Why Herceptin and not Tykerb?

[Donna]

Good Morning Amazing Group,

I was able to do the interview in San Francisco that was posted here a week ago. It was financed by Genentech - and I am still not sure what they were after - but they paid me for it :-)

After the interview, because of one of the questions, I started to wonder why Herpectin is firstline treatment instead of Tykerb. The way I understand it Tykerb, is actually protective of the heart muscle - and since it works inside the cell instead of at receptor sites, wouldn't this just be more effective with less chance of heart damage - better all the way 'round? Anyone?

Thanks - have a great day!

Donna

[jones7676]

Maybe because Tykerb is still so new and they are not sure whether or not new side effects that are yet unknown may crop up? Just a thought.

[KRISS]

I know I asked my Onc why not tykerb and he was flat out "we don't know enough yet" He said " why not go with what we know works" Maybe a few years down the road it will be different.

[AlaskaAngel]

Donna,

The TEACH trial is available to those who have had chemo but have not had Herceptin, so one could choose to be part of that trial using lapatinib (Tykerb). However, it is blinded and those in the trial are given either lapatinib or a placebo, and one can't choose which they would be given.

The TEACH trial is intended to help determine not only how well the drug works, but also whether it works for those who were treated some time ago with chemo but never treated with Herceptin.

AlaskaAngel

[John21]

I am a believer of don't waste anything. The drugs are limited. Use herceptin first. Keep Tykerb as a spare down the line when herceptin doesn't work. In the mean time, keep looking for the drug past Tykerb. Does anyone know about one yet?

JOhn

[Sandy in Silicon Valley]

Hi, Donna -

I think that the answer to your question comes from how the two drugs have been tested...

The Tykerb Phase III trial that GSK ran was exclusively for patients with bcmets, whose mets had progressed while they were on Herceptin, and who were willing to take Xeloda along with the Tykerb, and come off any other systemic chemo they were on. That's a fairly limited subject pool, out of all the people who will eventually get Tykerb off-label, as I am (taking it WITH Herceptin, and without any systemic chemo).

Herceptin has been tested, and found synergistic with, numerous chemo regimens. It does have the LVEF damage possibility - but not everyone gets that side effect (I haven't, in 4.5 years of effective Herceptin use), and has very few/minor other side effects. Plus, the left ventricle heart damage is reversible, if found on time, and Herceptin patients are monitored for signs of CHF (in which case, they're taken off the Herceptin).

Tykerb has nastier side effects, and for more of the patients taking it: rash/acne & itching/pain associated with the pruritis, and diarrhea. It isn't known how effective it is, or for which bcmets patients, or whether it is effective in an adjuvant setting (prior to dx with bcmets). It isn't known which chemo regimens it might work well with, and which might result in worse side effects, or might be antagonist (work against each other).

Personally, I'm taking Tykerb b/c I've had brain mets, and the Herceptin can't get through the BBB (blood brain barrier), being a large molecule drug. Tykerb is a small molecule drug, considered able to get through the BBB to prevent/decrease brain mets. But the verdict really isn't in yet about how effective it is, for how many HER2neu+++ patients. So it's a gamble... if my brain mets progress, I will go off the Tykerb, but stay on Herceptin, and possibly try another small-molecule biologically-targeted drug, like Sutent.

(((hugs)))
Sandy in Silicon Valley

[chrisy]

Herceptin is first line because it's been tested - tried and true and proven to be effective in the adjuvant setting (to prevent recurrence).

Tykerb has not been tested as extensively but is in trials now.

Although my personal experience seems to indicate Tykerb is easier on the heart, I think the official jury is still out on that in terms of "data". Nor has there been a "head to head" trial comparing Tykerb and Herceptin. Although it is believed Tykerb is protective to the brain because it's a small molecule and can cross the blood-brain barrier.

So, not necessarily proven that Tykerb is "better", in my view.

[doh2pa]

To John 21,

Actually, there's a new "herceptin" in the works - pertuzumab. It's good to see that researchers are focusing on targeted therapies, as they are generally so much easier to tolerate than traditional chemo. Lani posted the trial recently, - here's a cut and paste on it.

