Iressa and Other Target Therapies Forge Ahead
New York, PSA Rising Oct 20, 2003 -- According to sources at M. D. Anderson Cancer Center in Texas, the leading cancer research hospital in the US, there Iressa® is talked about as "a drug suffused in promise," a next-generation therapy that has shown "glimmers of powerful potential." Iressa (also known as Z-1839/Gefitinib) is the kind of treatment, M. D. Anderson's press office says, that oncologists dream of -- a pill that can be swallowed once a day, "a non-toxic therapy that causes few side effects."
Iressa® is a relatively new anticancer drug. On May 5th this year, Iressa received FDA approval as a single agent treatment for patients with advanced non-small cell lung cancer (NSCLC), the most common form of lung cancer in the US.
Iressa is approved as a treatment for patients whose cancer has continued to progress despite treatment with platinum-based and docetaxel. FDA speeded up review and approval for this drug under an "accelerated" program intended to allow patients suffering from serious or life-threatening diseases earlier access to promising new drugs not yet approved for general use.
"FDA believes it is crucial for cancer patients to have many safe and effective treatment options available to them in their battle against this disease" said FDA Commissioner Mark B. McClellan, M.D., Ph.D. "With the approval of Iressa, thousands of patients with lung cancer will now have access to an additional treatment after others haven't worked to stop the progression of their disease."
Iressa inhibits an enzyme (tyrosine kinase) present in lung cancer cells, as well as in other cancers and normal tissues, that appears to be important to the growth of cancer cells. Iressa is being tested on patients to find out how effective it may be to treat common solid tumors, starting with ones that lack effective therapies -- non small cell lung cancer (the commonest type of lung cancer) and head and neck cancer and continuing to breast cancer, colorectal cancer, and hormone-refractory prostate cancer
In clinical trials testing Iressa on patients with non-small cell lung cancer, 10 percent (15 of 142 patients) showed reduction of tumor volume. Responses were more frequent in women and in nonsmokers. Median duration of response was 7.0 months (range 4.6–18.6+ months). There were no cures. Patients who took Iressa with chemotheraopy showed no benefit at all.
M. D. Anderson says that for pre-treated patients who have used up two chemos and have "no other options left for them," Iressa "seems to make the difference between life and death." Another 30percent to 40 percent of patients who have used the drug, they say, "have a better, if not a longer, life."
There is not much evidence so far of "better" life. According to Iressa's manufacturer AstraZeneca, one of the world's largest pharmaceutical companies, "There are no controlled trials demonstrating a clinical benefit, such as improvement in disease-related symptoms or increased survival."
Common side effects during trials have been relatively mild and treatable -- diarrhea, rash, acne, dry skin, nausea, and vomiting. But some patients developed a type of pneumonia, and some of these patients died of that.
By February 2003, AstraZeneca acknowledged 173 Iressa-associated deaths in Japan. The dead were among 473 patients who developed lung disorders, mostly interstitial pneumonia, a company official said (Drug co. reports more deaths from lung cancer drug Feb 6, 2003; Iressa Update: Feb 7, 2003, Sunday Times, Australia).
The FDA, on reviewing the data, found that the rate of lung disease was about 2 percent in the Japanese experience, 1 percent in the two major U.S. clinical studies, and approximately 0.3 percent in the U.S. expanded access program. By this summer estimates ran thus: at least 65,000 patients world wide have taken Iressa. Some 1 percent developed interstitial peumonia. About a third of these patients died. Rarer side effects include alveolar hemorrhage.
When news of this pneumonia broke, sales in Japan, as Owen Dyer reported in BMJ, May 2003, fell by half. "The Japanese health ministry, however, has said that the benefits of gefitinib continue to outweigh the dangers," Dyer writes, "and that the rate of adverse events fell dramatically this year after new guidelines for use were introduced."
