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Physicians Update

 
Summer 2007 Oncology

‘Targeted’ Approaches Create New Inroads and Options in Oncology Treatments

UCLA Physician Update Summer 2007 issue: OncologyWhere once medical oncologists were forced to rely on the blunt instrument that is chemotherapy, increasingly there are new scalpels being introduced, in the form of “targeted” approaches.

Although advances in conventional treatments have resulted in small, incremental gains in survival for most common tumors, cancer researchers have long believed that the future rests in targeted therapies—drugs that take aim at the proteins, enzymes and pathways unique to cancer.

“Chemotherapy has the ability to kill tumor cells but it’s non-specific, so it’s also killing normal cells,” says Saeed Sadeghi, M.D., medical director of the UCLA/Santa Monica Cancer Center. “Targeted therapy is based on knowledge of the biology of the tumor—understanding what themechanismof the disease is and then designing drugs to block the various pathways that are essential to the tumor’s survival.”

Adds Fairooz Kabbinavar, M.D., medical director of the UCLA Kidney Cancer Program, “By selectively going after a target that is differentially over-expressed or overfunctioning in a cancer cell as opposed to a normal cell, the likelihood of side effects is decreased and we have a better chance of more precisely killing the cancer cells.”

With a handful of targeted cancer therapies approved for the treatment of certain diseases, and many more being tested in clinical trials, cancer patients and their physicians have far more treatment options than in the past, with exciting data showing progress against certain cancers that previously did not respond well to treatment. “It’s important for community physicians to be in close contact with a center that is offering clinical trials, especially when they’re dealing with patients who have failed standard treatments,” says Dr. Sadeghi. “We now have a number of good agents that can have a positive impact on patient survival, and every day there are more being tested.”

Targeted therapies are being tested in all stages for most cancers, with some evidence that they are more effective when used earlier in the disease course, so it behooves patients and their physicians not to delay in exploring potential options, Dr. Sadeghi adds.

The targeted-therapy approach to treating cancer was widely heralded in the late 1990s after two drugs provided proof of principle. The antibody Rituxan was approved in 1997 as a treatment for non-Hodgkin’s lymphoma. Even more celebrated was the drug Herceptin, which resulted in large part from investigational work conducted at the UCLA Jonsson Comprehensive Cancer Center. Herceptin was found to slow tumor progression in breast cancer patients with a genetic over-expression of HER2, a growth factor found on some cancer cells. It was approved by the Food and Drug Administration (FDA) in 1998 for advanced-stage patients with the HER2 genetic profile, and is currently being tested in earlier-stage patients.

Other targeted drugs have shown similarly dramatic results. Gleevec, which attacks a mutant protein in a cancercausing gene linked to chronic myeloid leukemia (CML), was approved in 2001 to treat CML, and in 2002 it was approved for the treatment of patients with gastrointestinal stromal tumor. “Before Gleevec was available, patients with an advanced stage of this malignancy were surviving about nine months,” says Frederick (Fritz) Eilber, M.D., UCLA surgical oncologist. “Now they can live for years by taking this relatively non-toxic pill.”

Avastin, a monoclonal antibody, blocks the vascular endothelial growth factor (VEGF)—a dominant angiogenic protein. Angiogenesis is the process through which tumors receive the blood supply that enables them to grow and thrive. Dr. Kabbinavar and other researchers across the country conducted key laboratory studies that have led to the class of drugs known as angiogenesis inhibitors, of which Avastin was the first to be FDA-approved. Avastin has been approved for the treatment of colorectal and lung cancers, and is also being looked at in breast and kidney tumors. Iressa and Tarceva, two drugs that inhibit the epidermal growth factor receptor (EGFR), a protein found on the surface of many tumor cells, have been approved to treat lung and (in the case of Tarceva) pancreatic cancers. The EGFR inhibitor Erbitux was approved to treat colon and head and neck cancers. More recently, Nexavar and Sutent, two drugs that interfere with a receptor called tyrosine kinase, were approved as first-line kidney cancer treatments.

Other targeted-therapy drugs—including already approved drugs being tested for different cancers or in new combinations with chemotherapy and with each other— are in clinical trials at major centers such as UCLA.

“In the past, cancer therapy has been a one-size-fits-all approach,” says Dennis Slamon, M.D., Ph.D., chief of the UCLA Division of Hematology/Oncology. “Now we understand that we are dealing with a heterogeneous group of diseases, even when they involve the same organ. We are beginning to learn how to characterize and classify those diseases and then tailor our therapy appropriately. That is changing the face of oncology.”

Ultimately, Dr. Slamon predicts, cancers involving a given organ will be broken into molecularly based subtypes, with different targeted therapies for each group. In breast cancer, he explains, there are likely at least seven important subgroups of patients, each with a different form depending on what was “broken” to trigger the malignancy. While more is understood about breast cancer than other cancers, the same is likely true across the board, he says.

