Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

Roche announced today that it's division, known as Genentech, has produced positive results in a phase three EMILIA study of a drug called trastuzumab emtansine (T-DM1). Genentech says that the drug met the endpoint target for the trial, showing marked improvement for women with HER2-positive metastatic breast cancer...

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Anitbody-drug conjugates (ADCs)
 

The EMILIA study found that trastuzumab emtansine (T-DM1) can improve progression-free survival in "some" women with metastatic breast cancer. The final arbiter of clinical approval is overall survival. Median overall survival for patients treated with T-DM1 was not reached. Drug response is not a reliable predictor of overall survival. Median progression-free survival was longer in patients treated with T-DM1 than in those treated with the standard therapy (9.6 vs 6.4 months). The difference reached is statistically significant?

The so-called immunoconjugates or antibody-drug conjugates (ADCs) are unique therapeutics that have become the focus of a plethora of recent and ongoing clinical trials, and for the first time since 2000 when Mylotarg (gemtuzumab ozogamicin) was approved in AML, the FDA gave the green light for another ADC, namely Adcetris (brentuximab vedotin) for the management of Hodgkins Lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL), like its sister agent in HER2-positive breast cancer, T-DM1, and other ADCs.

The ADCs do not work for all patients, T-DM1 is meant to treat only roughly 20 percent of breast cancer cases characterized by an abundance of that protein, and they are not totally free of side effects. And of course, T-DM1 is also likely to be very expensive, costing more than $100,000 for a typical course of treatment. One note: Mylotarg was removed from the market in 2010 after newer studies showed it did not prolong lives and had safety problems. At initial approval, Mylotarg was associated with a serious liver condition called veno-occlusive disease, which can be fatal.

T-DM1 is a "large molecule" and does not cross the blood-brain barrier (BBB). Some think that those on the T-DM1, they should also give the ladies some straight Herceptin, and give a certain amount of protection. The only way for that to happen is a patient may also have to be subjected to an "intrathecal" injection of T-DM1. Herceptin does not cross the BBB because it is a "large molecule" drug. Some on the trial developed brain metastases. Patients on T-DM1 will have to be on it "indefinitely" or until progression. Some on the trial developed brain metastases.

One thing you can definitely say is that T-DM1 is an investigational agent, or just plain experimental.

http://abstract.asco.org/AbstView_114_98675.html
http://cancerfocus.org/forum/showthread.php?t=3768

Blood Brain Barrier: Is Tykerb Better Than Herceptin?
 

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 pre-test (EGFRx Anti-Tyrosine Kinase Profile) is able to test molecularly-targeted anti-cancer drug therapies like Tykerb, Sutent and Nexavar, becasue of being small molecules. A variety of metabolic (cell metabolism) and morphologic (structure) measurements are used to determine if a specific drug (or drugs) was successful at killing the patient's cancer cells. The functinal profiling method differs from other tests in that it assesses the activity of a drug upon combined effect of all cellular processes at the cell "population" level (rather than at the "single cell" level).

Other tests, such as those which identify DNA or RNA sequences or expression of individual proteins often examine only one component of a much larger, interactive process. Functional profiling measures genes before and after drug exposure. Gene expression profiles measure the gene expression only in the resting state, prior to drug exposure.

Unlike (reversible) Herceptin, which only goes after the Her2 gene, also known as epidermal growth factor receptor (EGFR) type 2, (irreversible) Tykerb goes after Her1 (EGFR) but also Her2 (EGFR type 2). Tykerb irreversibly binds to EGFR and Her2. It works by blocking these receptors, preventing their activation and hopefully inhibiting the unwanted signaling pathways. And Tykerb is a BBB crossing drug.

So, will Tykerb be better than Herceptin? You be the judge.

http://weisenthalcancer.com/Services.html

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

Interesting opinion.
Stupid question: is it possible to develop L-DM1 instead of T-DM1? ( L for Lapatinib/Tykerb)
Michka

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

Michka

That's a smart question! They could have. The EMILIA trial, which was sponsored by Roche, compared trastuzumab (Herceptin) emtansine used alone, to lapatinib (Tykerb) plus capecitabine (Xeloda). It was Roche who developed trastuzumab (Herceptin). It was GlaxoSmithKline who developed lapatinib (Tykerb).

Roche was one of a number of pharmaceutical companies that conjured a new generation of combination medicines and spurred regulators to rewrite the rules for drug research, to shave five years off development timelines.

For a decade, researchers have crafted drugs to disrupt the cellular processes that fuel cancer. So far, survival benefits are measured in months, not years. That's because cancer evolves rapidly to evade a single treatment. Rather than mixing and matching approved drugs, scientist are now developing combinations designed to work in tandem to block cancer.