A group in Japan has argued that what caused deaths in the Japanese trials is Iressa's mechanism of action in inhibiting the tissue-repairing action of epidermal growth factor. Iressa, these physicians theorize, interfered with tissue repair needed for patients to recover from previous chemotherapy or radiotherapy or to fight infection contracted during the trial. They also claim that AstraZeneca underestimatesd the number of Iressa-associated deaths in Japan by classifying some as disease-related. This organization says that AstraZeneca's web sites "apppear to us to give a false expectation about the safety and efficacy of the drug."
Results so far of trials in the USA have allayed those fears.
As Dismal as All That?
In developing a new class of anti-cancer drug, companies, as a matter of self-interest, take into account likely future improvements in early detection. Patients in Iressa clinical trials have been gravely ill with rapidly progressing lung cancer. Today, most patients with non-small cell lung cancer (NSCLC) come in for diagnosis with advanced disease, in pain, coughing, and short of breath. According to a specialist at Northwestern University, "those who are able to tolerate chemotherapy can expect median survival increases of only 2 to 4 months." At present, then, a patient with this stage of disease would need to ask -- is a 10 percent chance for 7 months stable disease (18 months plus for the exceptionally lucky) worth it in exchange for (treatable) diarrhea and skin rash etc.? For 9 out of 10 patients it does not "make the difference between life and death." Nonetheless, 1 out of 10 chance of previously had had chemotherapy, it shrank tumor.
Why do 10 percent respond? Researchers at M. D. Anderson say this is " the central puzzle" that Iressa, and similar other targeted therapies, pose - what are the cancers that may best respond, and which patients will benefit? At the same time, no one really expects any single anti-cancer agent, even a "targeted" one, to work on everyone.
M. D. Anderson is heavily committed to testing Iressa, as well as a slew of other experimental drugs that target critical cancer cell pathways. They have been involved along with MSKCC and other cancer centers in US clinical trials looking at the effectiveness of Iressa in lung cancer. Now they are testing Iressa in malignant brain cancer and are plan to study it in a number of cancers, including head and neck, breast, and prostate, along with further investigations in lung cancer.
"So far, Iressa has been a good news, bad news story, says Frank Fossella, M.D., professor in the Department of Thoracic/Head and Neck Medical Oncology, who has treated many people with lung and other head and neck cancers. "The response rates are not as high as we would have liked, but the good news is that patients who do seem to respond have very dramatic gains, and many stay on the drug for long periods of time," Fossella says. "We are working to make the next chapter of Iressa very positive."
Roy Herbst, M.D., Ph.D., an associate professor in the Department of Thoracic/Head and Neck Medical Oncology, says it is obvious that the drug can add life, although no one can predict in advance which patient will be so fortunate. Herbst, who has been a principal investigator for Iressa lung cancer trials, can tick off on his fingers patients now alive who statistically should not be - had they not used Iressa. "You don't often develop that many long-lasting relationships in treating advanced lung cancer," he once commented for a report in The Wall Street Journal. "But now there are significantly more than before … this is what makes our jobs so satisfying."
Targeting cancer pathways
The attraction of targeted therapies is the notion that you can change cancer from an acute disease to a chronic, manageable disorder. All targeted therapies disrupt the "pathways" - the flow, from outside the cell to inside, of biological actions and reactions - that cancer cells use to grow, divide, repair themselves and communicate. To the extent that these drugs focus only on the special biology of the cancer cell and non-cancerous cells are not affected, patients are subjected to fewer of the toxic side effects of chemotherapy and radiation which can harm normal tissue.
That's the theory. In practice, at least one of these smart drugs, Herceptin, has turned out to affect heart muscle.
While each targeted therapy may work a little bit differently, most focus their activity on proteins that stimulate cancer cell growth, such as epidermal growth factor (EGF). Normally, the adult body uses EGF to grow new tissue for wound healing. A wide variety of cancers, such as lung, breast, ovarian, bladder, prostate, colorectal, kidney and head and neck cancer take advantage of this normal process and grow by forcing over-production of EGF proteins (to a varying extent depending on the type of cancer and specific tumor). Some of these tumors may be especially dependent on those proteins to maintain viability.
