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Old 09-22-2012, 11:35 AM
gdpawel gdpawel is offline
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Default T-DM1 Anitbody-drug conjugates (ADCs)

T-DM1 (or TDM-1) is a combination of Herceptin and a chemotherapy drug called emtansine. Both drugs are linked together and travel in the body together. At the 2012 ASCO trade show, Dr. Kimberly L. Blackwell from Duke University, presented results of the EMILIA study in HER2-positive metastatic breast cancer where T-DM1 was compared to treatment with the combination of Xeloda and Tykerb. The study included nearly 1,000 women whom had received prior treatment with Herceptin and a taxane.

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.

[url]http://abstract.asco.org/AbstView_114_98675.html
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Old 09-22-2012, 11:35 AM
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Default Early Reports at ASCO trade show on T-DM1 (TDM-1) Breast Cancer Trial

Dr. Kathy Miller from Indiana University, in a Medscape Oncology video blog, gave her "Welcome to press-release season in oncology." This is the season between the American Society of Clinical Oncology (ASCO) late-breaking deadline, when all of the updated results of phase 3 trials have to be available for eligibility for presentation at the annual meeting, and the meeting itself -- that frustrating interval where we learn science by press release. Those press releases say that a study met its primary endpoint and results will be reported at an upcoming national meeting, or that results failed to meet the primary endpoint.

The most recent press release is from her colleagues at Genentech and Roche about their novel drug, antibody-drug conjugate trastuzumab-DM1 (T-DM1). This is trastuzumab that is chemically linked to a very potent microtubule poison as a way of directly delivering this potent chemotherapy to HER2-positive breast cancer cells. They have seen fairly striking activity of this agent as monotherapy in heavily pretreated patients and in patients newly diagnosed with HER2-positive metastatic disease. Miller heard by press release that, at ASCO, we are likely to see the results of the first phase 3 study directly comparing T-DM1 monotherapy with the combination Xeloda (capecitabine) plus Tykerb (lapatinib) in patients with HER2-positive disease who were previously treated with Herceptin (trastuzumab).

She wishes she could tell use more. She has only seen the press release, not the actual data, and is anxious to see them. But it's press-release season. We all learn to love it and hate it at the same time.

Gary Schwitzer at HealthNewsReview.org (Health care journalism) in a recent blog posting, "ASCO & the news-making sausage factory," pointed out an important guest post on the Embargo Watch blog. It's about the release of information from the huge American Society of Clinical Oncology meeting - about to dominate the news cycle from June 1-5 from McCormick Place in Chicago.

It provides an insider’s look at the sausage-making factory where news is made from scientific/medical conferences.

I think this is a very important topic – as did those who left comments on the blog.

There’s a lot the public doesn’t know about how stories in their daily paper, evening newscast or online surfing move from:

*abstracts submitted to scientific conference;

*decisions made (how? by whom?) about which abstracts are accepted for short talks to be given at the conference;

*how little actual peer review may take place prior to abstracts being accepted or presented;

*how conference hosts decide which abstracts are to be highlighted in news releases;

*how journalists try to sort through hundreds of news releases and thousands of abstracts to make decisions about what’s important;

*how financial markets are affected by all of this…and when.

*and then, finally, how the sausage is delivered to consumers/patients/health care decision-makers.

[url]http://embargowatch.wordpress.com/2012/05/21/unintended-consequences-what-the-new-asco-embargo-policies-have-wrought/
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  #3  
Old 09-22-2012, 11:36 AM
gdpawel gdpawel is offline
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Default Annual ASCO Trade Show

Luke Timmerman, over at Xconomy, nails it with his ASCO Preview: Eight Cancer Drugs to Watch at the Big Show. Organizers have spent years carefully orchestrating this “show” to make sure it’s the place for all kinds of “market-moving,” medical practice-changing, and “front-page leading news” about cancer.

Yeah! The excessive hype in the multi-billion dollar cancer business, where a few extra months of survival counts as a breakthrough, and makes tons of money. That explains the spectacle that is ASCO.

The FDA has never approved a drug for cancer that was not patented or marketed or produced by a major pharmaceutical company. Today, the trend is towards more expensive cancer therapies with some costing up to $100,000 per patient per year.

