GSK Approves Tykerb - Compassionate Use

[Joe]

We have been negotiating with GSK to release Tykerb for compassionate use. It looks like we had great results.

Christine and Joe



TYKERBÒ (Lapatinib)


FREQUENTLY ASKED QUESTIONS



What is an Expanded Access Program (EAP)?

An Expanded Access Program is a defined protocol based on specific safety and efficacy data from a Phase III clinical development program for a specific disease. EAPs are offered before a drug is approved by the U.S. Food and Drug Administration (FDA) and the drug becomes commercially available.



Does GSK offer an Expanded Access Program for Tykerb?

On June 3rd, GSK announced the opening of an Expanded Access Program (EAP) for Tykerb, in combination with capecitabine for the treatment of advanced and metastatic breast cancer. Although Tykerb is not yet approved for marketing by the U.S. Food and Drug Administration (FDA) or any other regulatory body, GSK recognizes that at this stage in the development program physicians may wish to consider treating certain patients with Tykerb based on clinical evidence to date. GSK is currently enrolling sites for a Global Expanded Access Program (EAP). The EAP program will open Globally over the next several months, as regulatory approvals needed to start the EAP program in those regions are obtained. The EAP will provide access to Tykerb for the group of seriously ill patients that have been shown to benefit in our clinical trials.



What are the entry criteria for the Tykerb EAP?

If a patient is not eligible for another Tykerb clinical trial and has advanced or metastatic ErbB2 overexpressing breast cancer, she may be eligible for the EAP. In particular, those patients who have previously received therapies containing anthracycline, taxane and trastuzumab and have progressive disease may be eligible. Patients will work with their medical oncologists to determine eligibility. For more information regarding qualification and enrollment in the U.S. and additional details on the Tykerb EAP, please call: 1-888-4TYKERB (489-5372). In Europe and Internationally inquiries from physicians can be directed to the following website: breastcancereap@gsk.com (breastcancereap@gsk.com). Outside of the U.S. patients should consult their physicians.



How can I enroll in the Tykerb EAP?

Begin by talking to your oncologist about eligibility for the Tykerb EAP. The call center number for information about the Tykerb EAP in the U.S. is 1-888-4TYKERB (489-5372). Patients should press (1) and will be transferred to a call center representative at the National Organization for Rare Disorders (NORD).



Additional information on Tykerb studies is available at www.clinicaltrials.gov (http://www.clinicaltrials.gov/).



In Europe and Internationally inquiries from physicians can be directed to the following website: breastcancereap@gsk.com (breastcancereap@gsk.com). Outside of the U.S. patients should consult their physicians.



Will the Tykerb EAP be limited to breast cancer treatment?

At this time the EAP will be limited to patients with advanced or metastatic breast cancer.



How many patients can enroll in the Tykerb EAP and how long is the program expected to last?

There is no set limit on enrollment for patients who meet eligibility requirements. The Tykerb EAP is expected to continue until Tykerb is approved by regulatory authorities. Local guidelines will apply to the Tykerb EAP in countries outside the U.S.



Where will the Tykerb EAP be available?

In the U.S. existing Tykerb clinical trial sites are eligible to participate in the EAP program. Additionally, Medical Oncologists who are not participating in Tykerb clinical trials have an opportunity to become a participating site by contacting 1-877-4TYKERB. In Europe and International regions, physicians should contact GSK country staff. The Tykerb EAP will be available in most countries where GSK expects to file for regulatory approval.



What if I can’t get to a distribution site?

GSK is committed to optimizing the geographic distribution of participating sites to minimize the likelihood that this will occur. Throughout the course of the program GSK will be working with investigators, institutions, and regulatory agencies to address urgent patient need with the EAP.

Patients should begin by talking to their oncologist about Tykerb EAP sites in their area. If they can not receive Tykerb through their oncologists, they will be directed to the closest participating site.



How much will the product cost through the EAP?

Patients will not pay for Tykerb while enrolled in the EAP in the U.S.



Local guidelines will apply to the Tykerb EAP in countries outside the U.S.

[Annemarie]

So this is only for combo use in this program?

[Tom]

I want to personally congratulate both you and Christine for your tireless efforts to help those plagued by this particular form of breast cancer. Mom's oncologists have learned the hard way that there are those out there that refuse to sit by and wait for the "Promised Land" to come to them, but rather seek to get there under their own steam. They get the funniest looks on their faces when I tell them in advance of some new drug or treatment plan that will be unveiled at ASCO. I know they don't have time to follow all of the last minute breakthroughs, but damnit, they should hire people to stay on top of these things.