Some drugs (Erbitux, Herceptin) work on the first step in a pathway that ultimately leads to cell division - the docking of a "growth" protein to a receptor on the surface of a cell. These drugs, called epidermal growth factor (EGF) receptor antibody inhibitors, are large molecules that block growth-promoting EGF proteins from linking to the cell, thereby preventing the setting off of a cascade of signals that result in cellular proliferation
Other drugs, like Iressa, use the EGF receptor site as a porthole to get inside the cell, jamming the cascade of signals found along the critical pathways. These small molecule drugs are variously known as farnesyl transferase inhibitors (FTI), tyrosine kinase inhibitors (TKI), signal transduction inhibitors (STI), and EGF receptor inhibitors - depending on where in the cascade the drug acts.
The first such drug to be approved was Herceptin for breast cancer, which offers benefit to about 30 percent of women whose cancer expresses Her2, a receptor closely related to the EGF receptor. Gleevec™, which targets an intracellular protein which sends signals similar to the EGF receptor, has completely changed the way chronic myeloid leukemia (CML) is treated and it has also shown to work in rare gastrointestinal stromal tumors (GIST). Eribitux (C225) targeted the EGF and has had about the same response rate as Iressa; but the FDA found the clinical trials for colon cancer confusing and poorly designed, and the drug was put on hold. Iressa was the third such targeted therapy to be FDA approved.
Most cancers employ multiple pathways to grow and survive but targeted therapies tend to focus on a single pathway. Even Gleevec, which has initial high response rates in the relatively rare cancers it treats, cannot affect cancer cells that have mutated in order to use other pathways to grow. That's why many researchers believe future use of targeted therapies will involve "bundling" these drugs together to treat cancer that is early in its development - cancer which has not developed multiple survival mechanisms. And that means bundling side effects or "toxicities." Taken one at a time and rated against the threat of disease progression, the reisks may seem trivial. Bundled, a .03 percent risk of pneumonia, some risk (seen with Erbitux) of shock reaction, higher the risk (as with Herceptin) of heart damage -- safe for patients with early disease? No one knows.
Testing Iressa in prostate cancer
Prostate cancer researchers at M. D. Anderson have worked with other hospitals around the country to test Iressa as a single agent treatment. The trial, which was conducted in men with prostate cancer with androgen-independent cancer, is closed for additional patients. Although results are not yet available, Nizar Tannir, M.D., assistant professor in the Department of Genitourinary Medical Oncology intends to launch another study to be conducted only at M. D. Anderson.
In this planned clinical trial, Iressa will be used with hormonal therapy in patients whose PSA level is rising, or whose cancer is progressing after treatment with radiation or surgery. "We will be adding Iressa to the standard of care in these patients, to see if we can prolong the response to hormone therapy and reduce the duration of individual courses of hormonal therapy," says Tannir. "Prostate cancer does express EGF receptors in late stages and androgen independent cancers have high expression."
Tannir, as well as other M. D. Anderson researchers working with Iressa, say that while the drug has potential that has not yet been discovered, it probably will not be the single "magic bullet" that helps treat cancer in general.
Herbst, the lung cancer researcher, concludes that patients should be a "bit guarded" about Iressa's future success. "It is not proven to be a complete success in lung cancer or any other cancer yet," he says. "The fact is that we don't know why patients respond or don't respond but we do hope in the future to be able to identify those patients who can benefit." Such studies are soon to start at M. D. Anderson, Herbst says.
"Right now, Iressa is not so much a miracle drug in lung cancer as one more drug on list of drugs that we can use," says Fossella. "But, truth be known, we hope that as we learn to use it more effectively, Iressa and related drugs will eventually prove to be the magic bullets that will help more and more of our patients to enjoy life."
Iressa, a tyrosine kinase inhibitor, came to the attention of M. D. Anderson researchers in the late 1990s when news of the fledgling experimental therapy was brought to Houston by a former student of M. D. Anderson's president, John Mendelsohn, M.D.
The student, Jose Baselga, M.D, by then a full-fledged professor and researcher, had worked in Mendelsohn's laboratory while both were at Memorial Sloan-Kettering Cancer Center. Mendelsohn was among the first researchers to see the value of inhibiting EGF receptors, and, in collaboration with Gordon Sato, M.D., created the experimental drug Erbitux (IMC-225) to plug up the binding site for the growth protein on the outside of cells.
