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The latest on Iressa from the Oncology Nursing Society:


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In collaboration with the Food and Drug Administration (FDA), and as a service to our members, the Oncology Nursing Society will provide drug development information about therapies for cancer patients. This will allow the FDA to inform ONS members in a timely manner. Included in the email from the FDA is a link to product labels, which will provide the relevant clinical information on the indication, contraindications, dosing, and safety. The following is a message from Dr. Richard Pazdur:

To: ONS membership

From: Richard Pazdur, M.D., Director, Division of Oncology Drug Products, Center for Drug Evaluation and Research, FDA

Re: New Labeling and Distribution Program for Gefitinib (Iressa®)

The Food and Drug Administration (FDA) has approved new labeling for gefitinib (Iressa) that limits the indication to cancer patients, who, in the opinion of their treating physician, are currently benefiting, or have previously benefited, from gefitinib treatment. The FDA has agreed to AstraZeneca's proposal to limit distribution of this drug under a risk management plan called the Iressa Access Program, to the following patient populations:

patients currently receiving and benefiting from Iressa;

patients who have previously received and benefited from Iressa; and

previously enrolled patients or new patients in non-Investigational New Drug (IND) clinical trials approved by an IRB prior to June 17, 2005.

New patients may also be able to obtain Iressa if AstraZeneca decides to make it available under IND and the patients meet the criteria for enrollment under the IND.

Gefitinib, an orally administered epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, was approved for marketing in May 2003 for patients with non-small cell lung cancer (NSCLC) under Subpart H accelerated approval regulations that allow products to be approved on the basis of a surrogate endpoint for clinical efficacy. For gefitinib the surrogate end-point was tumor response rate. The response rate in patients taking the drug was approximately 10%. The approved indication was for the treatment of patients who were refractory to established cancer treatments (both a platinum drug and docetaxel). However, since the initial approval of Iressa, Tarceva (erlotinib) has been approved for treatment of this same group. Tarceva was approved based on improved overall survival.

FDA has carefully reviewed data from two failed clinical studies of Iressa, one of which was required by the agency as part of the drug's accelerated approval. This trial enrolled patients with regionally advanced or metastatic NSCLC who had failed one or two prior treatment regimens. In this large study, 1,692 patients were given either gefitinib or placebo. There was no significant survival benefit in the overall study population nor in patients who had high levels of a surface marker called "EGFR". In contrast, the presence of EGFR at high levels appears to predict a good response to Tarceva.

In the second trial in patients with stage III NSCLC, after completion of induction and consolidation chemotherapy and radiation therapy, patients were given either gefitinib or placebo maintenance therapy. No gefitinib survival benefit could be demonstrated.

The Food and Drug Administration is not considering market withdrawal of gefitinib at this time. New clinical trials are being developed, other ongoing trials are being completed, and there will be further analysis of the completed trials described above. These will determine the future role of gefitinib treatment.

The current revised Iressa label is available at www.fda.gov/cder/foi/label/2005/021399s008lbl.pdf.

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The cancer drug Iressa actually does work miracles, in "some" patients. The FDA limited Iressa's availability to cancer patients who have already taken the drug and whose physician believes it is helping them. Cell culture assays have found that a cellular signal for response to the drug can identify "some" responders but this limits Iressa's market profile significantly.

To the manufacturer, what good is the drug if it cannot be used by a broad base of the population? How will drug companies respond when studies show their drug to be highly effective, but only in 10% of the potential patient population? A failure? No, not by a long shot!

The Iressa situation is a great argument for pre-testing an individual's tumor. Iressa has been shown to benefit those that are benefitting from it. If the drug is working for some people, then obviously there are others out there who would also benefit. Who are those that benefit from its use? All the more reason to "test the tumor."

Assay-directed chemotherapy is an individualized approach to killing cancer. Cell culture assays are a bio-marker method used to determine what precise medications would kill the particular cancer. Doctors have assumed that stopping cell division would stop cancer, because most cancer cells divide and grow rapidly. But the approach didn't always kill the malignant cells. Cancer isn't a case of cells growing out of control, but of cells refusing to die on schedule.

There was a study using an angiogenesis assay, describing correlations between cell culture assay test results (cell death in response to Iressa exposure) and survival of 31 patients with non-small cell lung cancer who had received extensive prior chemotherapy. These correlations were based on the actual assay results which had been reported, in real time, prospectively to the doctors who had ordered the assay laboratory tests. There were striking correlations between test results and patient survival (not just response).

By inhibiting anti-apoptosis with Iressa, or even Tarceva (they are very similar drugs, small molecule inhibitors of tyrosine kinase, a key intermediary in the EGF cascade pathway), the cells undergo apoptosis and die. And it is detected at the whole cell level in the cell culture assays and reported out -- prospectively -- that this correlates strikingly with patient survival. It is a unique tool for identifying newer, better drugs, testing drug combinations, and serving as a "gold standard" to develop new DNA, RNA, and protein-based tests of drug activity.