Millions of cancer patients suffer because profitability, not efficacy and safety, is ultimately determining what cancer therapies are available to patients.

The American Association of Cancer Research (AACR) meeting is the premier cancer research convention for basic and translational research. The AACR was the original cancer research organization that pre-dated its sister organization – ASCO.

The focus of the AACR meetings is basic research and the presentations are often geared toward PhD level scientific discovery. The meetings are the most informative for it provides insights into therapy options that may not arrive in the clinical arena for many years.

AACR presentations continue to diverge from those at the ASCO meetings. Some of the observers at this year’s meeting were not sure they heard the word “chemotherapy” a single time. That is, all of the alphabet soup combinations that make up the sessions at ASCO are nowhere to be found at the AACR meetings.

[url]http://www.xconomy.com/national/2012/05/14/asco-preview-eight-cancer-drugs-to-watch-at-the-big-show/
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Old 09-22-2012, 11:37 AM
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Default Some reporting on the “smart bomb” bombed at the ASCO trade show

Harold J. DeMonaco, MS
Director of the Innovation Support Center
Massachusetts General Hospital

Journalists’ reporting on the information presented at the annual meeting of the American Society for Clinical Oncology (ASCO) is always interesting and this year is no exception. Cancer, after all, is a disease that can strike fear in the heart of just about everyone. So, it is understandable that many with the disease along with their friends and family members will be interested in realistic stories about new and promising treatments. But realism is not always present in the stories written about the ASCO meeting. Phrases that should never be used in a news report (breakthrough, miracle, stunning, etc.) seem to appear with some frequency. This year, stories about the results of a phase 3 trial of the experimental drug T-DM1 unfortunately follow the troubling trend of hyperbole and incomplete reporting.

This year’s media star of the ASCO meeting is a drug-antibody combination known as T-DM1 or trastuzumab emtansine. The phrase “smart bomb” appears in many of the stories we have seen, as does “magic bullet.” The phrase “magic bullet” was made popular in the 1940’s biopic film on the life of Dr. Paul Ehrlich and his development of a drug treatment for syphilis. Ehrlich envisioned his drug, salvarsan would selectively target the bacteria that caused syphilis and not produce any side effects. Although effective, salvarsan proved to be far less magical than it originally appeared, producing significant side effects. It was replaced with the discovery of penicillin, a far less toxic and more effective treatment.

T-DM1 is an antibody-drug conjugate and is designed to bind specifically to HER-2 receptors in breast cancer cells. Once bound to the HER-2 receptor, the toxic component (DM1) is released into the cancer cell. In theory the drug-antibody combination would only strike at HER-2 receptor positive cells while leaving normal cells unscathed. The results of the Phase 3 EMILIA study of T-DM1 in patents with advanced HER-2 receptor positive beast cancer were presented yesterday. And once again, many in the media appear to have only half read the report.

Here are a few of the story headlines I found online:

New ‘smart bomb’ drug attacks breast cancer, doctors say
Roche Smart-Bomb Cancer Drug Delays Breast-Tumor Growth
Breast cancer’s magic bullet?

The Phase 3 EMILIA study compared T-DM1 with a standard regimen for HER-2 positive patients who have failed previous treatment with Herceptin and a taxane chemotherapy drug. About 500 patients were treated in each arm. Here are the interim results from the company’s press release:

T-DM1 patients had a median time to disease progression of 9.6 months as compared to 6.4 months for the control patients

T-DM1 response rate was 43.6% as compared to 30.8% for the control group

T-DM1 one year survival was 84.7% as compared to 77% for controls

T-DM1 time to symptom progression was 7.1 months compared to 4.6 months in the control group

As for toxicity, T-DM1 patients had fewer grade 3 or higher side effects (40.8%) compared to those who received standard treatment (57%). It is important to remember that these results are interim and the final story won’t be known until 2014.

Here are a few of the snippets from the media’s reporting:

“Doctors have successfully dropped the first “smart bomb” on breast cancer, using a drug to deliver a toxic payload to tumor cells while leaving healthy ones alone.” Balderdash. T-DM1 is clearly not without side effects and does not leave healthy cells alone.

