Tykerb approval, then what?

[michele u]

I am going to take it off label. If any of you are going to do that also, how long? I had a talk with Dr. Salazar at Project LEAD and she was trying to talk me out of it. I know it's her job to believe in "Evidence based Science" but if my friend would have pushed for Hercepint OFF trial when she got the control arm, chances are she would still be here. I understand the point of "saving it for when you need it" but if it never comes back because it "cured" me then I WON"T need it?! I think I decided to take only 9 weeks of it. Just because the Finland trial showed to same results with Herceptin at 9 weeks. One would think the same rules apply since they are both targeted therapies. What does everyone else think???

[Margerie]

Hi Michelle- I am in your same boat. My onc is willing to Rx it off-label for me. But he wants to do it while I am still on herceptin (until Jan) because the studies out have it concurrent with herceptin or xeloda. We both have no idea how long- he doesn't have any patients taking it or other plans for patients to take it adjuvantly. We are waiting for information and we have a few months to see what info does trickle in the adjuvant setting- if any!

I can't start until August because I am doing the UW vaccine trial. So I was kind of thinking 2-3 months of Tykerb unless I hear anything otherwise. I wouldn't want to take it longer than herceptin- so I guess anywhere up to 5 months.

Yes- there are risks. I worry about my heart- being tested every 6 months and so far so good. But my gut says to do everything possible to prevent recurrance/mets from happening in the first place. I am at high risk for both and know that herceptin has little/no protection for the brain.

Another thing- how much is this drug? And will my insurance pay for it? Probably not-waaahh I want extra credit. Will have to be prepared to pay for it.

Any hint of an adjuvant trial that allows herceptin- will be looking for that also.

[RobinP]

I think that if you already had Herceptin and you are beyond the period of high relapse, after two years from diagnosis, then you probably could hold off on the Lapatinib. Primarily I am not a huge advocate of additional adjuvant with Tykerb if you already had Herceptin due to unknown cardiac side effects, particularly with prior Herceptin use. Besides, nobody really knows the added benefit of of adjuvant Tykerb either alone or combined with concurrent or sequential use of Herceptin. Furthermore, I think that 9 weeks of Tykerb would be less cardiotoxic than one year of it. However, I would think that because you already had Herceptin for some length of time, then the additional 9 weeks of Tykerb is difficult to compare to 9 weeks of virgin Herceptin.

This is just my two cents folks--which may mean nothing. If you are serious about Tykerb, talk it over with many knowledgeable oncologists. Then sum up your facts and make your choice. Remember your own choice is the right choice when it is based on sound knowledge.Good luck.

PS. If it is the brain relapse that you;re worried about because Herceptin doesn't pass the blood brain barrier, perhaps you just want routine MRI monitoring rather than Tykerb.

[Barbara2]

I was going to start a post on this same topic. I feel I need to be doing more in the continued fight against breast cancer. But what should the fight consist of?

I've pondered...
*More herceptin?
*Ask my onc for Tykerb?
*See a breast cancer specialist with a list of questions?
(My onc treats all kinds of cancer; He's the only onc for a large area;
very, very, busy.)
*Try Zometa in the hopes of keeping bone mets away? (I use Actonel,
but some studies suggest that Zometa may reduce chance of bone
mets)
*Vaccine trial? U of W only accepts you if you are stage 3 or 4; that trial
would be my preference, but am considering the Windber Medical Center
in PA.

I know there are no easy answers. What to do, what to do...

Thank the Lord for this site, it's been a God-send to all of us.

[Margerie]

Thanks Robin for your thoughts. I am within my 2 years ( 1 year 5 months) of my original diagnosis and that is why I am pulling all the punches. I have had a brain MRI, but these do not prevent brain mets. I am still gathering information- will see how it goes!

