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Erbitux (cetuximab) Approval Likely as Lung Cancer Treatment


Barb73

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http://www.curetoday.com/index.cfm/fuse ... le_id/1107

ARTICLE:

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Lung Cancer Patients May Soon Have New Drug Option

BY MELISSA WEBER

A drug temporarily withdrawn from the Food and Drug Administration for approval in non-small cell lung cancer will still likely get the green light when it's resubmitted, Alan Sandler, MD, told a group of medical professionals at the Practical Applications of New Agents in Oncology conference in March in San Antonio, Texas.

Sandler, chief of the division of hematology and medical oncology at Knight Cancer Institute at Oregon Health and Science University, devoted a portion of his presentation on new drugs for NSCLC to Erbitux (cetuximab) and the research study included in the approval application. (Lung cancer would be the third cancer to join the approved indications for Erbitux, behind colorectal cancer and head and neck cancer.)

The phase III FLEX trial, reported at last year's annual meeting of the American Society of Clinical Oncology, compared the chemotherapy combination of cisplatin and vinorelbine with or without Erbitux as initial treatment for advanced NSCLC. Overall survival reached 11.3 months for patients receiving Erbitux plus chemotherapy compared with 10.1 months for patients receiving chemotherapy alone. The time before the disease progressed was the same for both groups, reaching 4.8 months. The most common side effects of Erbitux included low blood counts and rash.

The numbers separated dramatically, however, when the researchers looked at responses in Asians versus whites. Sandler shared the FLEX investigators' slides, which showed median overall survival reached 19.5 months for Asians compared with 9.6 months for whites regardless of whether they received Erbitux. In fact, Asians appeared to do worse with the addition of Erbitux: Overall survival for Asian patients who received Erbitux was 17.6 months compared with 20.4 months for Asians on chemotherapy alone. Whites, on the other hand, lived a median of about a month longer if they received Erbitux plus chemotherapy (10.5 months compared with 9.1 months).

"I think this helps to illustrate … some of the things that we’ve seen in the past comparing results from Japanese studies, for example, versus U.S. studies, and seeing differences in outcome," Sandler said. "We may be starting to get some explanation for some of that." More specifically, the data indicated a higher percentage of Asians were female, never-smokers, had a type of NSCLC called adenocarcinoma (as opposed to the more common squamous cell carcinoma), and received other targeted anti-cancer drugs post-study. Because Asians made up only 10 percent of the roughly 1,100 patients in the study (whites made up about 86 percent), Sandler said the differences did not allow researchers to draw definitive conclusions.

As for the fate of Erbitux in lung cancer, ImClone Systems and Bristol-Myers Squibb, makers of the drug, pulled the FDA application in January, less than two months after submitting it, because of issues related to the drug’s formulation. The FLEX trial was conducted outside the U.S., and the formulation supplied by Merck KGaA, ImClone’s partner for Erbitux outside North America, was slightly different.

The FDA is allowing the companies to conduct a pre-clinical study to confirm the comparability of the drug manufactured in the U.S. with the one manufactured overseas, a spokesman for BMS said in an e-mail statement. Pending those results, they expect to resubmit the application for approval in NSCLC in the second half of this year.

The question is, according to Sandler, will the FDA approve Erbitux (cetuximab) for use in combination with cisplatin and vinorelbine—the regimen used in the FLEX trial. In the United States, a platinum-based drug (cisplatin or carboplatin) with a taxane, such as Taxol (paclitaxel) or Taxotere (docetaxel), is the most widely used combination for lung cancer treatment.

"I'd like everybody to raise their hand [if] you, in the past year, have utilized cisplatin/vinorelbine in the front-line treatment of metastatic non-small cell lung cancer," Sandler asked the audience. Of the nearly 200 physicians, nurses, and other health care professionals in the room, no hands went up. "That’s what I thought. So what’s going to happen if it’s approved and what is everyone going to do with it? We’ll find out."

The Practical Applications of New Agents in Oncology meeting was hosted by the University of Texas Health Science Center at San Antonio's Cancer Therapy and Research Center, well known for its San Antonio Breast Cancer Symposium held each December.

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(Cure Today Magazine, Article by Melissa Weber, April 29, 2009)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not being posted with the intention of being medical advice of any kind.

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The FDA has been seeking to broaden the range of use for cancer drugs. When they approve a drug for sale, they limit how drug makers sell it. A drug approved to treat only breast cancer cannot be marketed for lung cancer even if some studies suggest that the medicine may save some lung cancer patients.

But the FDA has proposed new guidelines that would change all this. The new rules would allow drug makers to provide physicians with copies of medical journal articles that discuss product uses that have not been vetted or approved by the FDA. Drug companies do not have to promise to adequately test the unapproved use discussed in the article.

Physicians are not overseen by the FDA. Medicine is regulated by state medical boards which let them prescribe drugs as they see fit regardless of FDA judgements. Physicians can prescribe drugs for unapproved uses. If the FDA doesn't end up approving Erbitux for lung cancer, it'll end up being used "off-label" for lung cancer anyway. It may end up finally being approved the way Avastin was finally approved for breast cancer.

