But for most patients, Iressa does not shrink their cancer. That fact has become a challenge to researchers at The University of Texas M. D. Anderson Cancer Center. They are dedicated to solving the central puzzle that Iressa, and similar other targeted therapies, pose - what are the cancers that may best respond, and which patients will benefit?
M. D. Anderson researchers have been at the forefront of testing Iressa, as well as a slew of other experimental drugs that target critical cancer cell pathways. They have been involved in all phases of clinical trials looking at the effectiveness of Iressa in common lung cancer, work that helped lead to federal Food and Drug Administration approval of the drug in early 2003 for use when standard therapy has not helped lung cancer patients.
Now, investigators at M. D. Anderson are testing Iressa in malignant brain cancer and are poised to study it in a number of cancers, including head and neck, breast, and prostate, along with further investigations in lung cancer.
"M. D. Anderson is one of the leading institutions in developing targeted therapies such as Iressa," says Frank Fossella, M.D., professor in the Department of Thoracic/Head and Neck Medical Oncology, who has treated many lung and other head and neck cancers where it has shown tantalizing benefit.
"So far, Iressa has been a good news, bad news story. 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."
The thing about Iressa that is obvious to patients and their physicians is that it can add life, although no one can predict in advance which patient will be so fortunate, says Roy Herbst, M.D., Ph.D., an associate professor in the Department of Thoracic/Head and Neck Medical Oncology.
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 - sometimes called smart cancer drugs - is the notion that you can change cancer from an acute disease to a chronic, manageable disorder.
All targeted therapies work to stealthily and steadily 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. Because these drugs focus only on the special biology of the cancer cell, non-cancerous cells are not affected; patients are not subjected to the toxic side effects of chemotherapy and radiation which can harm normal tissue.
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). These growth-stimulating factors act by either binding to specific receptors on the cell's surface or by using the receptor as an entry point, disrupting molecular signals that stimulate cell growth. A wide variety of cancers, such as lung, breast, ovarian, bladder, prostate, colorectal, kidney and head and neck cancer over-produce EGF proteins and some of these tumors may be especially dependent on those proteins to maintain viability.
Several smart cancer drugs that target receptors for EGF have revolutionized cancer treatment. The first such drug to be approved was Herceptin for breast cancer, which offers dramatic 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). Iressa was the third such targeted therapy to be FDA approved.
Still these drugs, even Gleevec, are not yet the holy grail that cancer researchers seek. 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.
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.
Tantalizing benefit
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 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.
An analysis Herbst presented last year 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."
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."
For further media information, contact Laura Sussman, Senior Communications Specialist, M. D. Anderson Cancer Center; 713-792-0655; email lsussman@mdanderson.org. For patient information, contact M. D. Anderson's Information line, 800-392-1611, option 3.
Written by: Renee Twombly