[michele u]

Robin, if Tykerb is oral, is there alot of cardiotoxicity? I didn't think there was. I've heard they are already started to do adjuvant trials with Tykerb. So there must be some evidence to support it. Where could i find the new graphs of overall survival after the Herceptin trial? Is there any new ones out there?

[RobinP]

Hi Michele,

According to the research, Tykerb is less cardiotoxic so far at least in the metastatic group. To quote one source: “In the cardiac safety evaluation,only 1.3% of patients (41/3,127) receiving lapatinib experienceda decrease in LVEF, which was mostly asymptomatic (i.e., 1.2%asymptomatic and 0.1% symptomatic). However, in contrast tothe breast cancer trials, a substantial number of participantsin the non–breast cancer trials had not received prioranthracycline therapy or trastuzumab and this could partiallyexplain the low incidence of cardiac failure in this analysis.However, LVEF was similarly affected by lapatinib in both thebreast cancer and non–breast cancer patients. Time toonset of an LVEF decrease was within 9 weeks of treatment in66% of patients, 10–16 weeks in 15% of patients, and 17–24weeks in 12% of patients. The 0.1% of symptomatic patients withdecreased LVEF presented with dyspnea, palpitations, and signsof CHF. However, they responded promptly to standard cardiacmanagement. The 1.3% incidence of symptomatic and asymptomaticdecreases in LVEF in patients treated with lapatinib was lessthan that expected within a matched cohort of the general population(3%–6% incidence of asymptomatic LVEF decrease) and lessthan that of trastuzumab-treated breast cancer patients [85 (http://theoncologist.alphamedpress.org/cgi/content/full/11/10/1047#R85),89 (http://theoncologist.alphamedpress.org/cgi/content/full/11/10/1047#R89)]. Thus, there is currently no firm evidence that lapatinibcauses cardiac toxicity at all. These cardiac safety resultsfurther support the rationale for studying lapatinib in theadjuvant setting.”

Thus, Lapatinib, at least in the short run seems safe. However, there were real decreases in LVEF after 9 weeks, so who knows if later cardiac issues will arise, particularly if one had prior anythracycline use.

I think the real issue at hand here is what added benefit does Laptinib offer that Herceptin hasn't already given you, Michele. You probably would tell me that you are looking into Tykerb primarily due to the CNS protection-- where indeed about 1/3rd of her2+ metastatic patients do relapse with a brain metastasis. (see quotes footnotes below). And note the risk of brain mets relapse is less, maybe about one percent or less, for early stage her2 postives, according to HERA trial data. Therefore, what is the true benefit value of Tykerb and what are the unknown long term side effects of Lapatinib, particularly for those who have already had cardiotoxic drugs like anthracyclines(AC) and Herceptin? These type of questions are unanswered and are why adjuvant Tykerb trials like TEACH and trails by BIG are going on now. Michele if you are seriously thinking about Tykerb, do you think it may be wise to wait to see what other insights will be offered at the spring ASCO meeting? I certainly will be tuning in for updates on Tykerb then.

Right now, I am just holding tight to the treatments that I already had. Last year Dr. Neil Spector, an oncologist and lead investigator at GSK for Tykerb recommended to me to do 9 weeks of late Herceptin. However, when I asked if I should take Tykerb once it was FDA approved in a year, he said no. He felt that immediate Herceptin was prudent at the time, but more delayed her2 inhibitors later were not indicated. In fact, he said that in his in vitro her2 studies, that no matter how many inhibitor drugs blocking her1, her2, her3, IGFR were used, in some strains of her2, there still was disease progression. In other words, other pathways are still unknown that facilitates the progression of her2.