I think that all of us here might have pushed the finish line a few yards back this year, and given many a little breathing room as well as hope. We all know that as long as there is hope, there is life. The painful loss of several of our close members recently hit me like a smack across the face, and reminded me that we aren't fooling around with some allergy, or indigestion problem here, but a real live disease of cells run amok, that can and will kill us or our loved ones if we don't do something about it. Again Joe and Christine, thank you for all that you do, and thanks to those who sit tirelessly searching the web and reading materials for answers. You all deserve a big "well done".

Sincerely,
Tom

[Sherryg683]

Would you have to get off Herceptin to qualify for this. Also, I see where it is taken in combination with Xeloda, is that a must do thing?...sherryg683

[chrislmelb]

That is great news for people who need it. Well done

Christine

[jhandley]

Well done...well done ....well done..

[pattyz]

I also have a question/s. This quote is from a post here:

" If you follow Dr. Spector's, a lead speaker for GSK, most recent research article on Lapatinib, you will note that it seems to turn on the estrogen receptor and that may need to be down regulated simultaneously with the erbs.See articles posted above for more details on this.I was also told that GSK does compassionate use but it takes about 8 months to get the medication once the paper work is filled.Hope this helps folks. And no as an early stager, I am not awaiting Lapatinib."

Is the '8 months' true of your current news?

Is it true about the estrogen receptor info?

Thanks,
pattyz

[RobinP]

Good question Patty, the above quotes are mine. I was told by Dr. Spector back in Dec. 2005 that compassionate use would take 8 months to process. However, this is June2006 now and it appears that the EAP is something new that GSK has opened.

Also, it does appear that commitant use of an er inhibitor is needed with lapatinib as the er receptor is activated with Lapatinib. See article below by Dr. Spector et. al. that I have posted again on her2support in order to address this issue. Perhaps an antiestrogen will be initiated with Lapatinib in the EAP use as it surely appears it is required for proper efficacy of Lapatinib.

A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer.

Citation:

Proc Natl Acad Sci U S A, ; Vol , No (5/10/2006): pp.

Affiliation:

Departments of Oncology Biology and Genomic and Proteomic Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709.

Authors:

Wenle Xia, Sarah Bacus, Priti Hegde, Intisar Husain, Jay Strum, Leihua Liu, Georgina Paulazzo, Ljuba Lyass, Patricia Trusk, Jason Hill, Jennifer Harris, Neil L Spector

http://www.asco.org/portal/beans/virtualmeeting/images/clear.gif http://www.asco.org/portal/beans/virtualmeeting/images/clear.gif http://www.asco.org/portal/beans/virtualmeeting/images/clear.gif 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.

[madubois63]

You and Christine are just AMAZING!!! Thank you for all you do for all of us....

[Cathya]

Joe & Christine:

God bless, bravo and thank you so much for pushing our needs in this forum.

Cathy

[Joe]

We are meeting with GSK's vice president of Oncology this afternoon and will question him on how much time it will take to process the paperwork.


I really don't feel that it will take 8 months as Tykerb has already been fast tracked by the FDA and full approval should take only about 6 months.

In 1998 the Herceptin results were announced at an ASCO meeting. This drug was also fast tracked by the FDA. Final Approval was in September of that year.

Warmest Regards
Joe

[pattyz]

Thanks for this extra info, Robin.

I didn't get your permission in advance, so did not feel it was just ok to quote you by name....

I am er+ so this will be something I need to figure out/ discuss with my onc.

pattyz

[RobinP]

Patty I am posting this article as well which further discusses the use of anti-estrogens with erb targeted therapies. Hope it helps...

Mechanism of action associated with response to erbB targeted therapy.


2005 ASCO Annual Meeting (http://www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCR D&vmview=abst_meeting_categories_view&confID=34)



http://www.asco.org/portal/beans/virtualmeeting/images/clear.gif http://www.asco.org/portal/beans/virtualmeeting/images/clear.gif http://www.asco.org/portal/beans/virtualmeeting/images/clear.gif Abstract No:

676

Citation:

Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 676

Author(s):

S. S. Bacus, J. Hill, G. Hortobagyi, N. Spector

Abstract:

Background: ErbB receptors are associated with aggressive cancers and are therapeutic targets for drugs, such as antibodies or small molecules that block receptor kinase activity and downstream signaling pathways. Nuclear cellular receptors, such estrogen receptor (ER) and progesterone receptor (PR), are also targeted for anti-hormone therapies. There is an inverse correlation between ErbB2 receptor expression and ER and PR. In patients with increased expression levels of ErbB2 anti-hormone therapies are less effective. In addition, the estrogen receptors pathway upregulates the anti-apoptotic factor Bcl2 which is associated with resistance to various therapies. Methods: Breast cancer biopsies from patients treated with small molecule inhibitors to erbB receptors or antibodies were analyzed for ER, PR, Bcl2 and ErbB receptors. In addition, the breast cancer cell line Au-565, that overexpresses ErbB2, was transfected with either ER or Bcl2 cDNAs. The cells were treated with Herceptin or a dual EGFR/ErbB2 inhibitor GW2974 (Lapatinib). Cells were analyzed by Western Blot analysis. Breast biopsies from patients before and after treatment were tested for the expression of various markers such as EGFR, ErbB2, IGF-1R, TGFα, Bcl-2, ER, PR, cyclin D1 and phosphorylated Erk, Akt and S6 ribosomal protein by immunohistochemistry (IHC). Results: Patients treated with the erbB inhibitors that expressed ER, PR and Bcl2 were resistant to treatments. Cells that expressed ER, PR and Bcl2 were resistant to ErbB targeted therapies. The addition of anti-hormone therapies overcame this resistance. Estrogen upregulated Bcl2 and downregulated ErbB receptors. Inhibition of ErbB receptors upregulated the estrogen and progesterone pathway and Bcl2. Conclusions: The nuclear hormone receptor pathway and the ErbB oncogenic receptor pathway interacts with each other to affect the response to ErbB targeted therapies. Strategies combining the selectivity of inhibitors to ErbB receptors together with anti-hormone therapies, hold promise in treating breast cancers.

[StephN]

I have been trying to sort through this posted info to see if the need for an estrogen inhibitor would be necessary for one such as me who is ER and PR negative. Just too fatigued today from all the yard work to think real well today.
My initial path tests from almost 6 years ago say I am neg - but maybe there is some change in the meantime?

[RobinP]

"Importantly, we confirm that lapatinib induces ER signaling in tumor biopsies from patients with ErbB2-overexpressing breast cancers receiving lapatinib therapy. "

I may be wrong but the word induces led me to believe that the er receptor could be turned on and activated in the her2+ hormonal negative situation with the addition of Lapatinib. However, I dare not comment for sure. Hopefully, GSK will clarify this at some point.

[pattyz]

Ok, thanks and hope you're right ofcourse.

pattyz

[pattyz]

Well, that was kinda helpful. It is just that my brain is defunct! But I think I get it by jumping down to 'results'. Maybe :o)

Thanks again. Just saw my onc and next appt is not for two mos. Maybe I can get info together to send him in advance of appt.

I have not been on any anti-est tx because of the side effects. So, I don't even know if I would respond. But, I did respond well to Herceptin/Navelbine. And most recently to Xeloda/Temodar for my brain mets.

But, if I can get something like Tykerb up past the bbb as well... maybe I would respond more than partial/stable. One can hope.

pattyz

[sherri]

Christine and Joe,

Chrsitine, look at you; you had BC and again and again, you went through hell, most people just give up and only have self pity. But look at you, you did find cure for yourself and decided to help others, and you are spending all your time doing this. What can I say about you?!
Lots of love and hugs,

[Sue2001]

Christine and Joe,

The two of you are amazing! Thanks so much to you both. Sue

[heblaj01]

Many thanks , Joe & Christine, for your wonderfull contribution in getting the drug available on a compassionate basis.

[heblaj01]

To the two above posts by Robin in which in vitro evidence of ERB inhibitors such as lapanitib (Tykerb) or transtazumab (Herceptin) upregulating the ER pathway one can add this small study in humans which seems to confirm the lab findings:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16417653&query_hl=1&itool=pubmed_DocSum (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16417653&query_hl=1&itool=pubmed_DocSum)
Breast Cancer Res. (http://javascript<b></b>:AL_get(this,%20'jour',%20'Breast%20Cancer%20Res.' );) 2006;8(1):R4. Epub 2005 Dec 7
Reverting estrogen-receptor-negative phenotype in HER-2-overexpressing advanced breast cancer patients exposed to trastuzumab plus chemotherapy.

