO plenary presentation (E. Perez, personal communication). It is indeed representative of a new class of very promising drug–antibody conjugates, of which brentuximab vedotin for Hodgkin’s lymphoma is a shining example.

How Do We Interpret the TDM-1 Phase III Trial?

We cannot interpret it, because all the data available in 2012 suggest that the control arm, lapatinib and capecitabine, is distinctly suboptimal and does not represent a standard of care. We do know that lapatinib-capecitabine is modestly superior to capecitabine alone in women whose tumor grew on other chemotherapy plus trastuzumab (Table 2).1 Alas, we still do not know if it is superior or even equal to capecitabine with continued trastuzumab in the same population. Perhaps it is even inferior to capecitabine plus lapatinib plus trastuzumab.

Stopping Trastuzumab for Even Six Weeks Costs Four Months In Median Survival in a Heavily Pretreated Population

Unfortunately, in 2012, we know very little about how and when to use lapatinib. Based on a study just published for the third time by Dr. Blackwell, all we know is how not to use it: We should not use it without trastuzumab.2 The authors of this paper, a very distinguished group indeed, concluded that their study showing the superiority of lapatinib plus trastuzumab over lapatinib alone supports the use of dual HER2 blockade (Table 3).

An attractive, simpler explanation is that it demonstrates the importance and value of continuing trastuzumab even after disease progression on multiple lines of trastuzumab-containing chemotherapy. The large deleterious effect on median survival of even a short hiatus off trastuzumab—4.5 months when prolongation of disease progression was just a few weeks (Table 2)—argues that continued trastuzumab has a major effect on disease progression that causes death even as disease continues to worsen on trastuzumab.


Several Points Remain

Choice of inferior comparators is common

It is common for pharmaceutical companies to choose inferior comparators in Phase III trials, as was done in EMILIA. Recent examples include using the “Mayo Clinic regimen” of low-dose 5-fluorouracil plus leucovorin as the comparator for adjuvant capecitabine for resected colon cancer and for capecitabine-oxaliplatin as chemotherapy for metastatic disease.

Roche similarly used docetaxel rather than vinorelbine as the drug partner for trastuzumab in the control arm of a Phase II trial of TDM-1 as first-line chemotherapy for metastatic breast cancer.4 It has long been obvious that vinorelbine is less toxic than docetaxel, and this has been recently documented in the published Phase III HERNATA (Herceptin Plus Navelbine or Taxotere) trial that found similar response rates but longer remissions with vinorelbine–trastuzumab, presumably because the chemotherapy partner could be given longer, with docetaxel having been stopped early more often because of toxicity. As Dr. Blackwell mentioned in her ASCO plenary presentation, in the Roche trial reported by Dr. Hurwitz at ESMO 2011, the advantage of TDM-1 was that remissions with TDM-1 seemed longer than those with the control arm of docetaxel-trastuzumab.

Drug companies choose to rely on marketing and sales skills, rather than convincing data, to sell their wares when their studies have weak or suboptimal control arms.

EMILIA was a very large study that proved little

It is really too bad that this study chose an inferior comparator because it is one of the largest studies of chemotherapy for metastatic HER2-positive breast cancer. With 991 patients, it is the largest trial I could identify for these women. The Genentech study proving a four-month increase in survival with trastuzumab had 469 patients randomized. EGF 104900, which looked at lapatinib plus trastuzumab, had 291 subjects; GBG 26 (capecitabine with or without trastuzumab) had 156; HERNATA (trastuzumab with docetaxel or vinorelbine) had 284; CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) had 808; MA.31 closed at 652; two studies looking at the addition of carboplatin to trastuzumab plus taxane had 196 and 263 each.

TDM-1 does not meet goals of a major advance

TDM-1, while subjectively well tolerated and low on serious toxicity, does not achieve the goals we really want to advance systemic therapy for metastatic breast cancer (Table 4). Data available to date suggest that TDM-1 provides at most a small incremental benefit without a major change in prognosis for these women.