There are many other drugs being studied to prevent her2 progression. Some include HSP 90 antagonist-clindamyacin, ominitarg- Pertuzumab, IGF inhibitors etc.You know, as each drug is FDA approved, we are faced with the question of doing more late adjuvant. Is there a stopping point where adjuvant ends? Alternatively, do we continue to try new drugs, and potentially poison ourselves with unknown side effects? These are difficult personal questions that each of us struggles to answer, and each of us will have various convictions based on our relative relapse risk and relative drug benefit.<o></o>



PS. Sorry this is so long of a response. Also, I do not have any further Herceptin survival curves Michele. And yes, I do remember that you were her1+, so was I. Perhaps this is another reason why you are looking into Tykerb.--Dr. Bacus, the pathologist that started TMD thought I should eventually take Tykerb. Dr. Spector felt otherwise as I have stated and I have sided with his opinoin. In the end, it seems everybody, even amoung the brightest professionals, will have different recommendations and convictions about varous treatments.I really think there is no one answer to many questions at times and as various trial data is accured, more presice decision making is made. Personally, I feel content having done just Herceptin, and I think that I am beyond the point of pondering any other treatments and mucking the pot and my HEAD.

PS Some quotes on
Brain Metastases
"Patients with ErbB-2–overexpressing breast cancer havebeen found to have a significantly higher risk for developingbrain metastases. Several studies have also found a higherincidence of brain metastases in patients treated with trastuzumab,further supporting the hypothesis that ErbB-2–overexpressingbreast cancer may have a predilection for metastasizing to thebrain . Stemmler and colleagues have investigated whyErbB-2–overexpressing metastatic breast cancer patientsreceiving trastuzumab suffer from an increased risk for developingbrain metastases, even though visceral disease might be responsiveto trastuzumab, and had failed local therapy . Theyfound that while trastuzumab was effective in treating liverand lung metastases, approximately one third of ErbB-2–overexpressingmetastatic breast cancer patients develop brain metastases.This observation suggests that the blood–brain barrierprevents trastuzumab from reaching adequate concentrations inthe central nervous system (CNS) . Therefore, clinicaltrials have been carried out with lapatinib for the treatmentof brain metastases because it is a small molecule able to penetratethe blood–brain barrier." Quotes from:
Lapatinib: Current Status and Future Directions in Breast Cancer

<nobr>Beverly Moy</nobr>, <nobr>Paul E. Goss</nobr><o></o>

[Rupali]

Robin, is there a test to find out if I was her1 and her3

Is that test possible though I had the mastectomy in December 2004.

[KellyA]

Robin-

Is the risk of brain mets 1/3 for all her2+ people? I don't know why, but I thought that I had read somewhere that it was around 11%. 33% is much higher. That is a huge risk as far as I'm concerned. Makes me want to seriously look into the Tykerb. My onc. said that he would give it to me off label. It's such a hard decision- damned if you do, damned if you don't. I guess that decision will require more research.

Love, Kelly

[Becky]

The risk of brain mets is approximately 25% in Her 2 women who have metastatic disease. It is not that high in women who are not Stage 4. The only reason to be diligent at the earlier stages is that for those of us who will develop metastatic disease (and remember this % not that high especially with the use of adjuvant Herceptin), 10% of the time the first metastatic site will be the brain. Basically, that is about 1% roughly average the risks of Stage 1 thru Stage 3C!!! But overall, for a Stage 2 person, this risk is less than 1% so Tykerb, to protect the brain, should be saved in case something happens in the future (and chances that nothing more will happen are in your favor).


Secondly - and Michelle - you were with me at this nightime presentation in San Antonio - Dr. Pegram stated that Tykerb works differently but his and Dr. Winer's opinion is that targeted antibodies (ie: Herceptin) will always outperform small molecule inhibitors (ie: Tykerb). But of course, for some patients one will work better than the other. The main thing is that it is another weapon we can use if we NEED to.

I say, be aware but take time to smell the roses and ... party on (that's why we are all working so hard and trying to stay ahead of the game).

Its almost Friday!!!

[Barbara2]

Thank you, ladies, for taking the time to explain things in such a clear and precise way. Your input and understanding of all the complex information we sort through, is so very much appreciated.