Cocktails that mix drugs still in development wouldn't have been possible just five years ago. FDA rules required that the merit of each active ingredient be proven before it could be added to another. Regulators were concerned about approving a "combination" where one of the ingredients didn't help, or worse, caused harm.

The FDA has allowed innovative testing of drug cocktails. The new research guidelines describe three basic principles for early combinations.

First, there should be a scientific rationale for how the drugs will work together in the body.

Second, there should be evidence from mouse tests or small human trials that the benefit of combining the drugs is more than additive (think 1+1=3).

Finally, there should be a compelling reason why each drug can't be successful independently.

If conditions are met, companies may develop components simultaneously and forgo differentiating the drugs on the last and most expensive trials needed for regulatory approval. Those studies, pivotal Phase III trials, can cost hundreds of millions of dollars and take years to complete.

The promise of targeted cocktails changed how companies do business. There are several approaches being pursued. Pfizer Inc. and Roche are developing the needed parts in their own labs. Roche has a combination that began safety tests in patients last year, and New York's Pfizer has four combinations in human trials.

According to an article in the Journal of the National Cancer Institute, it is becoming increasingly evident that cancers are dependent on a number of altered molecular pathways and can develop diverse mechanisms of resistance to therapy with single agents. Therefore, combination regimens may provide the best hope for effective therapies with durable effects (JNCI J Natl Cancer Inst Volume103, Issue16 Pp. 1222-1226).

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicated on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

The application of synergy analyses may represent one of the most important applications of the functional profiling platform; enabling clinicians to explore both anticipated and unanticipated favorable interactions. Equally important may be the platform's capacity to study drug antagonism wherein two effective drugs counteract each others’ benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs because they can.

Functional profiling consists of a combination of a (cell morphology) morphologic endpoint (DISC) and one or more (cell metabolism) metabolic endpoinsts (MTT, ATP, resazurin). It studies cells in small clusters or microspheroids (microclusters). The combination of measuring morphologic (structural) effects and metabolic effects constitutes the measuring of a profile at the whole cell level.

These analyses are revolutionizing the way cell-based functional profiling applies newer classes of drugs and has the potential to accelerate drug development and clinical therapeutics. Good outcomes require good drugs, but better outcomes require good combinations. Intelligent combinations are a principle focus of functional tumor cell profiling.

Cell-based functional profiling assay labs have always tested new drugs in combination with each other, simultaneously measuring direct antitumor activity and antivascular activity.

Greg

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

Another synergy to be better explored is combining treatment modalities. Much points to the benefits (additive, synergy, or just not conflicting) of combining chemos, bios, hormonals and radiation. Yet most oncologists are taught to keep much of this separate..sequential. Part of the difficulty in exploring this is likely the inability to "own" the results, making costly trials hard to finance.

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

"Median progression-free survival was longer in patients treated with T-DM1 than in those treated with the standard therapy (9.6 vs 6.4 months). The difference reached is statistically significant?"

MJ is currently on Tykerb/Xeloda. So, T-DM1 would baically give a median 3.2 month extension of time without progression of disease compared to what she is already on. Statistically, that looks great at a 33% improvement but in terms of keeping the disease at bay, it's only a matter of months for many patients. I'm trying not to sound negative but I need to understand more about how a median gain of 3.2 months is remarkable(+33% is remarkable, yes). T-DM1 is being hailed as another miracle drug and I hope everyone is right because that will be our next step after Tykerb/Xeloda, I'm imagining. I'm hoping it proves to increase overall survivability. That's the important statistic for me.

Greg

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

"Another synergy to be better explored is combining treatment modalities."

Very good point Rich!

I've always been an advocate of surgery then chemo or radiation, depending on the tumor type. For example: NSCLC is not intrinsically sensitive to chemo, where radiation if more of a factor. SCLC is intrinsically sensitive to chemo. BRCA cancers are hypersensitive to chemo.

MJ

Progression-free survival (PFS) is the length of time during and after treatment in which a patient is living with a disease that does not get worse.

Time to progression (TTP) is a measure of time after a disease is diagnosed (or treated) until the disease starts to get worse.

In the Annals of Oncology, it states that clinical investigators seem to be frequently using PFS and TTP interchangeably in cancer. Such use of terms may lead to confusion when results of different trials are compared.

The survival gain induced by chemotherapy is considered to be the time the tumor requires to return to a size similar to what existed before chemotherapy. In calculating survival gained by tumor shrinkage, it is approximately 2 months in 50% reduction, 3 and a half months in 75% reduction and 1 year in 99% reduction. The data indicate that in cases evaluated with reduction rates more than 90%, there may be a significant correlation between response rate and survival.

Clinical trials virtually always have time to disease progression as a primary endpoint. Without imaging studies, one can't get accurate time to progression data. So tests are performed for the benefit of drug companies seeking new drug approval, for clinical investigators seeking contracts and publications, and for clinicians seeking an easy way to make clinical decisions.