“An experimental breast cancer drug from Roche Holding AG (ROG) that carries chemotherapy directly into malignant cells while bypassing healthy ones delayed tumors longer and with fewer side effects than an established therapy.” True, but let’s put the results into perspective. The drug does not bypass healthy cells and 40% of patients had severe side effects from T-DM1.

“An experimental drug has shown stunning results in delaying the progression of a specific type of breast cancer and prolonging the lives of patients.” Stunning? How stunning is a 3 month difference in disease progression and an absolute difference of 6.3% in one year survival?

“For patients facing metastatic breast cancer, this is a breakthrough.” Promising, yes. But it is not a breakthrough. At least not based on the interim report.

The ability to specifically target cancer cells is certainly a worthy goal and the development of T-DM1 is a clear step in the right direction. The drug worked in less than half the patients treated in prolonging the disease-free interval and was not without significant side effects. That’s better than anything available at the moment. But it is remains to be seen if it is a “magic bullet, smart bomb or miracle drug.”
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  #5  
Old 09-22-2012, 11:38 AM
gdpawel gdpawel is offline
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Default T-DM1 Significantly Improves Breast Cancer Survival

The investigational drug, Trastuzumab Emtansine (T-DM1), improves survival of patients with HER2-Positive metastatic breast cancer "significantly", Genentech Inc. announced today as it published highlights of its Phase III EMILIA study results. T-DM1 was compared to lapatinib and Xeloda (capecitabine) combination therapy. The EMILIA study has met both of its co-primary endpoints: progression-free survival and significant improvements in overall survival, the company added.

Genentech, based in California, USA, is part of the Roche Group. Both companies announced that full study data will be presented at a medical meeting soon.

A BLA (Biologics License Application) has been submitted to the US FDA (Food and Drug Administration) by Genentech. Roche says it will soon do the same with EMA (the European Medicines Agency).

Hal Barron, M.D., chief medical officer and head, Global Product Development, said: "We are extremely pleased to announce that people treated with trastuzumab emtansine survived significantly longer than those who received a standard option for this aggressive advanced breast cancer. We believe that antibody-drug conjugates have the potential to change the future treatment of cancer, and we look forward to working with regulatory authorities in the hope of bringing another potential treatment option to people with HER2-positive metastatic breast cancer."

Trial participants in the lapatinib and Xeloda arm of the study will be able to switch over to trastuzumab emtansine if they wish. Genentech says that there are plans underway to initiate an EAP (Expanded Access Progam) in the USA so that under certain circumstances, patients with HER2-Positive metastatic breast cancer may have access to the investigational drug before it is finally approved.

Trastuzumab emtansine, an antibody-drug conjugate, has been studied by Genentech for patients with HER2-positive cancers. It is a combination of the chemotherapy DM1 and antibody trastuzumab; a stable linker was used to attach the two together.

Scientists designed trastuzumab emtansine to target and inhibit HER2 signaling, and to deliver the DM1 chemotherapy directly within the HER2-positive cancer cells.

Genentech says that its scientists have been investigating the HER2 pathway for over thirty years. The company says that "The development of HER2-targeted therapies represents one of the first successful examples of personalized healthcare".

The EMILIA Study is a Phase III, open label, randomized study which compares trastuzumab emtansine alone with a lapatinib/Xeloda combo. All the 911 participants have HER2-positive locally advanced or metastatic breast cancer. They had already received Herceptin and a traxane-based chemotherapy.

EMILIA has two (co-primary) endpoints: 1. Progression-free survival, and 2. Overall survival. Other endpoints include quality of life, one/two year survival rates, safety profile, duration of response, and objective response rate.

Globally, breast cancer is the most common cancer to affect adult females. 229,000 patients will be diagnosed with cancer in 2012 and 40,000 will die from it, says the American Cancer Society.

Higher levels of HER2 (Human Epidermal growth factor Receptor 2) are present on the surface of the tumor cells in patients with HER2-positive breast cancer.

Approximately 1 in every 4 breast cancer cases is of the HER2-positive type.

Roche, a major player in the cancer drugs market, is looking for a replacement for Herceptin, its third best-selling drug. In 2015 Herceptin will have to face competition from "biosimilar" generic makers. The company hopes T-DM1 may make up for the expected drop in Herceptin sales in 2015.