TDM-1 likely to be very expensive

Roche likely will charge a steep premium for TDM-1 compared with trastuzumab plus chemotherapy. I predict that Roche will commission studies of cost-effectiveness based on lower administration costs and cheaper treatment for toxicity (although compared with unnecessarily toxic “standard treatments”). It is not fashionable to discuss costs at medical meetings or in journals, but drug companies were careful to pay their lobbyists to induce Congress to forbid Medicare from negotiating prices in the legislation authorizing Medicare Part D prescription plans. Drug prices now seem to be set at the estimated maximum the market will bear (with secret discounts to large customers in a position to negotiate on price).

A rational purchaser of chemotherapy who is morally conscientious but frugal could not use currently available data to support purchasing TDM-1 at a substantial cost premium over trastuzumab plus generic chemotherapy (like paclitaxel, docetaxel, cyclophosphamide, gemcitabine, cisplatin, carboplatin, fluorouracil and vinorelbine, alone or in combination) or capecitabine. American taxpayers and those who purchase health insurance, be they employers or individuals, unnecessarily spend a great deal of money because they have not insisted on rational control of medical charges. It is likely that TDM-1 will add to these costs. Hopefully we will one day have a government that can help us spend our resources wisely.

Pertuzumab is very active, making the role of TDM-1 uncertain

The CLEOPATRA study does indeed suggest that dual antibody therapy with pertuzumab plus trastuzumab in addition to docetaxel is preferable to trastuzumab alone for HER2-positive metastatic breast cancer, although survival data are not yet mature.5 Adding pertuzumab increased the response rate from 69% to 80%, increased median progression-free survival from 12.4 to 18.5 months, and appeared to decrease the early death rate. Whether pertuzumab should continue with trastuzumab for the lifetime of the patient as chemotherapy varies is unclear. It is also not clear whether trastuzumab is really necessary in addition to the pertuzumab, or whether pertuzumab should be added to TDM-1.

These are fruitful lines of study rendered difficult to interpret because HER2-positive metastatic breast cancer has become a chronic disease, because these constitute only 20% of breast cancer patients, and because most patients with localized or regional HER2-positive breast cancer are now being cured by adjuvant trastuzumab and chemotherapy, leaving very few who develop metastatic disease later. Like follicular lymphoma, all patients with metastatic disease will likely receive multiple lines of therapy containing many or all of the active agents, and studies will be assessing their order of administration, whether they should be administered singly or in combinations of two to four at a time, and their length of administration.


Should we give TDM-1 now?

Absent more data, will I be giving TDM-1 if it is approved in 2012? Perhaps, but I will favor it only if the price is right, and if payers restrict the use of pertuzumab to first-line therapy. Now that pertuzumab is approved for first-line therapy based on the very impressive CLEOPATRA results, the appropriate comparator for first-line therapy with TDM-1 alone is now chemotherapy—docetaxel or vinorelbine, with the latter favored because it is less toxic and produces longer time to disease progression—plus trastuzumab plus pertuzumab. Pertuzumab may well need to be included with trastuzumab in the comparators for later rounds of chemotherapy as well.

References

Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743, PMID: 17192538.
Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 study. J Clin Oncol. 2012;30:2585-2592, PMID: 22689807.
von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27:1999-2006, PMID: 19289619.
Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29:264-271, PMID: 21149659.
Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119, PMID: 22149875.

[phil]

we can agree to disagree. i saw this article before, not impressed. he has not worked with t dm-1. researchers who have , and the t dm-1 responders , are your best source of info. writer reminds me of Dr. pazdur and his FDA t dm-1 analysis team , tunnel vision on piles of stats , and they were biased against drug , wanting to punish pharma. authors statement at end about " possibly " prescribing t dm-1 is ridiculous , if i were one of his her2 + metatstatic pts i'd find another doctor immediately. at least he sees pts . FDA bureaucrats are too far from chemo rooms .
I do not see myself as a luddite, wanting to dismantle trial structure, actually i think it just needs re-structuring to reflect 21st century advances in tx. more flexibility .
i am not impressed with curent NBCC leadership who are too close to fda , trying to make " points " , distinguish themselves from other advocacy grps. they talk about stopping transplants yrs ago , as justifying thier current pro fda , pro prolonging testing. those transplant pioneers had no options, showed us it was not right path , now move on.
I want special tx for this special drug. like herc back in 90's, given to all stage iv her2 + now. The TDM-1 trial pioneers had progressed on many, many nasty combos , ALL HAD PROGRESSED ON TAXANES, Lorraine twice , on 2 different ones. so, instead of this biased article, tell me why we need to compare taxanes to t dm-1 in a trial that takes another 3 yrs ? or pert ?