2007 ASCO Annual Meeting


Abstract No:

14149
Citation:

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 14149
Author(s):

H. Nakajima, S. Tanuma, I. Fujiwara, N. Mizuta, K. Sakaguchi
Abstract:

Background: HER2 is a unique receptor molecule for which no ligand has been found and functions as a coreceptor to form homo-and hetero-dimers with other three HER (1, 3 and 4) family members. The dimerization results in the activation of HER tyrosine kinase. This, in turn, promotes the tyrosine phosphorylation of certain proteins, leading to the stimulation of cell proliferation, invasion, and antiapoptosis. The overexpression of HER2 in breast cancer correlates with increased tumor growth and metastatic potential, and thereby poor long-term survival for the patient. A monoclonal antibody against HER2, named trastuzumab, is approved for breast cancer patients, while pertuzumab is currently in phaseIIclinical trial. The two antibodies bind to different epitopes in the extracellular domains of HER2. Trastuzumab binding mainly mediates the antibody-dependent cytotoxicity (ADCC). On the other hand, pertuzumab binding directly inhibits HER2 dimerization with its partner receptors, blocking the growth signaling and inducing apoptosis. Furthermore, the unique binding pockets on HER2 for trastuzumab and pertuzumab have been resolved and provide the important target domains for creation of new anticancer drugs. Methods: Based on these mechanisms, we are trying to design and create both antibodies-mimetic molecules using our in silico methodologies COSMOS (Conversion to small molecules through optimized-peptide strategy) and SARM (Self-assembling regulatory molecule). We design HRAP (HER2 reactive peptide)- SARM and HRAP- SARM- FAB (Fc?-binding peptide). HRAP-SARM may bind to HER2 pertuzumab binding site and sterically interferes with HER2 dimerization and induces apoptosis. HRAP- SARM- FAB is expected to induce both ADCC and apoptosis. Results and Conclusion: In this presentation, we will show the preliminary results and functions of the Ab-mimetics, HRAP-SARM and HRAP- SARM- FAB on human breast cancer cells overexpressing HER2, as compared to those of trastuzumab and pertuzumab. Since those Ab-mimetics are small molecules and cheap, the successful results are sure to promise the revolutionary therapy for refractory breast cancer

[gdpawel]

Tykerb is one of the first oral agents with the potential to compete directly with the IV drugs which is both a high-volume and high-revenue part of office-based practices. Early use of Tykerb will likely be limited to patients whose breast cancer is refractory to Herceptin. In the longer term, it could supplant or perhaps find a place in combination with Herceptin.

Although oral tyrosine kinase inhibitors, like Tykerb, offer patients a well-tolerated, conveniently administered alternative to intravenous (IV) therapy, Decisions Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, found that oncologists are not yet ready to use Tykerb as a replacement for Herceptin. Ninety-one percent of surveyed oncologists stated that intravenous (IV) cancer therapies are more profitable than oral therapies. And fifty-eight percent of oncologists say they would favor IV Herceptin over oral Tykerb because administration of IV drugs remains an important source of income for their practices.

Of course, will patients be able to afford the cost of these drugs? Herceptin's wholesale price on an annualized basis is approximately $45,000 per year. Tarceva, $40,000 per year. Nexavar, $60,000 per year. Avastin, $47,000 per year. Will the price of Tykerb approximate these novel agents or exceed their costs? The problem is not unique to these drugs, but also to all of the new molecularly-targeted agents.

Lee Newcomer, former chief medical officer and currently an executive with United Health Group, stated at the 12th annual conference of the National Comprehensive Cancer Network, that "Avastin improves outcomes in about 20% of patients, but we have no idea which cancer patients will benefit from a course of treatment. Because Avastin is included with numerous drug cocktails, it costs $354,000 per year of life extended with Avastin because of today's 'cookie-cutter' approach to chemotherapy. You don't know in advance who is going to respond."

Everyone is scared to death (and rightly so) at what is going to happen to the healthcare economic system with the introduction of increasingly expensive new drugs that benefit only a small percentage of patients who receive them, hence the headlong rush to develop tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

The FDA finds themselves under increasing pressure to allow new drugs into the marketplace, while at the same time protecting the safety of potential recipients of those drugs and also the financial interests of those who will have to pay for them. The pressure is so great that companion molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

It should be in the FDA's interest in saving the healthcare system perhaps billions of dollars a year (and thereby the healthcare system itself) by ensuring that expensive treatments are used appropriately. It should serve their interest not only in discovering new cancer treatments, but also using currently-available cell culture assay technologies to improve the effectiveness of existing drugs and save lives today by administering the right drug to the right patient at the right time.

The methods of cancer medicine during the last thirty some years are coming to haunt the "one-size-fits-all" establishment. Technologies, developed over the last twenty years by private researchers, hold the key to solving some of the problems confronting a healthcare system that is seeking ways to best allocate available resources while accomplishing the critical task of matching individual patients with the treatments most likely to benefit them.