Munzone E (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Munzone+E%22%5BAuthor%5D), Curigliano G (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Curigliano+G%22%5BAuthor%5D), Rocca A (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Rocca+A%22%5BAuthor%5D), Bonizzi G (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Bonizzi+G%22%5BAuthor%5D), Renne G (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Renne+G%22%5BAuthor%5D), Goldhirsch A (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Goldhirsch+A%22%5BAuthor%5D), Nole F (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Nole+F%22%5BAuthor%5D).

Department of Medicine, Division of Medical Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. elisabetta.munzone@ieo.it (elisabetta.munzone@ieo.it)

INTRODUCTION: The amounts of estrogen receptor (ER) and progesterone receptor (PgR) in a primary tumor are predictive of the response to endocrine therapies of breast cancer. Several patients with ER-positive primary tumors relapse after adjuvant endocrine therapy with no ER expression in the recurrent tissue; much fewer with a recurrent disease after an ER-negative primary tumor may become endocrine responsive. These sequences of events indicate that a phenotype based on ER expression may not be a permanent feature of breast cancer.
METHODS:
Ten patients with advanced breast cancer whose tumors overexpressed HER-2, but not ER or PgR, were treated with weekly trastuzumab at standard doses with or without chemotherapy.
RESULTS:
Three out of 10 patients showed overexpression of ERs first appearing after 9, 12 and 37 weeks, respectively, from the initiation of trastuzumab. Two of these patients were subsequently treated with endocrine therapy alone: one of them received letrozole for 3 years without evidence of progression. CONCLUSION:
Therapeutic targets enabling the appearance of an endocrine responsive disease may increase treatment options for patients with breast cancer. Furthermore, these clinical data suggest that an ER-negative phenotype is a multi-step process with a reversible repression modality, and that some ER-negative tumors may either revert to an ER-positive phenotype, allowing an endocrine treatment to be effective.

One wonders if the fast success of treatment seen in some women taking an aromatase inhibitor (such as letrozole,Anastrozole,fulvestrant...) in addition to Herceptin is in part explained by attacking both ER & HER pathways.

If someone has a contact with a knowledgeable researcher or clinician it would be interesting to have his opinion on these questions:

1. Over the long term are all takers of ERB inhibitors likely to need endocrine treatments for ER+? Or which subset of patients?

2. Should anti estrogens treatments be started concurrently with Tykerb or Herceptin (even if there is no initial evidence of ER+ disease)?
Would the benefits (hopefully faster & better outcomes) outweight the increased side effects?

3. If on the othe hand the antiestrogen treatments are to begin after reversion from HER+ to ER+ what are the tests providing the earliest diagnostic of the reversal? (if possible non invasive to avoid frequent biopsies or bone marrow aspirations which are also limited in scope by their localized nature)

[MGordon]

Speaking as a family member that "looks like (fingers firmly crossed)" will be placed on this compassionate Release program - I can not thank Joe/Christine and all of the HER2 Board Members enough for all of your efforts with GSK and Tykerb. Lisa and I will keep everyone in the loop as to when she starts Tykerb and how the treatments progress.

Thanks again!

Love and Light
Mel Gordon

[Unregistered]

Johanna from Iceland here,

I am so thankful for this site and for Joe and Christine, what a wonderful people. I was thankful that Joe answered my brain post. Suddenly I´m on hurry in this battle, starting radiation tomorow and believe in good resulsts and have talked to two oncs. (young women that stdied in USA) and pushing them to help me to get tykerb to save me. I have responded well to all meds. uptil now and I want to have more time with my family.

Love and hope

Jóhanna

[Marily]

I also want to thank you very much for all the work you have done to make this drug available. We are truely blessed that people like you exist!
I do have a question on the qualification.
It seems to be stating that you must have agressive cancer and tumor growth? not responding to Herceptin .. if i am understanding what I read.
Also it would be wise to be on something like on of the Aromatase inhibitors. Does this mean If I can not take Herceptin because I am allergic to it, but my cancer which was VERY AGGRESSIVE but which has not changed from NED, (of which I am very thankful ), I would not qualify?
When I read the compassionate use statement I am confused on this?
Thank you
Marily

[Nwehrell]

I just found out in the last few weeks that my mets have "fired" back up while on herceptin.

I have called Glaxo Smith to see if I can be enrolled in the EAP.

Based on what they are looking for I qualify (fingers crossed)

THANK YOU SO MUCH FOR THIS!!!

[Unregistered]

Christine & Joe, Many, Many thanks for all your efforts.. It's people like you who make the world a better place. Kathie