Erbitux is a monoclonal antibody just like Avastin, but directed at a different protein. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF. Erbitux binds to EGFR, a protein on the surface of a cell. It targets EGFR protein-tyrosine kinases.

But all the EGFR mutation or amplification studies can tell us is whether or not the cells are potentially susceptible to this mechanism (pathway) of attack. It doesn't tell you if Erbitux is better or worse than another drug which may target this. There are differences.

The drugs have to get inside the cells in order to target anything. In different tumors, either Erbitux or another drug 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. Remember, why do some lung cancers stop responding to Tarceva? Why go through so much "trial-and-error?"

EGF-targeted drugs are poorly-predicted by measuring the ostensible target EGFR, but can be well-predicted by measuring the effect of the drug on the "function" of live cells. Without "individualized" testing, it's difficult to determine which drugs are best for patients.

More and more physicians and patients are turning to individualized therapies to treat cancers. Under this approach, scientists study how an individual's cancerous cells respond to several drugs. Doctors have learned that even when the disease is the same type, different patients' tumors respond differently to chemotherapeutic drugs. Without individualized testing, it's difficult to determine which drugs are best for patients.

There are numerous different therapeutic drug regimens out there. Any one or combination of them can help cancer patients. The system is overloaded with drugs and under loaded with wisdom and expertise for using them. What's needed is to make extensive use of bio-marker tests in treatment decisions.

The cell culture methodology maintains cancer cells in their native state, making cell-based assays of chemo compounds more reliable. The test relies on cells, rather than genetic tests, because the complexities and redundancies of human biology are beyond the ken of genomics.

Cancer is a complex disease and needs to be attacked on many fronts. The best thing to do is to combine these different tests in ways which make the most sense. The future of cancer therapy will be personalized treatments for individual patients, and will require a combination of novel diagnostics and therapeutics.

Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual's particular cancer and enable oncologists to prescribe personalized treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.

Literature Citation: Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 17117

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Ah! Barbara. That's the kicker! There is "individualized treatment" of various cancers, today.

In an issue of Nature, scientists reported that surveying the human genome has found that many more gene mutations drive the development of cancer than previously thought. All cancers are thought to be caused by gene mutations. Genes control the behavior of cells, and when abnormal genes either issue faulty instructions or the correct instructions at the wrong time or both, it leads to abnormal cell development and cancer.

If you take 1,000 mutations in kinase genes alone, which are putatively associated with cancer, and try to figure out how many combinations of these mutations one could have, and then consider that mutations are only the beginning because it depends on the factors which regulate those genes, and how much the genes are expressed or repressed, and how all those things interact with all the other things which are going on, you have a pretty major challenge if you want to build a model of the cancer cell from the bottom up.

Tissue culture methods have made gene therapy possible. The ability to introduce cultured cells with DNA gene sequences (an ordered list of events) has allowed scientists to assign functions to different genes and understand the mechanisms that activate or redress their function. The interaction between cell biology and genetics gave birth to molecular biology. Without cell culture, gene therapy would be beyond imagination.

Cell function analysis allows identification of clinically relevant gene expression patterns which correlate with clinical drug resistance and sensitivity for different drugs in specific diseases. There is no single gene whose expression accurately predicts therapy outcome, emphasizing that cancer is a complex disease and needs to be attacked on many fronts.

A couple of private cell-based assay labs, using a functional profiling methodology, have been clinically evaluating anti-tumor and anti-microvascular activity on individual (not population trends) patients live (fresh) cancer cells, based on using real-time, real patient data, under real-world conditions, to guide medical evidence and treatment.

These two labs have the capabilities to measure the net effect of all processes. Both of them utilize what is called functional profiling. Functional tumor cell profiling is a combination of a morphologic endpoint (DISC) and one or more metabolic endpoints (MTT, resaqurin, ATP). It measures morphologic (structural) effects and metabolic (cell metabolism) effects, measuring the "profile" of the whole cell (it's entire genome). It is analogous to measuring thousands of genes before and after drug exposure.

The key to understanding the genome is understanding how cells work. The ultimate driver is a functional assay (is the cell being killed regardless of the pathway/mechanism) as opposed to a target assay (does the cell express a particular target the drug is supposed to be attacking). While a target assays tells you whether or not to give one drug, a functional assay can find other compounds (up to 30 of them) and combinations and can recommend them from the one assay.

The core of the functional assay is the cell, composed of hundreds of complex molecules that regulate the pathways necessary for vital cellular functions. If a "targeted" drug could perturb any one of these pathways, it is important to examine the effects of the drug within the context of the cell. Both genomics and proteomics can identify potential new therapeutic targets, but these targets require the determination of cellular endpoints.

Cell-based functional assays are being used - today - for screening compounds for efficacy and biosafety. The ability to track the behavior of cancer cells permits data gathering on functional behavior not available in any other kind of assay.

Good review papers exist and are increasingly appreciated, understood and applied by the private sector and European clinicians and scientists. The literature has not been understood by many NCI investigators and by NCI-funded university investigators, because their knowledge is almost always geared toward an assay technique that has not been used in private labs for almost twenty years.