Baselga visited M. D. Anderson talking of a new exciting molecule (then known as ZD1839 or gefitinib) that worked on the inside of cells to shut down the EGF receptor signaling pathway. ZD1839 was developed in the labs of AstraZeneca pharmaceuticals after researching many new chemical entities that had a high affinity to the EGF receptor site.
Baslega, currently at a university hospital in Barcelona, Spain, met with Herbst - and Herbst, an oncologist trained in molecular biology, jumped at what he recognized as a huge opportunity to change lung cancer treatment. His chairman Waun Ki Hong, M.D., supported him.
"I pursued this drug very aggressively," Herbst remembers. "We had lots of enthusiasm for this kind of targeted therapy, long before Gleevec became a household word.
"From a lung cancer, head and neck cancer point of view, the idea of using an oral drug for treatment, possibly even as a chemoprevention or maintenance therapy, was very attractive," he says.
Herbst and his colleagues quickly accrued patients to test Iressa in a number of clinical trials, including the first continuous dosing Phase I study, which yielded positive insights about how the drug acts.
M. D. Anderson was one of the largest participants in a nationwide trial - the one that eventually led to FDA approval of the drug - that showed Iressa shrank tumors in about 10 percent of lung cancer patients that were not helped by multiple prior chemotherapy treatments and it provided symptom benefit for nearly half of the patients who took it. The researchers also led a clinical trial that tested a combination of Iressa and chemotherapy in advanced lung cancer patients. While that study was negative, demonstrating no advantage to using Iressa in that setting, it further demonstrated the safety of the drug, Herbst says.
The trials, as mixed as they were, have made a huge difference in the treatment of advanced lung cancer because Iressa demonstrated it could substantially help a subset of patients, says Herbst.
"Iressa offers obvious advantages for some patients," says Ralph Zinner, M.D., assistant professor in the Department of Thoracic/Head and Neck Medical Oncology. "I recall people who were bound to wheelchairs because of pain or need for oxygen, but within a few weeks of using Iressa, they were able to walk again, and they sustained that quality of life for as much as six months. That is reason enough to consider using this drug.
"But what is especially significant about Iressa is that it validates a drug development strategy that is only recently available to us. This is the targeting of only recently identified molecular errors that are the underlying cause of cancer," he says. "Chemotherapy has reached a therapeutic plateau with little improvement in survival expected from additional chemotherapy development. The hope is that these new drugs, which I believe will become better and better, will allow a significant rise above this plateau."
Expanding Iressa's use in head and neck, and thoracic cancers
In addition to continuing to test the drug as a treatment for lung cancer, Iressa also will be tested as a possible preventive agent in early stage disease and may further be helpful as maintenance therapy.
Many researchers at M. D. Anderson, relying on past experience with Iressa as well as current studies, believe the drug will best be used in combination with other targeted therapies, including possibly chemotherapies for some cancer. Iressa may show its best effect when used for cancer that isn't as far advanced as has been tested to date, or used sequentially—following surgery or chemotherapy.
A recent analysis Herbst presented in May at the annual meeting of the American Society of Clinical Oncology suggested the drug can keep cancer at bay by forcing it into dormancy. Herbst and his colleagues found that some lung cancer patients who used the drug as maintenance therapy following chemotherapy slowed recurrence of lung tumors.
“Using Iressa as a maintenance therapy is a very nice concept, and may offer some advantage in our goal to make lung cancer a chronic, manageable disease,” says Herbst.
Suspecting that other cancers of the head and neck may respond to Iressa, M. D. Anderson researchers are working on a variety of trials to test the drug, including the study of Iressa in thymoma, a malignancy of the thymus gland; in adenoid cystic carcinoma; and in refractory squamous cell carcinoma of the skin, an aggressive rare variant of common skin cancer.