References: "Trastuzumab Emtansine (T-DM1) Significantly Improves Breast Cancer Survival." Medical News Today. MediLexicon, Intl., 27 Aug. 2012.

Sources: Roche Group, Genentech, Reuters
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Old 09-22-2012, 11:39 AM
gdpawel gdpawel is offline
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Default Another Antibody-Drug Conjugate: Transcend + Herceptin (trastuzumab)

Vancouver, B.C. June 11th, 2012 – biOasis Technologies Inc. announced that research underway at Texas Tech University Health Sciences Center has yielded some compelling data on preclinical studies designed to evaluate the pharmacokinetics of BT2111 (a proprietary conjugate of Transcend and Herceptin) in animal models of breast cancer metastasis to the brain.

The studies were conducted for biOasis under the direction of Drs. Quentin Smith and Paul Lockman, both recognized experts on the Blood-Brain Barrier and in evaluating drug delivery to the central nervous system for the treatment of brain tumors. The data showed that 6.6% of the injected dose of BT2111 penetrated the Blood-Brain Barrier and entered brain tissue.

This is consistent with previous studies showing that Transcend can effectively deliver several types of different compounds to the brain. The rate of BT2111 uptake into the brain was 1000-fold greater than Herceptin on its own. BT2111 was clearly present in the metastatic breast cancer tumors as determined by measurement of radioactive molecules using phosphorescence imaging of normal brain and brain metastases.

The uptake of BT2111 into the brain was similar to that observed for the Transcend vector alone, supporting previous observations that Transcend can effectively carry large biologics across the Blood-Brain Barrier. The next steps at Texas Tech University are to complete the study plan to show that the delivery of BT2111 into the brain has a therapeutic effect on metastatic breast cancer.

BT2111 is a conjugate between biOasis’ Transcend brain delivery vector and trastuzumab (trade name Herceptin), a humanized monoclonal antibody used clinically in the treatment of HER2+ breast cancer. It is reported that up to 30% of HER2+ breast cancer patients develop brain metastasis for which therapeutic options are limited. Because of its ability to cross the blood- brain barrier, biOasis is researching the potential of BT2111 for treatment of HER2+ metastatic breast cancer in the brain.

biOasis Technologies Inc. is a biopharmaceutical company in Vancouver, Canada. Based on Transcend, a proprietary brain delivery platform of biOasis, the Company is focused on creating new drugs that can cross the blood-brain barrier to address unmet medical needs in the treatment of brain diseases such as neurodegeneration, metastatic cancer and metabolic diseases. [url]http://www.bioasis.ca/index.htm

Just what is the blood-brain barrier?

The blood–brain barrier (BBB), an anatomic structure consisting of endothelial vessel cells, astrocytes and pericytes with tight junctions (TJs) and a number of carrier proteins, controls and limits the passage of molecules to the brain. In the presence of an intact BBB, only small lipophilic molecules (molecular weight [MW] <400 Da) can cross the BBB by diffusion, while the passage of other molecules is regulated by the carrier proteins.

Apart from a few drugs, such as temozolomide, melphalan, carmustine and irinotecan, chemotherapeutic agents, which are large hydrophilic molecules, are unable to cross the BBB, which is furthermore characterized by a high concentration of multidrug resistance efflux pumps, which may be another cause of the low concentration of drugs reaching the site of action.

Recently, Lin et al. underlined the role of astrocytes in preventing chemotherapeutic drugs from reaching metastatic sites in the brain, and observed in murine models that in pathological conditions, astrocytes are activated and come into direct contact with tumor cells, thus confirming the role of the microenvironment in brain metastases (1). This may lead to calcium sequestration, with a *consequent marked reduction in chemotherapy-induced apoptosis.

The role of the BBB in drug resistance has been called into question, since macroscopic intracranial lesions cause BBB disruption due to neoangiogenesis, which produces vessels that lack tight junction molecules and cannot therefore create an effective barrier (2,3).

Nonetheless, BBB disruption may be a characteristic of larger lesions, while the barrier could remain effective in small metastases, as demonstrated by contrast-enhanced images showing enhancement in large intracranial lesions but not in small infiltrative tumors.