[RobinP]

Kelly,

I think Becky did a good job of stating your brain mets relapse and the use of Tykerb. I have also made some edits in my orginal post to clarify the brain relapse percentages (note with referrences and quotes from medical journals)for you and others who come along to read these posts. I hope this helps and best of luck to you with your health.

[KellyA]

Thanks Becky and Robin. Those are much better figures. Sorry I misunderstood. :-)

Happy Weekend!
Love, Kelly

[saleboat]

Hi Michele,

I share a concern that you raise-- I think the trials of Herceptin have caused a lot of us to distrust the medical community in some ways. There are too many of us on the boards that didn't get access to Herceptin for early stage disease, all for the fickle hand of fate and the trust we put in our doctors. Like you, luck was on my side and I was able to get Herceptin to fight a scary Stage III dx.

But a seed of doubt has been sown in our minds...will we miss something? And we're angry for our friends who now have more difficult battles that they may have avoided altogether.

Good luck with your decision. I would take a lot of confidence in the fact that you're over three years out from your dx.

Jen

[kk1]

"if Tykerb is oral, is there alot of cardiotoxicity?"

Michele I just wanted to remind people that the reason that Herceptin has the potential to impact heart function is that the cells of the heart are the only "normal" cells in our body that continue to express low levels Her2 as adults.

Tykerb which interacts with Her1 and Her2 receptors has the theorectical potential to have cardiac toxcity regardless of how it is delivered.

kk1

[michele u]

the heart toxicitiy from Tykerb is a good question. Does anyone else have more information about that?

[Lani]

lapatinib compared to herceptin:
http://www.tmdlab.com/images/061215TMDPoster.JPG

[MGordon]

"In the 3,500 patients who are part of its clinical development program, Tykerb to date has shown a low incidence of cardiotoxicity, a condition associated with some breast cancer treatments. The most frequently reported adverse events associated with Tykerb have been mild to moderate itching, rash, diarrhea, acne, and dry skin."

See http://www.gsk.com/ControllerServlet?appId=4&pageId=402&newsid=697

[Sherryg683]

I am definately getting on Tykerb along with my Herceptin, has it finally been fda approved. Why would we have to get it off label and exactly what does that mean. I'm confused with the off label thing. I also want to keep it away instead of fighting it off again and the use of both only seems logical. And 1/3 is too high a quote of brain mets, I've read it's more like 23 percent...sherryg683

[MGordon]

Confused - well who isn't! Off label simply means that you will use a drug (prescribed by a wonderful Dr. who cares more for you than FDA rules) although you might not meet the "label" requirements. Still confused? The FDA approves a drug like Tykerb (Lapatinib) for specific case types, histories or combinations - and your case MAY NOT fall within these specific guidelines. Some specifics may include initial diagnosis, HER2 status, previous chemos/treatments, area of metastatis, response to current treatments, so on and so on and so on...

A caring Onc can perscribe the drug "off label" and you can still "legally" take it, but INSURANCE may through a fit AND not pay for it! And guess what - they have that right. It is how the FDA/Insurance Companies can control the wrong meds for the wrong diagnosis - which happens more than the true need for off-label. Kinda like electroshock therapy perscribed for a headache - or Herceptin for a HER2 neg patient. Go ahead if you want, but not on our dime (errr.... dollar). Sometimes if a drug is used Off Label and time proves that it is the correct drug, insurance companies pickup the bill retroactively - not often - but enough to mention. Typically, you'll be on your own for the full price of the perscription up to the point that it is no longer considered off label in your specific case.

Any clearer - or did I just muddy the waters even more?

Love and Light
Mel

[RobinP]

I think this post topic is very important for individuals like AA, Michele and Sherry who are considering Laptinib. Perhaps Becky would consider a chat on this topic for you folks.

Michele, if you take Tykerb, are you going to take an IGFR inhibitor since I think you posted a while back that you were IGFR positive? I've read that IGFR inhibitors and Tykerb taken together increases the efficacy of Tykerb if you are IGFR positive because IGFR positive may be involved with Tykerb resistance.

