Genentech receives FDA approval for Kadcyla to treat HER2-positive metastatic breast

[News]

The U.S. Food and Drug Administration today approved Kadcyla (ado-trastuzumab emtansine), a new therapy for patients with HER2-positive, late-stage (metastatic) breast cancer.

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[ElaineM]

Super news !!

[gdpawel]

I've heard from breast cancer patients 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 like this?

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.

http://cancerfocus.org/forum/showthread.php?t=3768

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.

Clinical trials virtually always have progression-free survival 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.

[Mandamoo]

I was "bumped" off trial for disease progression - that's part of the deal - are you suggesting that my progression was not included (I was on the trial 4months? The trial criteria for progression is 25% growth in target tumor from its smallest size during trial. I was scanned every 6 weeks and asked for an earlier scan near the end of the trial as my previous scan had been questionable. While the treatment didn't work for me it drastically slowed the progression of my disease during the time I was on the drug - not good enough
I am not sure what you are suggesting with your post gdpawel? It remains that this is a very effective drug for some people - should they be denied the option because it is not effective for others?

[gdpawel]

A patient being bumped from a clinical trial because of disease progression is not considered evaluable. The response rate is calculated after removing patients who have been excluded, thus giving a more optimistic look at a therapy that may have limited success. The drug can improve progression-free survival in "some" women with metastatic breast cancer. Median overall survival for patients treated with the drug was not reached, according to the researchers (not company spokespeople). The antibody-drug conjugate shrinks "some" breast cancer tumors. Because this drug may work in "some" women, is that a reason to give it to all others, risking mutagenic effects of ineffective therapy? The mutagenic effects of chemotherapy on a genetically-unstable tumor can drive the tumor into a state of more aggressive behavior. You might kill off a whole lot of cancer, only to cause a mutation in the remaining cancer, such that the remaining cancer behaves in a more aggressive fashion.

[Mandamoo]

So all patients who progress on the therapy are not included? I don't understand - I would have thought I for example would be included as a patient who was stable for 4months until disease progression?
As to you question, until they can tell who will we respond and who wouldn't I would be happy to take the risk - after all, 'they' tell me I'm going to die anyway so why not try something that may work? Not all would feel like this but I do, I would also go back on this drug in combination with something like Perjeta.

I don't thin tdm1 is game changing but am thankful that there is another option out there. I wonder when there might ever be something game changing - probably not in my lifetime. Until then I'm a lab rat living with some hope.

[gdpawel]

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what's observed with duel inhibitor combinations.

With Perjeta (pertuzumab), this novel monoclonal antibody functions by preventing dimerization of HER-2 with the other members of the human epidermal growth factor family HER-1, HER-3 and HER-4. In so doing, the cross-talk between receptors is abrogated and downstream signaling is squelched.

Researchers had discovered that several small-molecule inhibitors of HER family kinases have shown limited efficacy in HER-2-driven breast cancers, despite effective inhibition of kinase activity. It is the failure to completely inhibit the kinase activity of HER-2 that allows oncogenic signaling through the kinase-inactive family members HER-1, HER-3 and HER-4 to continue.

When tested as a single agent early in its development, Perjeta showed only modest antitumor activity, however, it demonstrated synergy when used with Herceptin (trastuzumab). It provide a more comprehensive blockade of HER signaling family and results in greater antitumor activity than either agent alone.

Again, Perjeta is not a cure, added to standard treatment with Herceptin. Perjeta gives the "average" breast cancer patient only about six months more of calm before the disease starts to stir again. Given the limited benefit, the price is startling. A full course of the drug combination will cost about $188,000.

Best of luck!

[gdpawel]

Dako, an Agilent Technologies Company and worldwide provider of cancer diagnostics, announced today it has received approval from the U.S. Food and Drug Administration for the addition of Kadcyla in the labeling of two Dako companion diagnostic assays.

Kadcyla (ado-trastuzumab emtansine) is Genentech's new medicine for patients with HER2-positive metastatic breast cancer who have received prior treatment with Genentech's cancer medicine Herceptin (trastuzumab) and a taxane chemotherapy.

