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Old 09-19-2013, 10:36 AM   #1
'lizbeth
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Post Tykerb? Better with Herceptin for MBC

J Clin Oncol. 2012 Jul 20;30(21):2585-92. doi: 10.1200/JCO.2011.35.6725. Epub 2012 Jun 11.
Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study.

Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J.
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Department of Medicine/Medical Oncology, Duke University Medical Center, Durham, NC 27710, USA. black034@mc.duke.edu

Abstract

PURPOSE:

Phase III EGF104900 data demonstrated that lapatinib plus trastuzumab significantly improved progression-free survival (PFS) and clinical benefit rate versus lapatinib monotherapy, offering a chemotherapy-free option for patients with heavily pretreated human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (MBC). Final planned overall survival (OS) analysis from EGF104900 is reported here.
PATIENTS AND METHODS:

Patients with HER2-positive MBC whose disease progressed during prior trastuzumab-based therapies were randomly assigned to receive lapatinib monotherapy or lapatinib in combination with trastuzumab. OS and updated PFS data are presented using Kaplan-Meier curves and log-rank tests stratified for hormone receptor and visceral disease status. Subgroup analyses were conducted to identify characteristics of patients deriving the greatest clinical benefit.
RESULTS:

In this updated final analysis of all patients randomly assigned with strata (n = 291), lapatinib plus trastuzumab continued to show superiority to lapatinib monotherapy in PFS (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .011) and offered significant OS benefit (HR, 0.74; 95% CI, 0.57 to 0.97; P = .026). Improvements in absolute OS rates were 10% at 6 months and 15% at 12 months in the combination arm compared with the monotherapy arm. Multiple baseline factors, including Eastern Cooperative Oncology Group performance status of 0, nonvisceral disease, < three metastatic sites, and less time from initial diagnosis until random assignment, were associated with improved OS. Incidence of adverse events was consistent with previously reported rates.
CONCLUSION:

These data demonstrated a significant 4.5-month median OS advantage with the lapatinib and trastuzumab combination and support dual HER2 blockade in patients with heavily pretreated HER2-positive MBC.
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Old 09-19-2013, 07:54 PM   #2
NEDenise
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Re: Tykerb? Better with Herceptin for MBC

Good to know... since this is what I'm doing!!
Thanks Lizbeth!!
Denise
Who, BTW is still celebrating the Brain MRI!!
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Old 10-08-2013, 11:28 PM   #3
gdpawel
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Is Tykerb better than Herceptin?

Maybe, for these reasons.

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 and Erbitux 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.

Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, "small" molecules that act on multiple receptors in the cancerous cells, like Tykerb and Sutent. About six years ago, targeted "small-molecule" therapies ruled at one of the annual ASCO trade shows. The trend is away from the monoclonals to the small molecules, a trend in which a new predictive test may be able to hasten.

The EGFRx assay is able to test molecularly-targeted anti-cancer drug therapies like Iressa, Tarceva, Tykerb, Sutent and Nexavar, because of being small molecules. The EGFRx assay relies upon a technique known as Whole Cell (functional) Profiling, in which living tumor cells are removed from an individual cancer patient and exposed in the laboratory to the new drugs.

Basically, Whole Cell (functional) Profiling measures the response of the tumor cells to drug exposure. Following this exposure, it measures both cell metabolism and cell morphology. The effect of drugs on the whole cell, resulting in a cellular response to the drug, measures the interaction of the entire genome.

A variety of metabolic and apoptotic measurements are then used to determine if a specific drug was successful at killing the patient's cancer cells. The whole cell profiling method differs from other tests in that it assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic (cell metabolism) and morphologic (structure) endpoints, 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. Whole Cell (functional) Profiling measures genes before and after drug exposure. Gene Expression Profiles measures the gene expression only in the "resting" state, prior to drug exposure.

The EGFRx Assay is the only assay that involves direct "visualization" of the cancer cells at endpoint. This allows for accurate assessment of drug activity, discriminates tumor from non-tumor cells, and provides a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.

What is of particular note is that monoclonal antibodies (like Herceptin) are large molecules that attach to specific proteins on the outside of cancer cells and do not have a convenient way of getting access to a large majority of the targeted cells on the inside, which are protected from the drug. 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. The cells may pass small molecules back and forth. This would be a very good reason Tykerb may be much better than Herceptin.

Source: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings
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