Furthermore, the loss of tight junction molecules in the tumor vascular system does not necessarily incur the loss of other biological BBB components, such as detoxification and drug resistance mechanisms, which may remain effective and compromise drug *concentrations in BM (4).

1. Lin Q, Balasubramanian K, Fan D et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia 12(9), 748–754(2010).

2. Muldoon LL, Soussain C, Jahnke K et al. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J. Clin. Oncol. 25(16), 2295–2305(2007).

3. Papadopoulos MC, Saadoun S, Binder DK, Manley GT, Krishna S, Verkman AS. Molecular mechanisms of brain tumor edema. Neuroscience 129(4), 1011–1020(2004).

4. Lee G, Dallas S, Hong M, Bendayan R. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol. Rev. 53(4), 569–596(2001).

The Blood-Brain Barrier: Bottleneck in Brain Drug Development [url]http://www.ncbi.nlm.nih.gov/pmc/articles/PMC539316/
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  #7  
Old 09-22-2012, 11:41 AM
gdpawel gdpawel is offline
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Default PECAM-1 and T-DM1 + Pertuzumab

PECAM-1 (platelet endothelial cell adhesion molecule) is also known as cluster of differentiation 31 (CD31), which in an immunohistochemistry (IHC) assay, is used primarily to demonstrate the presence of endothelial cells in tissue sections. This can help to evaluate the degree of tumor angiogenesis, which can imply a rapidly growing tumor.

Endothelial cells form capillaries in a process called angiogenesis. Capillaries carry oxygen and nutrients to tumor cells. Newer classes of drugs called angiogenesis inhibitors, target these endothelial cells. This starves tumor cells of oxygen and nutrients, interferes with the elimination of cellular wastes, shuts-down routes of tumor metastasis, and potentially aids in the delivery of other types of anti-cancer drugs to the tumor mass.

A cancer physician invented a test for those newer classes of drugs that cut off a tumor's blood supply (anti-angiogenesis). He uses CD31 cytoplasmic staining to confirm morphological identification of microcapillary cells in a tumor microcluster. So the test can visualize both tumor and microvascular cells and assess both anti-tumor and anti-microvascular drug effect.

In other words, he can measure whether a drug like Avastin is sensitive (effective) or resistant (ineffective) to an individual's cancer cells, before Avastin would be infused into the body. Will it work or not. If it's "resistant," you do not want to take Avastin. If it's "sensitive," you want to receive Avastin, with other conventional chemotherapy.

In regards to T-DM1 and pertuzumab? A blind study with two test groups, one with T-DM1 and pertuzumab and the other with T-DM1 and a placebo. A lot of trial-and-error with this one, as are just about all clinical trials. A major pitfall for clinical trialists who simply combine drugs because they can.

[url]http://cancerfocus.org/forum/showthread.php?t=3692

Pertuzumab is one of a number of new targets in breast cancer therapy.

[url]http://cancerfocus.org/forum/showthread.php?t=3638

It is one of the breakthroughs in what is called Metabolomics, a newly emerging field of "omics" research concerned with comprehensive characterization of the "small molecule" metabolites in biological systems.

[url]http://cancerfocus.org/forum/showthread.php?t=3615
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Old 10-05-2012, 02:13 PM
gdpawel gdpawel is offline
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Default Antibody-Drug Conjugate Shrinks Some Breast Cancer Tumors

Interim results from a mid-stage trial of Celldex Therapeutics Inc's experimental drug showed trends toward reducing tumors in patients with advanced breast cancer, with rates improving for those patients with high levels of a key surface protein.

The drug, CDX-011, "also demonstrated strong response rates in patients with triple negative breast cancer...where treatment options are extremely limited," the researchers said in a statement.

CDX-011 or glembatumumab vedotin, was tested in 122 patients whose breast cancer had progressed despite several previous rounds of standard therapy.

The National Cancer Institute's drug dictionary defines the agent as "consisting of the fully human monoclonal antibody CR011 directed against glycoprotein NMB (GPNMB) and conjugated via a cathepsin B-sensitive valine-citrulline linkage to the cytotoxic agent monomethyl auristatin E."

In the study, released by the company on Wednesday, 19% of patients taking the antibody-drug conjugate saw their tumors shrink, compared with 14% of those treated with standard chemotherapy.