The final arbiter of clinical approval is overall survival. Progression-free survival does not address the patient's quality of life during what little additional months of some serious side effects that can be experienced. And drug response is not even a reliable predictor of overall survival. Overall survival is based on death from any cause like side effects of treatment and effects on survival after relapse.

Greg

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

The more I learn about TDM1 the more I am puzzled. The benefits seem so small...but thank you Greg and Rich for informing us even if I do not like some of those stats.

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

I do like this statistic even though it fell short of the goal they were trying to reach. That shows more women living for two years or more. I read that the complete OS study will be continued to 2014.

"Two-year overall survival was 65.4% among women in the T-DM1 group and 47.5% among women in the Xeloda and Tykerb group."

Reference:
http://news.cancerconnect.com/t-dm1-...breast-cancer/

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

I wouldn't get discouraged by the limited success of TDM-1, because for a handful of women- it could have been their magic bullet. Furthermore, with additional testing and screening, perhaps researchers can determine which subtypes and genotypes would benefit from TDM-1 most.

I love the LDM1 idea, except I think it would be so chalk full of side effects that it wouldn't be a big money maker. My experience on tykerb/lapatinab hasn't been pretty.

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

What does this mean exactly? What adds up? Different treatments or cycles of TDM1? I do not understand.


"Women getting T-DM1 had 9.6 months of progression-free survival, the time between starting the treatment and the cancer getting worse again, compared with 6.4 months in the standard therapy group. That's a median improvement of three months.
This may not seem like a long time, but as Dr. Eric Winer of the Dana-Farber Cancer Institute in Boston explains, it means a lot to the individual patient.
"I've had patients on this drug for one, two, three years," he explained. Winer says that if a patient gets an additional three months before the tumors start growing again each time she goes through a treatment cycle, that can add up to almost a year."

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

T-DM1 worked in less than half the patients treated in prolonging the disease-free interval and was not without significant side effects. T-DM1 patients had fewer grade 3 or higher side effects (40.8%) compared to those who received standard treatment (57%), but it's important to remember that these results are interim and the final story won't be known until 2014. It may be somewhat better than anything else available at the moment, but it remains to be seen if it is a "magic bullet," "smart bomb," or "miracle" drug.

I heard of women who were bumped from the T-DM1 clinical trial because of disease progression, which meant that their cancer was growing despite the drug. Bumped off the trial because of disease progression? Wonder how many more patients there were?

Response rates (how much a tumor decreased in size) can be inflated when excluding patients during clinical trials (evaluable patients). Patients not considered "evaluable" are often those who do not get the benefit of an entire treatment plan. The response rate is calculated after removing patients, who die or have been excluded, from the calculation. This inflates the response rate.

But clinical oncologists want to publish their papers. They need to report on the outcomes of their experiments, but if they had to wait for survival data, it could take years until all the data was aggregated. That wouldn't bode well for them to participate in pharma-sponsored trials in the future.

Response rates give clinical oncologists the opportunity to take a more optimistic look at therapies that have limited success. They can describe results as being complete remission, partial remission or simply clinical improvement.

If they treat all patients for three weeks, they can fairly evaluate the efficacy of a compound, which takes that lone (on average) before it can be regarded as effective. If they disregard all patients who die or were excluded after onset of therapy, and include only those treated three weeks or more, they can improve their data.

To justify their existence, they have to publish papers. That's what they do.

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

How much to expect from "experimental" T-DM1 drug which was compared with Tykerb/Xeloda, a combination drug who's evaluation was halted early because of superior performance.

Some of the highlights:

50% improvement in PFS, from 6.4 months to 9.6 months.

absolute difference in overall survival of 7.7% at one year and projected 18% at 2 years, i.e. at two 18 more persons will remain alive on this therapy.

adverse events favoring t-dm1 included diarrhea (20.7% vs 1.6%), hand-foot syndrome (16.4% vs 0) and vomiting (4.5% vs 0.8%). Not surprisingly, there was a higher treatment discontinuation arm in the control arm as well (11 vs 6%). Five deaths were recorded on the control arm vs 1 on T-DM1 arm.

More detailed information to be found looking at numerous trial reports on the web.http://www.oncolink.org/conferences/...ss=357&id=2237

Re: Genentech's Trastuzumab Emtansine (T-DM1) Reduces The Risk Of Cancer Worsening
 

I understand that it may not be a miracle but it may just be another option. We are not a herd of cows - we are all unique - it had a response in about 40% that's still a lot of women/men. What about them and those of us who may be like them? Are we to be denied an option because it may not work for others?

The sooner they can test for who will respond to what - true personalized oncology the better. How many other drugs get left on the shelf because the only work for a few?

Randomized Clinical Trial Paradigm