EGF is Epidermal Growth Factor. EGF is a receptor on many normal tissues/cells, and also on many cancer cells. It is a growth hormone, locally secreted by cells. It attaches to a receptor on the cell membrane called EGFR (Epidermal Growth Factor Receptor). It then activates so-called signalling pathways within the cell, a cascade of biochemical events, including phosphorylation of proteins, leading to cell growth/proliferation/division. One type of an enzyme which is involved in the pathway which is involved in protein phosphorylation is called tyrosine kinase.

The EGF system is a target for a number of newer anti-cancer drugs, including Erbitux (a monoclonal antibody which binds to EGFR), and Iressa, Tarceva, the latter two being inhibitors of the EGFR-activated tyrosine kinase.

EGF-targeted drugs (Iressa, Tarceva, Erbitux) are poorly-predicted by measuring the ostensible target (EGFR), but can be well-predicted by measuring the effect of the drugs on the "function" of live cells. It is an area of cancer research which has been abandoned by the entire cancer research establishment. A bioengineering problem overcomed by a band of private-lab cell biologists.

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 who don't respond to standard therapies.

There are over 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.

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

http://www.weisenthal.org/asco_06_egfr_ ... enthal.htm

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 bioloty are beyond the ken of genomics.

The 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 (includes newly-emergent drug combinations).


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Something which puzzles me about this is that when Barry was given iressa he felt better within a few days. The rash appeared very quickly and think that there is a correlation between rash etc and efficacy. So why not just try the drug? What is there to lose? I know it is expensive but so is the testing or am I missing something


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  • 2 months later...

I have responded wonderfully to Iressa. Am so thankful it was available. What is the difference between Iressa and Tarceva? For some reason I had gotten the impression that they were the same drug marketed under different names. Thanks for anyone who can help and thanks for the research people. pammie

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They are similar drugs. Both are epidermal growth factor receptor inhibitors, but they work differently.

They target the same spot on the cancer cell, but they block the receptor in different ways.

I have not heard any updates regarding the people for whom Iressa (gefitinib) does work, but clearly there are people who benefit from it. Last I heard, the drug company was still researching who benefits and why.

- Teresa

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  • 7 months later...

Targeted drugs are based on a variety of biological mechanisms (pathways) that essentially stop cancer from spreading. They interfere with specific molecules (receptors and enzymes inside and outside a cancer cell) involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth.

The most common targets on the outside of a cancer cell are receptors, which are proteins that help relay chemical messages. Many targets on the inside of a cell are enzymes, which are proteins that help speed up chemical reactions in the body.

By focusing on these molecular and cellular changes, targeted cancer drugs go after the "target" in these cells, rather than just all cells. In other words, they focus on molecular and cellular changes that are specific to cancer.

Small molecule (enzyme) inhibitors of tyrosine kinase make biologic processes happen faster and are often key junctions in the signaling pathways. It is a key intermediary in the EGF cascade pathway.

Large molecule antibodies 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.

Because many cancer cells use similar pathways, the same drug could be used to treat one person's breast cancer and another person's lung cancer, as long as each tumor contained similar targets. This is why many of these treatments are being used in a variety of cancer types.

Although targeted therapy is appealing, it is more complex than meets the eye. Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.

In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell.

There has been a continuous parade of new targeted small and large molecule therapies that will continue to be introduced into the market virtually blind. Most of them have been developed for use in solid tumors but some have also emerged for hematological malignancies. These targeted drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.

Multi-targeted drugs can be well-predicted by measuring the effect of the drugs on the "function" (is the cell being killed regardless of the mechansim) of live cells, as opposed to a "target" (does the cell express a particular target the the drug is supposed to be attacking).

While a "target" assay tells you whether or not to give "one" drug, a "functional" assay can find other compounds and combinations and can recommend them from the one assay.

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. Because these new “smart” drugs will work for “some” but not “all” cancer patients who receive them, functional profiling can accurately identify patients who would benefit from treatment with molecularly-targeted anti-cancer therapies.

In regard to toxicities, cancer sufferers are taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need. Emerging evidence shows that many of the highly expensive targeted cancer drugs (Herceptin, Avastin and Rituximab) may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses.

Pharmaceutical companies are attracted to studies looking at the maximum tolerated dose of any treatments. It is suggested that we make the search for minimum effective doses of these treatments one of the key goals of cancer research.

One example is Avastin, used to fight colon and lung cancers, the dose being tested is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram.

The study of cell function analysis tells us that even when the disease is the same type, different patients' tumor respond differently to the same agents. A large molecule targeted drug may be more beneficial to some patients than a small molecule targeted drug (sometimes not).

Whatever the percentage of patients benefit from these drugs, the point is, targeted drugs are not for everybody. Pre-tests can help identify the individual cancer patient the drug works extremely well for, or it can tell that the drug is resistant. This could be Tykerb, Tarceva, Iressa, Sutent or Nexavar, because of being small molecule drugs. It is important to "personalize" cancer treatment, and this can be accomplished by "testing the tumor first."

There are huge economic problems here. Pharma cannot make drugs unless they can realize a profit. The ordinary trial system will not suffice if we are to encourage new drugs for restricted numbers of patients. More and more physicians and patients are turning to individualized therapies to treat cancers. Without individualized testing the efficacy of these drugs, it's difficult to determine which drugs are best for patients who don't respond to standard therapies.

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