In trial patients with GPNMB on the surfaces of at least 25% of tumor cells, 32% responded, compared with 13% of chemotherapy patients.

"GPNMB helps the tumor cell to move around," said Dr. Linda Vahdat, director of the breast cancer research program at Weill Cornell Medical College and the study's lead investigator. "It almost seems like this drug puts the brakes on that process by taking away its legs."

For patients with high levels of GPNMB as well as triple negative breast cancer, the response rate was 36%, compared with no responses in the control group. In this group, a statistically significant progression-free survival benefit is currently observed (p=0.0032), the researchers say.

Side effects included rash and peripheral neuropathy.

The company said it expects to announce updated results from the Phase II trial in the fourth quarter of this year.

"This patient population has a very real need," said Tom Davis, chief medical officer at Celldex. "It is reasonable to consider a single-arm study ... a randomized study is also a possibility."

About 15% of breast cancer patients are triple negative, while high expression of GPNMB occurs in about 27%, according to Celldex. Because there is some overlap, both groups account for an estimated 35% of the total breast cancer population.

Source: Medscape Oncology
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Old 12-12-2012, 02:59 PM
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Default Primary results from EMILIA

991 patients: PFS and OS favored T-DM1 versus capecitabine and lapatinib (PFS: 9.6 mo versus 6.4 mo; OS: 30.9 mo versus 25.1 mo). T-DM1 was well tolerated, but transient thrombocytopenia and minor LFT abnormalities were observed.

According to Dr. Neil Love of Research To Practice, perhaps the most important new oncologic agent in the past decade, T-DM1 will transform the way clinicians approach the management of HER2-positive metastatic disease, once it is approved, based on findings from this "second-line" study. However, massive upheaval of traditional treatment algorithms could really be in store, hopefully soon, when they receive data from the already accrued MARIANNE trial comparing this novel antibody-drug conjugate, alone or in combination with pertuzumab, to trastuzumab with a taxane in the front-line setting. Beyond providing important clues about the efficacy of this agent, the results of that study have the potential to offer patients something quite special — an effective treatment that comes without many of the toxicities commonly associated with chemotherapy.

Primary results from EMILIA, a phase III study of trastuzumab emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC) previously treated with trastuzumab (T) and a taxane.

Sub-category:
HER2+

Category:
Breast Cancer - HER2/ER

Meeting:
2012 ASCO Annual Meeting

Session Type and Session Title:
Plenary Session, Plenary Session Including Science of Oncology Award and Lecture

Abstract No:
LBA1

Citation:
J Clin Oncol 30, 2012 (suppl; abstr LBA1)

Author(s):

Kimberly L. Blackwell, David Miles, Luca Gianni, Ian E. Krop, Manfred Welslau, José Baselga, Mark D. Pegram, Do-Youn Oh, Veronique Dieras, Steven R. Olsen, Liang Fang, Michael W. Lu, Ellie Guardino, Sunil Verma; Duke University Medical Center, Durham, NC; Mount Vernon Cancer Centre, Middlesex, United Kingdom; San Raffaele Hospital, Milan, Italy; Dana-Farber Cancer Institute, Boston, MA; Praxis Aschaffenburg, Aschaffenburg, Germany; Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea; Department of Medical Oncology, Institut Curie, Paris, France; Genentech, South San Francisco, CA; Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada

Abstract:

Background:

T-DM1 is an antibody-drug conjugate comprising T, a stable linker, and the potent cytotoxic agent DM1; it incorporates the antitumor activities of T and the HER2-targeted delivery of DM1.

Methods:

EMILIA is a randomized study of T-DM1 vs XL, the only approved combination for T-refractory HER2+ MBC. Patients (pts) received T-DM1 (3.6 mg/kg IV q3w) or X (1000 mg/m2 PO bid, days 1–14 q3w) + L (1,250 mg PO daily) until progressive disease (PD) or unmanageable toxicity. Pts had confirmed HER2+ MBC (IHC3+ and/or FISH+), and prior therapy with T and a taxane. Primary end points were PFS by independent review, OS and safety. An interim OS analysis (efficacy boundary: HR= 0.617; p=0.0003) was planned at the time of the final PFS analysis.