Sara Hurvitz, M.D., UCLA oncologist and breast cancer specialist, participates in trials involving Avastin. The national E2100 trial found that adding Avastin to the standard Taxol regimen resulted in prolonged progression-free survival for metastatic breast cancer patients, though overall survival improvements have yet to be shown. Dr. Hurvitz and colleagues are among those who believe Avastin may be more effective in earlier-stage breast cancer, when there are fewer growth factors besides VEGF. They recently launched a trial to study the adjuvant use of Avastin with chemotherapy for early-stage breast cancer patients. (HER2-positive patients will get Herceptin plus Avastin and chemotherapy.) Another trial, with Mark Pegram, M.D., is weighing the use of Avastin with chemotherapy in the pre-surgical setting for locally advanced breast cancer patients. Dr. Pegram also heads a clinical trial of the combination of Avastin and Herceptin inmetastatic breast cancer— one that is of particular interest in that it involves two targeted agents without chemotherapy. Dr. Hurvitz is heading a clinical trial of a new multi-targeted tyrosine kinase inhibitor, taken orally, that goes after multiple VEGF receptors as well as other receptors implicated in breast cancers, such as platelet-derived growth factor (PDGF) and the receptor tyrosine kinase, c-Kit.

“Our goal in the breast cancer program is for each patient who comes in to have available to them an appropriate clinical trial of a targeted agent as an option in addition to standard therapy,” says Dr. Hurvitz.

Novel compounds are also being tested in genitourinary cancers, with a trend toward new combinations of available agents and trials involving earlier-stage patients. In prostate cancer, for example, in addition to trials for late-stage patients, the combination of Avastin and Tarceva is being given to patients immediately after radical prostatectomy, while another trial is administering the kidney cancer drug Sutent to prostate cancer patients prior to surgery.

Kidney cancer has proved to be an excellent model for testing novel targeted therapies, Dr. Kabbinavar says. “In the past, once these patients failed Interleukin-2 or Interferon, there wasn’t much to offer them,” he explains. “That has really changed, and now we are aggressively studying these targeted-therapy molecules in prostate cancer in the hope that we will have something to offer those patients beyond surgery and/or hormonal manipulation. I am optimistic that within a few years, the selective targeting of the cancer cell will become a standard of care for prostate cancer, as it has for kidney cancer.”

In UCLA’s thoracic oncology program, nearly a dozen clinical trials are ongoing for lung cancer patients. These trials include combinations of the approved targeted therapies for lung cancer, Avastin and Tarceva. Researchers are also investigating whether Avastin can be safely used in new settings in the treatment of patients with lung cancer, such as with patients with squamous cell lung cancer and patients who have lung cancer that has metastasized to the brain. Newer agents are also being tested. One trial combines Tarceva with Faslodex, an anti-estrogen drug, following laboratory research at the Jonsson Cancer Center showing that lung cancer cells often express the estrogen receptor and send signals via this receptor. The drug Nexavar, recently approved for kidney cancer, will soon be tested in a trial of older patients. Zactima, an oral medication being tested for patients who have previously received chemotherapy, inhibits both VEGF and EGFR, the targets of Avastin and Tarceva. 

“For many years, there were few drugs available for treatment of lung cancer patients. We are excited that we now have different types of drugs available, and we are looking at new ways to combine these drugs to get the best possible results,” says Edward Garon, M.D., a medical oncologist in the thoracic oncology program. “In addition, patients who have already been treated or have had brain metastases have traditionally been considered poor candidates for studies. Based on the promise of these newer agents, there is hope that there can be improvements in their traditionally very poor prognoses.”

The new targeted-therapy drugs are also raising hope among researchers who are studying melanoma, which does not respond well to chemotherapy. Antoni Ribas, M.D., UCLA medical oncologist, was until recently focusing on immunotherapy, with only slightly better results—typically about one in 10 patients responds— but with response durations that last years rather than months. With the new targeted-therapy drugs and the growing body of knowledge of what goes wrong in melanoma cells to make them malignant, he sees an opportunity to merge targeted therapies with immunotherapies.

“Our hypothesis is that some cancers, for whatever reason, are sensitive to immunotherapy, and for those that aren’t, by crippling them with a targeted drug that blocks a key pathway, we can produce changes in the cancer cell that makes it more prone to be attacked by the immune system,” Dr. Ribas explains.

Among oncologists, there was an initial sense that the emergence of targeted therapies would result in fewer patients requiring surgery. The opposite appears to be occurring. “These drugs are in many cases creating new surgical candidates out of patients whose disease is so widespread that in the past they were considered inoperable,” says Dr. Eilber. “Now, if the disease can be arrested with one of these new drugs, we are often operating to take out the tumors.When the agents are effective, combining themwith surgery can improve their outcomes.” Optimally, he notes, the targeted drug is administered prior to surgery, which not only appears to improve surgical outcomes but also allows a better assessment of the patient’s response to the drug.

Indeed, there is a growing consensus among cancer researchers that the best strategies looking forward will combine several weapons from the growing treatment arsenal. “There is a lot of redundancy in biological systems,” says Dr. Sadeghi. “Cancers are smart. They have alternative pathways that allow them to grow, and one of the things that we are beginning to notice is that attacking them in multiple ways may get better results.” The future, he adds, lies in an improved understanding of the pathways leading to more precise strategies, as well as a better understanding of which drugs will work best in which patients.

Concludes Dr. Slamon: “We have now had enough examples to show that if we identify the target, prove that it’s driving the tumor, correctly identify the patients who have it and develop a drug that hits that target and stays around long enough to inactivate it, we can make a major impact.” 

Recommended reading

Tap WD, Federman N, Eilber FC. Targeted therapies for soft-tissue sarcomas. Expert Rev. Anticancer Ther. (2007); 7(5); 725-733.

Eilber FC, Tap WD, Nelson SD, Eckardt JJ, Eilber FR. Advances in chemotherapy for patients with extremity soft tissue sarcoma. Orthop Clin North Am. 2006 January; 37(1)l; 15-22 Review.





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