Also, I recall, Michele, that you were pten positive. Of course, that was a very good thing to be since you took Herceptin. Pten positivity confers to a likely good repsonse to Herceptin because once PTEN is activated with Hercpetin, the HER2 molecule undergoes a series of internal cascading events ( much like the effect of Laptinib on her2 or EFGR2) that decreases phosphorlazation; thus, the her2 signaling pathway.

I can somewhat, theoretically, see why those who are pTen negative and took Herceptin MIGHT ?? be interested in Laptatinib, as opposed to someone like myself who knew that they were pTEN positive when they took Herceptin. As you may know folks, studies suggest that you don't have to be PTEN positive for Tykerb to work. However, there are some pre-clinical studies indicating that you probably have to be pTen positive for Herceptin to fully work. See the following supportive links... http://health.yahoo.com/topic/breastcancer/medications/article/mdanderson/76D33E18-70DD-40E4-9276D43B3B3923FD)

http://breast-cancer-research.com/content/8/6/215#B31
http://www.cancerwise.org/june_2006/display.cfm?id=76D33E18-70DD-40E4-9276D43B3B3923FD&method=displayFull&color=red

[Lani]

I THINK THE DECISION ON WHETHER TO CONSIDER TAKING LAPATINIB IF OFFERED OFF-LABEL MIGHT DEPEND ON WHETHER ONE WOULD BE HER2+ER+ OR HER2+ER-.

OF THE 11% RISK OF BRAIN METS IN THOSE WITH EARLY (NOT STAGE 4) BREAST CANCER, THE MAJORITY IS IN THOSE WHO ARE ER NEGATIVE. SO LET'S SUPPOSE THE RISK IS BETWEEN 3 AND5 PER CENT. NOT QUITE AS BAD...

IN ADDITION, DR. SPECTORS AND BACUS HAVE PUBLISHED A PAPER IN WHICH THEY NOT ONLY LOOKED AT HER2+ER+ AND HER2+ER- BREAST CANCER CELL LINES, BUT ALSO GAVE LAPATINIB NEOADJUVANTLY (in mice if I recall) and found that the her2+ER+ tumors quickly became resistant to
lapatinib if the ER PATHWAY WAS NOT SIMULTANEOUSLY BLOCKED.

RESISTANCE DEVELOPS TO ANTIJHORMONALS WHEN GIVEN ALONE AND ONE WAY THE RESISTANCE DEVELOPS SEEMS TO BE VIA THE EGFR PATHWAY, ANOTHER MAY BE VIA THE HER2 PATHWAY, BUT THERE MAY BE MANY OTHER PATHWAYS UTILIZED TO "GET AROUND" THE ANTIHORMONALS AND REACTIVATE THE ER PATHWAY. THESE MAY MAKE THE LAPATINIB INEFFECTIVE (AND IT MAY BE LAPATINIB MAY BE MORE USEFUL LATER WHEN OTHER PANHER2 INHIBITORS ARE AVAILABLE)

SO STATISTICALLY LAPATINIB WOULD PROBABLY BE ABLE TO DECREASE THE CHANCE OF GETTING BRAIN METS MORE IF ONE IS HER2+ER- AND PERHAPS ALSO MORE LIKELY TO REMAIN EFFECTIVE (IN MICE I BELIEVE IT WAS A MATTER OF WEEKS BEFORE IT LOST EFFICACY WHEN THEY LOOKED NEOADJUVANTLY IE GIVING THE DRUG AND THEN BIOPSYING THE TUMOR AT VARIOUS TIME INTERVALS) I WILL POST THE LINK TO THAT ARTICLE.