"Whereas many cancers use redundant pathways to maintain their growth and so would not be especially damaged by EGF receptor inhibitors, we believe some, such as the squamous cell carcinoma of the skin, may be especially dependent on the EGF receptor pathway for survival," says Bonnie Glisson, M.D., a professor in the Department of Thoracic/Head and Neck Medical Oncology. "We need to determine which individual tumor is dependent on the EGF receptor pathway to proliferate, spread, and become resistant to cell death. I suspect that may not be a large percentage of tumors, but our study will help us select the patients and the cancers that will benefit most in the future."
Glisson says she is eager to get started on these studies. "We have plenty of patients who come from all over the nation that are waiting for these trials to open."
“We want to expand the setting in which we study the drug because there is such optimism for the potential that drugs like Iressa represent," says Edward Kim, M.D., assistant professor in Department of Thoracic/Head and Neck Medical Oncology.
Treating stubborn brain tumors
Because some brain tumors also overexpress EGF receptor, M. D. Anderson researchers are testing Iressa in two different ongoing clinical trials in patients with malignant gliomas who have failed other treatments. Those trials, by the seven centers within the North American Brain Tumor Consortium (including M. D. Anderson), test Iressa by itself as therapy, and in combination with chemotherapy.
"Between 40 percent to 60 percent of gliomas could potentially be helped with Iressa because of their EGF receptor status," says Mark Gilbert, M.D., associate professor in the Department of Neuro-Oncology. "It could be very exciting if this pathway could be blocked, but we don't have enough data yet to know its impact."
Gilbert suspects that a combination of different targeted therapies - including several that block EGF receptor - may be necessary to treat stubborn, entrenched brain tumors. To that end, the Brain Tumor Program, one of the largest in the country, is testing an alphabet soup of experimental drugs that target growth factor proteins or related molecules in or outside cancer cells, including PTK787, OSI774, CC1779, and others. The group is even testing Gleevec, the drug that has transformed treatment of a blood and a stomach cancer, chronic myeloid leukemia (CML) and gastrointestinal tumors (GIST).
"Future treatment probably will be a combination of chemotherapy and other signal transduction inhibitors," says Gilbert. "We need to block more than one pathway in a tumor that uses many pathways."
EGF receptors in breast cancer
Iressa will soon be studied in treatment of breast cancer in a nationwide clinical trial to be led by Massimo Cristofanilli, M.D., assistant professor in the Department of Breast Medical Oncology.
The trial will enroll 175 patients at up to 15 centers, and will be the first randomized study to test a combination of Iressa and Armidex to treat post-menopausal women with metastatic, estrogen-positive disease. Iressa used as a single agent did not prove beneficial in treating breast cancer, but it may work in combination with Armidex by reducing or preventing the development of hormone-resistance, thus increasing the chance of long-term benefit, says Cristofanilli.
Armidex is an aromatase inhibitor that works to stop estrogen production, reducing the fuel that feeds estrogen-positive breast cancer. Arimidex has been approved for use in early breast cancer and as a first line treatment option for advanced or locally advanced postmenopausal, hormonally-sensitive breast cancer.
Citing the example of Herceptin, the first targeted therapy drug approved by the FDA, Cristofanilli says Iressa may ultimately show benefit in breast cancer treatment because "there are plenty of indications the EGF receptor family is important for breast cancer progression and hormone-resistance."
Herceptin blocks a different but closely related growth receptor, HER-2, which is found in great abundance in about 30 percent of breast cancer, often resulting in more aggressive cancer cells that don't respond to standard treatments. The drug is also being studied in other forms of cancer that have cells with HER-2 receptors.
"EGF receptors collaborate with other members of the HER-family of receptors that affect the way cancer cells behave in presence of estrogen or respond when exposed to anti-estrogens," Cristofanilli says. "So if you control or modulate EGF receptor, you may be able to control the effect of estrogenic presence and deprivation more effectively.
"We want to play a major role in development of these new agents," says Cristofanilli. "If our trial with Iressa is positive, it could change the way we treat breast cancer."
Source, M. D. Anderson. This story edited by J. Strax. Page updated Oct 17, 2003.
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