[Lani]

there are trials begnning with tykerb and herceptin. and the safety phase so far has shown no additional toxicity, but the trials are still new and not all side effects show themselves right away.

There is also the new chemofused to herceptin being developed by GENENTECH, Pertuzumab plus herceptin already some interim reports in metastatic her2+ bc were reported at ASCO --and the safety phase so far has shown no additional toxicity, but the trials are still new and not all side effects show themselves right away. in addition there were initial reports on herceptin plus an mTor inhibitor, an Hsp90 inhibitor and others. Lots of those posters were up on Sunday morning or Saturday afternoon poster sessions as I recall.

I would think by donating portions of their biopsy specimens patients could contribute to speeding up this process, as it is essential to see which pathways contribute in each patient to the aggressiveness of their tumor to find biomarkers to determine in which patients to test each of these combinations. If they would not have found FISH by her2 as a marker for herceptin, herceptin trials would have failed to show efficacy and the drug would not have been developed!!!

Sorry to sound like a bully on the pulpit, a nagging mother/spouse/mother-in law, but how many would like to step up to the plate or are you one would would rather wait around for something to be found, developed, tested, approved (which could be ten to twenty years)?

[Lani]

Sorry I did not mean YOU personally. Just those who read, post and/or lurch at this site.

[StephN]

Lani -
Many of us answered about donating our tumor or blood on another thread. Your question will get buried here.

We just will need a new post or forum where the mechanics of this will be discussed and a plan put in place.

I can't speak for everyone, but I feel that those who volunteered already will come through when the time comes.

[gdpawel]

A recent company-sponsored study showed that Tykerb's blood levels increased by 167% when taken with a low-fat meal, compared with taking the drug on an empty stomach, and by 325% after a high-fat meal.

In a recent editorial in the Journal of Clinical Oncology, researchers ruffled some industry feathers by arguing that taking Tykerb with food (THE LABEL SAYS NOT TO) might allow patients to take lower doses, leading to a potential cost savings of 60% off the drug's $2,900-a-month price tag.

Savings could be about 80% if Tykerb were taken with grapefruit juice, since the drug interacts with an enzyme in the gut (CYP3A4) that breaks down drugs before they enter the bloodstream. People with lots of CYP3A5 may have less medicine enter their bloodstream than people who don't have so much.

Grapefruit juice has a compound that temporarily gets rid of CYP3A4, which allows more of a drug to enter the bloodstream. For people who take statins with grapefruit juice, the drug can build up to unhealthy levels in the body.

Some researchers feel that the grapefruit effect could ultimately allow patients to take lower doses of drugs like Tykerb. With oral oncology therapies being very expensive, this may lower the costs by as much as 50% saving hundreds of millions of dollars.
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[hutchibk]

GD - "Tykerb taken with food potentially cuts drug costs"...

This is not a new controversy or idea... My doctor and I talked about it last summer (and he was not yet interested in something so speculative without any scientific studies behind it) and then I talked to doctors at SABCS who were heavily involved in phase 1 to phase 3 trials of Tykerb (Dr. Burris and Dr. Hayes) as well as one of the scientists who was on the team that "invented" it... and they all strongly agreed with this response from GSK.
_______________________________________________

GSK’s Response to JCO commentary – July 17, 2007
In response to commentary published by Ratain and Cohen in the July 20,2007 issue of the JCO, GlaxoSmithKline issues the following statement:

Speculative statements by Ratain and Cohen in a recent JCO commentary have the potential to be misunderstood and misused by clinicians and patients. TYKERB® (lapatinib) is indicated in combination with capecitabine for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Breast cancer is a serious and potentially life threatening disease. In order for treatments like TYKERB to be used safely and effectively, it is critical that TYKERB is prescribed and taken correctly, as approved by the FDA. The effectiveness of TYKERB depends on the right amount of medicine reaching the cancer cells. TYKERB should be taken at least one hour before or at least one hour after food. The current FDA-approved labeling for TYKERB was established based on the efficacy and safety data from the pivotal Phase III study, in combination with capecitabine. Currently there is no evidence to support that adjusting the dose of TYKERB, in combination with either food or grapefruit juice may be as safe or effective for the patient. While dosing TYKERB with food has been found to increase absorption, food effects are highly variable and hard to predict. Taking TYKERB with food could result in increased side effects and decreased efficacy. Additionally, concurrent medicines that patients may be taking, including capecitabine, must be considered. Each medicine has its own potential for drug and food interactions. Therefore, it is imperative that patients follow the current FDA approved TYKERB dosing and administration recommendations without food so that a consistent amount of the medicine is absorbed by the body. Finally, our clinical experience indicates that dosing with food does not impact the incidence of diarrhea associated with TYKERB. The speculation that this side effect is due to unabsorbed drug in the intestine, and that dosing with food would decrease this toxicity, is not validated by our clinical experience. Identifying cost-savings for the healthcare system and cancer patients is necessary. However, making speculative dosage adjustments for this potential “value meal” does a disservice to patients with this life threatening disease and the healthcare professionals who treat them.