As a cancer patient advocate, I've been interested in and studied the aspects of cell function analysis (harken back to my college days studying biology) for a number of years, like anyone would have an interest in molecular science or biological science. My point with respect to cell function analysis is to educate patients and doctors that such science and technology exists, and might be very valuable.

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Let's say that many of us wish that testing were more prevalent in the medical operation of things.

Surely, patients asking aren't as powerful as doctors changing the modus operandi.

Although I did find a link to a type of genetic testing being done through online in my morning email:

http://www.medicalnewstoday.com/articles/156027.php

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As scientists continue to decode the human genome and the information becomes publicly available, private companies that offer online genetic testing are multiplying. Scientists at the National Institutes of Health were concerned that perhaps these tests posed a risk.

They evaluated responses to an online test among smokers who did or did not have a common genetic variant associated with risk for lung cancer. The results, published in a recent issue of Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, raise a new set of questions, but also allay some of the early concerns.

"Up until now we have had a clear model for genetic testing. You see a professional genetics counselor, undergo a battery of tests and that professional helps you interpret your results," said Saskia Sanderson, Ph.D., a postdoctoral fellow in the Department of Genetics and Genomic Sciences at Mount Sinai School of Medicine, who completed the study while working at the Social and Behavioral Research Branch of the National Human Genome Research Institute of the NIH.

"That model is coming under increasing pressure as more and more genetic information is generated, and as a greater number of genetic tests become available on the internet," said Sanderson. "What we found was encouraging in that people who got these online genetic results recalled them correctly, and no one regretted having taken the test; though it is important to remember that this was a small group of select smokers and that others may respond differently."

Patients at higher risk genetically displayed short-term signs of decreased confidence that quitting smoking could reduce their risk of lung cancer, but scientists did note that all of those who took the test chose to receive at least one of several offered known smoking cessation aids.

"Genetic information is complex, and there is a risk that providing unfiltered information will result in heightened worry and misinterpretation of results," said Jamie Ostroff, Ph.D., chief of behavioral science services at Memorial Sloan-Kettering Cancer Center and an editorial board member of Cancer Epidemiology, Biomarkers & Prevention. "This pilot study found no harm in undergoing these tests and underscores the importance of conducting future research as to how to best educate smokers about gene-environment risks."

Scientists are reluctant to endorse the tests based on this one study, because the sample was limited to 44 individuals who were biologically related to people with lung cancer and who smoked. The online test assessed the presence or absence of the GSTM1 gene, the absence of which has been associated with a slightly increased lung cancer risk.

Exactly half of the smokers were missing GSTM1, thus presenting as higher risk and the other half had GSTM1 present. All the GSTM1 missing individuals correctly identified themselves as "higher risk." Of the GSTM1 present group, 55 percent accurately labeled themselves as "lower risk" while 41 percent interpreted their result as "average risk."

These patterns of accurate interpretation remained at six months, suggesting that these individuals retained the information.

Overall, the individuals taking this test found the results to be believable, trustworthy, easy to understand, relevant and important. At follow-up, no one regretted taking the test.

After taking the test, all of the smokers selected some sort of smoking cessation help with no difference between the higher risk or lower risk groups. Scientists agreed that regardless of the genetic test result, quitting smoking is the single most important step a smoker can take in preventing lung cancer and that a larger comparison study would be needed to determine if knowledge of genetic risk encourages an individual to quit smoking.

Source:

Jeremy Moore

American Association for Cancer Research

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(Medical News Today, Lung Cancer, July 1, 2009)

Disclaimer:

The information contained in these articles may or may not be in agreement with my own opinions. They are not being posted with the intention of being medical advice of any kind.

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The whole concept of proper genetic markers is not to put patients in the position of having to receive toxic cancer drugs if they're not going to do any good. However, genomics is far too limited in scope to encompass the vagaries and complexities of human cancer biology.

The situation with Erbitux and Vectibix for colon cancer, Iressa and Tarceva for lung cancer, and Herceptin for breast cancer is that all the mutation or amplication studies can tell us is whether or not the cancer cells are potentially susceptible to this mechanism of attack.

They don't tell you if one drug or the other is worse or better than some other drug which may target this. The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions.

No genetic profile can discriminate differing levels of anti-tumor activity occurring among different targeted therapy drugs. Nor can it identify situations in which it is advantageous to combine a targeted drug with other types of conventional cancer drugs (I'm talking about drug selection).

"Targeted" drugs are poorly-predicted by measuring the ostansible "target," but can be well-predicted by measuring the effect of a drug on the function of live cells, the net effect of all processes, not just the individual molecular targets.

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Cancer is extremely complicated on the cellular level, involvement of the immune system, and each individual's personal constitution, but I believe that there can be much hope for "controlling" cancer in our time.

The summer issue 2009 of Cure Magazine has an interesting article regarding targeted treatments.

They refer to "hitting the mark - but it's no bull's-eye." I guess that says it succinctly.

Barbara

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