[Joan M]

Phil,

I also progressed on a taxane. When originally diagnosed as stage 2 in fall 2003, I had AC, T + H (off-label). I declined to go into the adjuvant Herceptin trial because I had 7+ nodes and didn't want to draw the arm without the antibody. But my onc gave me the drug anyway since it had already been approved for advanced bc.

Yes, perhaps, tdm-1 and docetaxel is a waste of time, but since the trial is already underway we'll get an idea of just how good tdm-1 is. Right now, t-dm1 is surpassing the taxane for PFS, but they're neck and neck on OS.

And even though I agree with Dr. Vogl's point about using a suboptimal combo in EMILIA, I wouldn't go to him either because as a metastatic patient I want options, regardless.

http://www.ncbi.nlm.nih.gov/pubmed/23382472

Joan

[Joan M]

There are a lot of good tidbits in Dr. Vogl's piece, including, everybody know that patients do better when Herceptin is continued and researchers chose docetaxel over vinorelbine in the phase 2 trial. All I'm saying is that the devil is in the details. Joan

[Jackie07]

If I remember correctly, the advantage of T-DM1 is not so much on its better outcome as on its less harsh effect on the patient.

A patient whose heart function decreases during Herceptin treatment now has an option to go on T-DM1. Perhaps more patients can receive longer Herceptin by means of T-DM1.

It's a significant improvement for someone like me who had to stop Herceptin after just 18 weeks of TCH + 4 weekly Herceptin due to decreased MUGA score.

I'm feeling much hopeful that in the event of getting another recurrence, I will (probably) be able to receive Herceptin via the less toxic method.

[pibikay]

Hello Phil
Any idea what is the cost of one dose of TDM1 is.

[phil]

I think 9,600 $ per dose, every 3 weeks , un-fortunately. Comparable to other recent tx's. Gen. may help some with income issues.
Wish This FDA did give proper sense of urgency to this drug . did they have to reject using expanded access data back in 2010 ? never think about shortening the trail over the past 2 and a half yrs ? giving t dm-1 any special consideration , based on the great stats in 2010 ( far better than tyk. , which previous admin. gave acclerated appr to ) ?
Did they have to take 6 full months for a " priority " review , with data last Sept. saying that 65 % of EMILIA pts getting t dm-1 had lived TWO YRS or more ??
No , but they did, because its not their wife or daughter, sister.
What have u heard about Perjeta getting to stage iv , since partial approval last June ? How urgent is This FDA with that ?
Didnt the old FDA stop the Phase III trial for original Herceptin before it finished ? What excuse do they have in 2102 ?

[phil]

I think 9,600 $ per dose, every 3 weeks , un-fortunately. Comparable to other recent tx's. Gen. may help some with income issues.
Wish This FDA did give proper sense of urgency to this drug . did they have to reject using expanded access data back in 2010 ? never think about shortening the trail over the past 2 and a half yrs ? giving t dm-1 any special consideration , based on the great stats in 2010 ( far better than tyk. , which previous admin. gave acclerated appr to ) ?
Did they have to take 6 full months for a " priority " review , with data last Sept. saying that 65 % of EMILIA pts getting t dm-1 had lived TWO YRS or more ??
No , but they did, because its not their wife or daughter, sister.
What have u heard about Perjeta getting to stage iv , since partial approval last June ? How urgent is This FDA with that ?
Didnt the old FDA stop the Phase III trial for original Herceptin before it finished ? What excuse do they have in 2012 ?

[KristinSchwick]

Just wondering if anyone has gotten TDM-1 since its approval? My doc. has me scheduled to start it on Tuesday if my labs show my current therapy has run its course.

Also, just for discussion sake- I have heard that in order for cancer cells to get into your brain, your BBB must be compromised in some way, therefore- a large molecule like TDM1, may still be able to enter and circulate some in the brain. Anyone else heard this?

