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2005 Meet the Expert: Targeted Therapies—The Next Generation
Introduction
A better understanding of the biology of cancer cells has led to the identification of the genes, proteins, and pathways involved in cancer cell growth, survival, and metastasis. During the last decade, therapies that target these specific characteristics of cancer cells have been developed, and these therapies represent a new type of cancer treatment.
"Molecular targeted therapy allows us to identify specific targets in individual tumors, and that is the basis for treatment, not necessarily treating the place in the body where the cancer began," said Robert F. Ozols, MD, PhD, Chair of ASCO's Meet the Experts event on Targeted Therapies—The Next Generation, Chair-Elect, ASCO Communications Committee, and Senior Vice President for Medical Sciences at Fox Chase Cancer Center in Philadelphia. The information in this publication was presented at this event in New York City in December 2005.
Introduction
Cells are the most basic structure of the body. Cells make up tissues, and tissues make up organs, such as the lungs or liver. Each cell is surrounded by a membrane, a thin layer that separates the outside of the cell from the inside.
For a cell to perform necessary functions for the body and respond to its surroundings, it needs to communicate with other cells in the body. Communication occurs through chemical messages in a process called signal transduction. The purpose of these signals is to tell the cell what to do, such as when to grow, divide into two new cells, and die.
In cancer cells, the signaling process is defective. Targeted therapies stop or slow the spread of cancer by correcting or modifying the defective communication pathways in a cancer cell. Some of these processes include: - Uncontrolled cell growth
- Evasion of the natural process of cell death
- Production of a blood supply for the growing tumor
- Invasion of nearby tissues, which is the beginning of metastasis
Types of targeted therapies
Targets can be located on the outside or inside of a cancer cell. 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.
Targeted therapies currently consist of different types of drugs: - Monoclonal antibodies are substances made in the laboratory that recognize and then attach to specific proteins on the outside of cancer cells. They may be used to stimulate the immune system to attack cancer cells or to deliver radiation, chemotherapy, or other biologic therapies more directly to a tumor.
- Epidermal growth factor receptor (EGFR) inhibitors are a class of anticancer drugs that block a protein called the epidermal growth factor, which fuels the growth of cancer cells.
- Enzyme inhibitors block enzymes inside the cancer cell. Some newer drugs are designed to block multiple enzymes.
- Proteasome inhibitors block a group of enzymes known as proteasomes, which help regulate the functioning of the cell, including cell death. Proteasome inhibitors can stop the growth of cancer cells and allow the cells to die in a process called programmed cell death.
- Angiogenesis inhibitors prevent the formation of new blood vessels. In cancer cells, angiogenesis is essential for the growth of tumors, supplying blood and nutrients to the tumor and enabling cancer cells to spread from the original site to other parts of the body.
Development and evaluation
Most oncologists believe that targeted therapies will be the most useful when combined with standard chemotherapy or other targeted therapies. "It's clear that we will continue to use traditional therapies because many studies show that the targeted therapies being developed work better in combination with traditional therapies, especially chemotherapy," said Dr. Ozols.
One method to measure the effectiveness of a cancer treatment is through endpoints. A typical endpoint is survival, meaning that doctors measure the length of time a patient lives while receiving a particular therapy. Other clinical benefits associated with targeted therapies that may not necessarily improve survival include: - A reduction in tumor size
- Stable disease, which is no new growth or spread of the tumor
- Progression-free survival, which is the time a patient lives without any new tumor growth or metastasis
Results from clinical trials indicate that most targeted therapies do not cause the usual side effects associated with cancer treatment, such as hair loss and fatigue. However, other side effects may occur with these drugs, including rash, hand/foot syndrome (sores on the hands and feet), and an increased risk of heart attack and stroke. The specific side effects vary by drug.
The future of targeted therapies
Although research into targeted therapies is promising, no single drug can cure all cancers. Research results suggest that some of these drugs can control the cancer for many years, but little is known about the long-term effects of these therapies.
The effectiveness of current and future targeted therapies depends on understanding how these drugs actually work and which targets they affect. For example, trastuzumab (Herceptin) is a targeted therapy for breast cancer that only works if the breast cancer cells have a protein called human epidermal growth factor receptor 2 (HER-2). The ways that other targeted therapies work are still being studied. Finally, doctors are learning more about the genetic differences that help determine how a patient responds to a drug.
Despite the advances that have already been made, additional research is needed to develop new targeted therapies and test the ones that have been developed. "Drug development is never fast enough. We need to perform a lot of clinical research to show that these drugs work." A limiting factor, noted Dr. Ozols, is the number of patients enrolled in clinical trials. "We need to encourage patients to participate in clinical trials, which will help us find answers to our questions."
Targeted Therapies Approved by the U.S. Food and Drug Administration (FDA)
Targeted Therapy
| Type of therapy
| Cancer Type
| Bevacizumab (Avastin)
| Monoclonal antibody, angiogenesis inhibitor
| Colorectal cancer
| Bortezomib (Velcade)
| Proteasome inhibitor
| Multiple myeloma
| Cetuximab (Erbitux)
| Monoclonal antibody, EGFR inhibitor
| Colorectal cancer
| Erlotinib (Tarceva)
| EGFR inhibitor
| Non-small cell lung cancer, Pancreatic cancer
| Gefitinib (Iressa)
| Enzyme inhibitor
| Non-small cell lung cancer
| Ibritumomab (Zevalin)
| Radiolabeled monoclonal antibody
| Non-Hodgkin lymphoma
| Imatinib (Gleevec)
| Enzyme inhibitor
| Chronic myelogenous leukemia (CML), Gastrointestinal stromal tumor (GIST)
| Rituximab (Rituxan)
| Monoclonal antibody
| Non-Hodgkin lymphoma
| Sorafenib (Nexavar)
| Angiogenesis inhibitor, enzyme inhibitor
| Kidney cancer
| Sunitinib (Sutent)
| Enzyme inhibitor
| GIST, Kidney cancer
| Tositumomab (Bexxar)
| Radiolabeled monoclonal antibody
| Follicular lymphoma
| Trastuzumab (Herceptin)
| Monoclonal antibody
| Breast cancer
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A Summary of Targeted Therapies - Targeted therapies are a more specific way to treat cancer, although they are not completely free from side effects.