The two assays are Dako's HercepTest and HER2 IQFISH pharmDx.

Today's announcement is the result of a collaboration between Dako and Genentech, a member of the Roche Group. The collaboration was initiated in early 2012, and later the same year Dako submitted applications to the FDA requesting approval of the two Dako assays as companion diagnostics for Genentech's drug candidate for patients with HER2-positive metastatic breast cancer.

Genentech's Kadcyla, an antibody-drug conjugate, and Dako's HercepTest and HER2 IQFISH pharmDx have received simultaneous approvals from the FDA.

Dako's HercepTest and HER2 IQFISH pharmDx will serve as diagnostic tools to identify cancer patients with HER2-positive metastatic breast cancer who may be eligible for Kadcyla treatment.

"At Dako, we focus on advancing cancer diagnostics, because patients' lives depend on it," said Lars Holmkvist, CEO of Dako and senior vice president, Agilent. "Partnering with companies who are also relentless in their commitment to fighting cancer is an important element in achieving this goal. Today's FDA approval is the result of excellent collaboration between Dako and Genentech."

Dako's ongoing strategy is to combine its strength in developing companion diagnostics with its proven ability to partner with pharmaceutical companies to increase the number of companion diagnostic assays and ultimately improve personalized medicine.

Citation: Agilent Technologies. "FDA Approves Two Dako Assays As Companion Diagnostics For Genentech's New Breast Cancer Medicine Kadcyla." Medical News Today. MediLexicon, Intl., 7 Mar. 2013

[gdpawel]

The area of pharmacogenomics was ripe for proprietary tests invented alongside a drug and owned by the drug developer and/or a partner in the diagnostic field.

HercepTest uses immunohistochemistry (IHC) analysis for the detection of HER2 protein over-expression in breast cancer. It measures the level of proteins in cancer cells providing clues about which therapies are "likely" to have clinical benefit.

HER2 IQFISH pharmDX is a direct fluorescence in situ hybridization (FISH) assay, It uses breast carcinoma specimens (FFPE) stained with HER2 IQFISH pharmDX. FISH is used to examine gene copy number variation in the tumor.

These tests serve as a companion diagnostic tool to identify cancer patients with HER2-positive metastatic breast cancer who "may" be eligible for Kadcyla treatment.

Because the results of the IHC test can sometimes be ambiguous, many doctors suggest the FISH test for a second opinion.

According to noted pathologist Dr. Michael Press, 20% of the time the HER2/neu negative results are reported by IHC solely, instead of utilizing FISH technology, were inaccurate and the results were actually HER2/neu positive, which would open the HER2 inhibitor door with Kadcyla for women with advanced breast cancer.

Tumors that are 3+ positive by IHC and those that test positive by FISH are most likely to benefit from HER2-inhibitors.

Tumors that test 1+ by IHC are considered HER2/neu negative and those that test 2+ are considered equivical, in which case FISH testing is done to make the determination.

Tumors that test negative for HER2/neu by FISH are "unlikely" to benefit from HER2-inhibitors.

Either test examines "dead" tissue that is preserved in paraffin or formalin. According to Dr. Eric J. Topol, professor of translational genomics at the Scripps Research Institute, specimens obtained from biopsy or surgery are formalin-fixed, paraffin embedded (FFPE). FFPE ruins sequencing capabilities, denatures everything, and ruins the samples.

How is that going to be predictive to the behavior of "living" cells in spontaneously formed colonies or microspheres? Can it describe the complex behavior of living cancer cells in response to the injury they receive from different forms of chemotherapy? There is a big difference between "living" and "dead" tissue.

All the gene amplificaton studies can tell us is whether or not the cells are potentially susceptible to this mechanism of attack. They don't tell you if one drug inhibitor is better or wrose than another drug inhibitor which may target this.

No gene-based test 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 conventional cancer drugs.

The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems’ response to drug treatments, not just one target or pathway.