[Mary Anne in TX]

Sandy and Brenda, I just got the best class on Tykerb from you two. It makes really good sense the way you described it. Plus, it fits what my onc has talked about with me. I see him tomorrow and am to have herceptin. However, my insurance company has now refused to pay for herceptin (I'll get help working on that issue while I'm there, I hope) and your explanation plus others I have read the past few weeks about the trials and the combinations available give me peace of mind. I must admit that I was already into the "what ifs"..... Thank you for sharing your knowledge and experience and for being such terrific communicators. You guys are wonderful! Now I can get back to basketball, Texas politics, and grandkid watching! Oh, yes, better work too!!! Lots of love and appreciation for each of you warriors! ma

[CLTann]

I have earlier written about the combination of grapefruit effect with certain drugs. It is totally irresponsible for the drug industry to ignore or reject this important idea. What they should do is to sponsor or undertake a project using the essential ingredient from grapefruit with the candidate drug to see the efficacy of this combined drug. Not only the cost can be lowered, but the reduction of drug side effects is critically important to many patients. This type of thinking is the core of being a responsible coporate citizenship.

Of course, I am aware of the fact that the cost of drug is highly inflated in USA. The same drug can be purchased much cheaper in Mexico and Canada. Drug companies should immediately make their pricing more rational, perhaps with the help of congress in enacting a drug cost/profit law. They should be more transparent in how they come up with these astronomical new drug costs. Sooner or later, the new politicians will press this issue since the overall costs of health care involve the high cost of new medicines.

[gdpawel]

I've read about the FDA citing GSK for downplaying risks of Tykerb, while exaggerating the benefits, in letters to doctors. This wouldn't be the first time that information was left out of GSK's marketing letters to doctors.

Although oral tyrosine kinase inhibitors, like Tykerb, offer patients a well-tolerated, conveniently administered alternative to intravenous (IV) therapy, Decisions Resources, one of the world's leading research and advisory firms for pharmaceutical and healthcare issues, found that oncologists are not yet ready to use Tykerb as a replacement for Herceptin.

Ninety-one percent of surveyed oncologists stated that intravenous (IV) cancer therapies are more profitable than oral therapies. And fifty-eight percent of oncologists say they would favor IV Herceptin over oral Tykerb because administration of IV drugs remains an important source of income for their practices.

Medical oncologists should be taken out of the retail pharmacy business and force them be doctors again. Selling cancer chemotherapy with concessions creates conflicts of interest for oncologists.

[dlaxague]

I see that this question was asked last fall. And now the answers are being sought in a large international trial - see Joe's post about the ALTTO trial, looking at both Tykerb and Herceptin for adjuvant therapy. ( http://her2support.org/vbulletin/showthread.php?t=32869&highlight=altto+trial )
That's a big link - here's the tinyURL: http://tinyurl.com/yq24u8

Either one alone or both (together or sequentially), neo (see link to neo-ALTTO at the alttotrials.com site ), or regular adjuvant, after chemo or concurrent with taxol - very complex trial.

Debbie Laxague

[hutchibk]

GW - Tykerb and Herceptin target two different things, so it wouldn't make medical sense to favor one over the other. It seems that the premise of the survey of oncologists is flawed since Tykerb is available only in the metatstatic setting for now. And due to that fact, it is not even a choice that oncologists would have to make at this time. That may change when the results of the ALTTO trial come to bare, but until then it seems to not be a fair point to raise.

[runtolive]

the next drug in line is coming from genentech.. its called TRASTUZUMAB-DM1..

its actually herceptin conjugated with a toxin ( poison) ..DM1 ... while herceptin is typically only active in about 25% of its patients.. the conjugated version actually showed an 80% response rate.. 7 patients had stable disease and 5 patients showed a partial response.. out of 15 total patients.. genentech reported these results at the SABC in san antonio in december 2007. genentech is currently running two separate tras-dm1 trials... a phase 2 trial dosed every 3 weeks.. and a phase 1 trial dosed once a week.. at least 5 women i know of our involved in this trial with a 6th lady scheduled to begin in 2 weeks..

http://clinicaltrials.gov/ct2/show/NCT00509769?term=Breast+Cancer&recr=Open&spons=Genentech&spons_ex=Y&rank=4&flds=Xabce&show_locs=Y#locn

this is a link to the every 3 week trial..

run to live

[gdpawel]

Hutchibk. Cells are the most basic structure of the body. Cells make up tissues, and tissues make up organs, such as the lungs or liver. Each cell is surrounded by a membrane, a thin layer that separates the outside of the cell from the inside.