THAT SAID, I HAVE HEARD DR. SLAMON SAY THAT HE THINKS HERCEPTIN AND LAPATINIB IS A GOOD COMBINATION...EVEN FOR HER2+ER+

SINCE HEARING THAT, HOWEVER, I HAVE COME ACROSS ANOTHER PAPER
WHICH IMPLIES THE ER PATHWAY WOULD BE USED TO GET AROUND LAPATINIB (WILL TRY TO POST THAT TOO), SO I GUESS WE NEED TO WAIT UNTIL THERE IS RESEARCH PUBLISHED ON THE LAPATINIB/HERCEPTIN COMBINATION.

I THINK MANY ONCOLOGISTS WILL FEEL UNCOMFORTABLE, AS FEW PATIENTS HAVE BEEN ON THESE DRUGS TO UNDERSTAND ALL THE IMPLICATIONS OF THE RESPONSE OF OTHER PATHWAYS AND RESISTANCE MECHANSMS AND ALL THE SIDE EFFECTS WHICH MIGHT EMERGE .

LET'S ALL KEEP OUR EYES OPEN FOR RESEARCH RESULTS WHICH MIGHT MAKE THINGS A BIT LESS MURKY!

[Lani]

Proc Natl Acad Sci U S A. 2006 May 16;103(20):7795-800. Epub 2006 May 8. Links
A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer.

Xia W,
Bacus S,
Hegde P,
Husain I,
Strum J,
Liu L,
Paulazzo G,
Lyass L,
Trusk P,
Hill J,
Harris J,
Spector NL.
Department of Oncology Biology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
The development of acquired resistance to ErbB2 tyrosine kinase inhibitors limits the clinical efficacy of this class of cancer therapeutics. Little is known about the mechanism(s) of acquired resistance to these agents. Here we establish a model of acquired resistance to N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2 (methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (lapatinib), an inhibitor of ErbB2 and ErbB1 tyrosine kinases by chronically exposing lapatinib-sensitive ErbB2-overexpressing breast cancer cells to lapatinib, simulating the clinic where lapatinib is administered on a daily chronic basis. Analysis of baseline gene expression in acquired lapatinib-resistant and parental cells indicates estrogen receptor (ER) signaling involvement in the development of resistance. Using gene interference, we confirm that acquired resistance to lapatinib is mediated by a switch in cell survival dependence and regulation of a key antiapoptotic mediator from ErbB2 alone to codependence upon ER and ErbB2 rather than loss of ErbB2 expression or insensitivity of ErbB2 signaling to lapatinib. Increased ER signaling in response to lapatinib is enhanced by the activation of factors facilitating the transcriptional activity of ER, notably FOXO3a and caveolin-1. Importantly, we confirm that lapatinib induces ER signaling in tumor biopsies from patients with ErbB2-overexpressing breast cancers receiving lapatinib therapy. These findings provided the rationale for preventing the development of acquired resistance by simultaneously inhibiting both ER and ErbB2 signaling pathways. Establishing clinically relevant models of acquired resistance to ErbB2 kinase inhibitors will enhance therapeutic strategies to improve clinical outcomes for patients with ErbB2-overexpressing breast cancers.
PMID: 16682622 [PubMed - indexed for MEDLINE]

[Lani]

briefly translated section of importance to this discussion--ie either MCF7 transfected with her2 or BT474 breast cancer cell lines, blocking EGFR (like lapatinib does) upregulated ER pathway unless an mtor inhibitor was also given

Like a puppy dog who wants to chase the squirrels in the front door, you can close the front door, but he will find a way out the back door, side door, garage door or an open window! It seems to me it makes sense to try to discover which windows may be important in any one individual (or at least subsubtype) of tumor and try to block those rather than using something which may leave the tumor to escape through a path for which there is no inhibitor available yet.

Her2+ breast cancer has its first peak of recurrence 24 months after surgery in those not treated with herceptin or those whose tumor was not sensitive to herceptin. Lets hope for those still on herceptin or just getting off that the research in the next 12-18 months helps elucidate the right path and that additional inhibitors get approval for use within that time as well.