Results:

991 pts were enrolled; 978 received treatment. Median (med) durations of follow-up were 12.9 (T-DM1) and 12.4 (XL) months (mo). Baseline demographics, prior therapy and disease characteristics were balanced. There was a significant improvement in PFS favoring T-DM1 (med 9.6 vs 6.4 mo; HR=0.650 [95% CI, 0.549–0.771]; p <0.0001). The med T-DM1 OS was not reached vs 23.3 mo (HR=0.621 [95% CI, 0.475–0.813]; p=0.0005); the interim efficacy boundary was not crossed. T-DM1 was well tolerated with no unexpected safety signals. The most common grade ≥3 adverse events (AEs) per treatment were for T-DM1: thrombocytopenia (12.9% vs 0.2%), increased AST (4.3% vs 0.8%), and increased ALT (2.9% vs 1.4%); for XL: diarrhea (20.7% vs 1.6%), palmar plantar erythrodysesthesia (16.4% vs 0) and vomiting (4.5% vs 0.8%). The table lists other end points.

Conclusions:

T-DM1 conferred a significant and clinically meaningful improvement in PFS compared with XL. Other end points support T-DM1 as an active and well-tolerated novel therapy for HER2+ advanced BC.

Note:

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.
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Last edited by gdpawel : 02-22-2013 at 11:43 PM. Reason: additional info
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Old 01-03-2013, 04:14 PM
gdpawel gdpawel is offline
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Default Response to anti-HER2 therapy after treatment with T-DM1

Retrospective analysis of patients previously receiving treatment with single-agent T-DM1. 15 of 20 patients who discontinued T-DM1 received further therapy, 12 with anti-HER2 agents, and 5 experienced partial responses.

According to Dr. Neil Love of Research To Practice, while there was no particular reason to doubt that patients experiencing disease progression on T-DM1 would respond to further anti-HER2 treatment alone or with chemotherapy, it is reassuring to learn about the 5 patients in this report who did in fact achieve subsequent objective partial responses. From a more macro standpoint, this study further contributes to an extensive tableau of clinical research data supporting the concept of continuing anti-HER2 therapy beyond disease progression and switching out the partner agent(s). The true biology and pharmacology behind this therapeutic paradigm are far from clear, but the clinical implications have definitely become apparent as most patients with metastatic disease these days receive indefinite HER2 blockade.

Ann Oncol. 2012 Jan;23(1):93-7. doi: 10.1093/annonc/mdr061. Epub 2011 Apr 29.

Responses to subsequent anti-HER2 therapy after treatment with trastuzumab-DM1 in women with HER2-positive metastatic breast cancer.

Olson EM, Lin NU, DiPiro PJ, Najita JS, Krop IE, Winer EP, Burstein HJ.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.

Abstract

BACKGROUND:

Women with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) can respond to multiple lines of anti-HER2 therapy. It is unknown whether these patients will derive further clinical benefit following treatment with trastuzumab-MCC-DM1 (T-DM1).

PATIENTS AND METHODS:

We retrospectively identified HER2-positive MBC patients treated with T-DM1 and characterized outcomes during subsequent lines of anti-HER2 therapy. Response was determined by a blinded radiology review. Time-dependent analyses were carried out using Kaplan-Meier estimates.

RESULTS:

We identified 23 patients treated with single-agent T-DM1 and report on the 20 patients who discontinued protocol therapy. All patients received trastuzumab-based metastatic therapy before initiation of T-DM1 [median 7 regimens (range 3-14)]. Of these 20 patients, 75% (15 of 20) received further therapy with or without anti-HER2 agents after discontinuing T-DM1. Partial response to either first- or second-subsequent line(s) of therapy was seen in 5 of 15 (33%) treated patients, including 33% (4 of 12) who received a regimen containing trastuzumab and/or lapatinib. Median durations of therapy to first- and second-subsequent regimens after T-DM1 were 5.5 and 6.4 months, respectively.

CONCLUSIONS:

In heavily pretreated HER2-positive MBC patients, prior exposure to T-DM1 does not exhaust the potential benefit of ongoing anti-HER2 therapy with trastuzumab- and/or lapatinib-based regimens.

PMID: 21531783

[url]http://www.ncbi.nlm.nih.gov/pubmed/21531783
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