For a cell to perform necessary functions for the body and respond to its surroundings, it needs to communicate with other cells in the body. Communication occurs through chemical messages in a process called signal transduction. The purpose of these signals is to tell the cell what to do, such as when to grow, divide into two new cells, and die.

Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific molecules involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth. By focusing on molecular and cellular changes that are specific to cancer, targeted cancer therapies may be more effective than current treatments and less harmful to normal cells.

However, the monoclonal antibodies like Herceptin are "large" molecules. These very large molecules don't have a convenient way of getting access to the large majority of cells. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside, which are protected from the drug. The cells may pass small molecules back and forth (in the same way that neighbors can share food).

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, "small" molecules that act on multiple receptors in the cancerous cells, like Tykerb. The trend has away from the monoclonals to the small molecules, a trend in which new predictive tests may be able to hasten.

Some years ago, GSK had supplied some private cell-based assay labs with small molecule Tykerb so they can work out an assay for it before its impending FDA approval. A variety of metabolic and morphologic measurements were used to determine if it was successful at killing a patient's cancer cells.

Functional profiling can discriminate between the activity of different targeted drugs and identify situations in which it is advantageous to combine the targeted drugs with other types of cancer drugs. It measures over 100,000 genes before and after drug exposure. Gene expression profiles measures the gene expression only in the resting state, prior to drug exposure.

Researchers had put enormous efforts into genetic profiling as a way of predicting patient response to targeted therapies. However, no gene-based test as been described that can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can an available gene-based test identify situations in which it is advantageous to combine a targeted drug with other types of cancer drugs. Functional profiling tests have demonstrated this critical ability.

The "forest and trees" analogy can explained the fact that conventional chemo treatments try to kill "all" cancerous cells (along with non-cancerous cells). The whole forest of cells. The new "targeted" drugs go after a "pathway" within or on cancerous cells. Hence the "trees" instead of the "forest."

With "functional" cell-based assays, the "forest" is looked at and not the "trees." There are many pathways to altered cellular (forest) function (hence all the different "trees" which correlate in different situations). The "functional" profiling technique of cell-death assays, measures what happens at the end (the effects on the forest), rather than the status of the individual trees. Cancer is a complex disease and needs to be attacked on many fronts.

Cancer therapy needs to be thought of "outside the box" with "personalized" treatments for "individual" patients, and requires a combination of novel diagnostics and therapeutics. If "some" drugs are working for "some" people (not average populations), then obviously there are others out there who would also benefit. Who are those that would benefit? All the more reason to test the tumor first.

A cell culture assay with "functional" profiling, using a cell-death endpoint, can help see what treatments will not have the best opportunity of being successful (resistant) and identify drugs that have the best opportunity of being successful (sensitive). Cell "function" analysis doesn't claim to have a perfect model, but all retrospective studies have documented that killing cells in the test tube does correlate with dead cancer cells in the patient.

"Funtional" profiling measures the response of the tumor cells to drug exposure. Following this exposure, they measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell (forest), resulting in a cellular response to the drug, measuring the interaction of the entire genome. No matter which genes are being affected (trees), "functional" profiling is measuring them through the surrogate of measuring if the cell is alive or dead.

For example, the epidermal growth factor receptor (EGFR) is a protein on the surface of a cell. EGFR inhibiting drugs certainly do target specific genes, but even knowing what genes the drugs target doesn't tell you the whole story. Both Iressa and Tarceva target EGFR protein-tyrosine kinases. But all the EGFR mutation or amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack.

It doesn't tell you if Iressa is better or worse than Tarceva or other drugs which may target this. There are differences. The drugs have to get inside the cells in order to target anything. So, in different tumors, either Iressa or Tarceva might get in better or worse than the other. And the drugs may also be inactivated at different rates, also contributing to sensitivity versus resistance.

In an example of this testing, researchers have tested how well a pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast and colorectal cancers. The pre-test can report prospectively to a physician specifically which chemotherapy agent would benefit a cancer patient. Drug sensitivity profiles differ significantly among cancer patients even when diagnosed with the same cancer. One-size-does-not-fit-all.