[gdpawel]

Joan

That you for the url link on Vogl's piece. He told Medscape Oncology that the data on Kadcyla (T-DM1) are not as clear as they should be. The study's control regimen (Tykerb and Xeloda) was "distinctly suboptimal" and not a standard of care, even though it is an FDA-approved treatment option in this setting. The 5.8 month difference in overall survival in the two study groups might have been inflated by this control regimen. He would have preferred to see the control patients also receive Herceptin, which he believes to be a necessary complement to Tykerb.

He went on to say that Kadcyla (T-DM1) does not meet the goals of a major advance, explaining that such an advance, in his opinion, must cure some patients, increase the rate of clinical complete remission, or produce a high rate of very long partial response.

This all should remind physicians that it is the good outcome of the patient not the therapy applied that constitute successful application of the healing arts. We must remember that the best medical care is not always the most expensive. We can still hope for a good outcome if you use all the available drugs at our disposal that best meet the needs of the patient. http://cancerfocus.org/forum/showthread.php?t=3768

[Becky]

Tykerb was paired with Xyloda because (I think) they wanted to test a regime where patients do not have to go to the cancer center for treatment. They are both pills that you can just take at home.

From friends and all the women on this board, Xyloda seems not to do much or last very long. Other chemos seem far more effective (taxanes etc). Even Tykerb works better with other things other than Xyloda.

They should have tested it against a taxane with Herceptin.

[CoolBreeze]

Kristin,

Anecdotal, but I have a friend who was on TDM1 for two years (I think). She had mets in her lungs, bones and liver. All disappeared. Unfortunately, she had to discontinue the trial when it got into her brain. It does not protect the brain. She still only has it in her brain though. She's on ten years with mets.

Is Emelia the only trial on TDM1? I had thought there were several.

I am not sure I understand your question, Phil. Are you asking why it needs to be tested against a taxane when we already know what a taxane does? Don't you think we need to test these drugs against the gold standard, to understand if they work better? You can't take me and not give me a taxane and just assume I'll fail and put me on TDM1. Maybe I would have done well on the taxane. You have to compare with what you know is going to happen against what you don't know.

Why do they do smaller trials? It's probably easier to keep track of a thousand people than 40,000. Who knows what those 40k are doing? Plus, why make that much drug when it may not work?

Are you saying we shouldn't have trials? I, for one, even now, don't want to take a drug that has never been tested. I want the optimal chance that I will survive with minimal side effects.

I had a hard time understanding your post, but I'm on perjeta. Stage IV. So not sure what you mean there.

I read that one article that was skeptical but most oncologists and professionals seem to be excited about TDM1. I'm going to assume they know more than me.

I know better than to be very excited now anyway. I already had a liver resection that failed almost instantly. Taught me never to get really sure I may get a cure or long life again. But I do want TDM1 and my oncologist said he'd put me on it right away. After 7 chemos have failed me, this is the one I hope will do it, like my friend.

[Joan M]

Greg, I also read Gary Schwitzer.

I also think, Becky, that capecitabine + lapatinib without Herceptin was one of the first combos for metastatic women who progressed on Herceptin. That's why the combo is listed as an FDA-approved treatment. Now doctors realize that patients should stay on Herceptin, regardless of advancing.

I'm bothered by the trial design because, as Greg pointed out, a stellar OS response of 5.8 months might have been inflated because of the weak control arm of EMILIA, and I fear that women who advance fairly quickly on Kadcyla might feel that this "powerful" drug failed them. Whereas, perhaps the drug only appeared to be powerful because it was compared against a suboptimal arm. We'll get more info from MARIANNE and I guess TH3RESA, too.

Genentech deserves a lot of credit for developing the novel drug delivery system of Kadcyla, despite what in the opinion of probably many oncs was not a good trial design because of a weak control arm.

We all have Dr. Dennis Slamon to thank for his scientific ingenuity in developing Herceptin and perserverance in hounding Genentech at a time when the company was planning to get out of the cancer drug business. I believe Herceptin was the second monoclonal antibody after rituximab (Rituxan), which is also manufactured by Genentech.

Joan