- Many targeted therapies shrink the tumor, stop the tumor from growing, or slow down the tumor's growth.
- Receptors and enzymes inside a cancer cell are the most common targets for these new therapies.
- Many targeted therapies are being used with chemotherapy. In some cases, the targeted therapy makes the chemotherapy more effective.
- Using combinations of targeted therapies helps to attack the tumor cell in several different ways and increases the chance that the treatment is successful.
- In the future, doctors hope that they will be able to select a patient's therapy based on specific characteristics of the tumor and a patient's genetic information to find the most effective treatment with the fewest side effects.
Last Updated: April 03, 2006
A Word From The President
Dear Friends,
Targeted therapies represent a new era of cancer therapy. Some of the most encouraging advances seen in cancer treatment are the result of decades of basic research studying the complex processes that direct a healthy cell to become cancerous and a cancerous cell to develop into a tumor that is capable of spreading throughout the body. To help patients and their families understand these and other new developments in cancer, ASCO publishes Cancer Advances, a series of consumer information resources about the latest advances in cancer research. This issue of Cancer Advances: Information from the Experts provides the latest information about targeted therapies for the treatment of breast, colorectal, kidney, and lung cancers, and lymphoma.
Because targeted therapies are more specific than conventional cancer treatments, more research is needed to identify the patients most likely to benefit from these therapies, learn how best to use them, and study their long-term effects. I am pleased to announce that ASCO has formed two task forces to address these areas. The Translational Research Task Force and the Biomarkers and Imaging Task Force are responsible for examining the development, delivery, and evaluation of these new therapies and will advise ASCO on how the organization can best incorporate new clinical science into our educational and scientific programs.
Finally, the only way in which these therapies progress from the laboratory to the clinic is through clinical trials. The progress in cancer treatment described in this issue of Cancer Advances comes from hundreds of patients who have enrolled in clinical trials. Continued progress in the development of targeted therapies is dependent on patients who participate in clinical trials, and I encourage patients to talk with their doctors to learn more.
I hope you find this newsletter helpful in understanding targeted therapies. For more information, visit ASCO's People Living With Cancer website at www.plwc.org.
Sincerely,
Sandra J. Horning, MD
ASCO President
Last Updated: April 03, 2006
Breast Cancer
A recent targeted therapy success story is in breast cancer. About 25% of women with breast cancer have extra copies of the human epidermal growth factor receptor 2 (HER-2) protein. HER-2 is a receptor that sits on the outside of cells and controls cancer cell growth, invasion, and metastasis (spread of cancer to other parts of the body). Tumors that have HER-2 tend to grow faster, and women with HER-2-positive tumors are more likely to have the cancer come back and less likely to live as long as women with tumors that do not have HER-2.
Trastuzumab (Herceptin) is a targeted therapy that blocks the HER-2 receptor and is already approved to treat metastatic breast cancer. Trastuzumab was recently studied for use as an adjuvant therapy (therapy after surgery). This clinical trial compared the combination of trastuzumab and standard chemotherapy with standard chemotherapy only. In addition, this clinical trial looked at the best time to give patients trastuzumab: with chemotherapy or after chemotherapy. The results showed that adding trastuzumab to chemotherapy lowered the risk of cancer returning by 50%, and that giving trastuzumab along with the chemotherapy was better than giving each therapy separately.
"Clearly these are preliminary, but based on these data, we are recommending trastuzumab be used concurrently with chemotherapy, after appropriate surgical removal of the breast cancer in patients with HER-2-positive disease," said Edith A. Perez, MD, Professor of Medicine at the Mayo Medical School in Jacksonville, Florida.
A notable side effect of trastuzumab is congestive heart failure, a weakening of the heart muscle. Clinical trial data after three years show about a 3% risk of developing this side effect, and patients taking this drug should be carefully monitored for heart problems. However, trastuzumab does not cause hair loss, vomiting, and other side effects associated with standard chemotherapy.
The next step for targeted therapy in breast cancer is the combination of targeted therapies that inhibit the HER pathway. Lapatinib (GSK572016) is a targeted therapy that blocks HER-2 from inside the cancer cell (instead of outside the cell, like trastuzumab). In clinical trials of women with metastatic breast cancer, a combination of lapatinib and trastuzumab shrank tumors and prevented new tumor growth. In the future, doctors plan to study the effectiveness of these targeted therapies as adjuvant therapy for early stage breast cancer.
Facts About Breast Cancer- Breast cancer is diagnosed in more than 200,000 women each year in the United States.
- More than 2 million women in the United States have been diagnosed with and treated for breast cancer.
Targeted Therapy Summary for Breast Cancer- Targeted therapy is being used to treat metastatic breast cancer in women with HER-2-positive breast cancer.
- Trastuzumab is a recommended addition to adjuvant chemotherapy to lower the risk of recurrence in women with HER-2-positive breast cancer.
- Use of trastuzumab could prevent recurrence in 6000 women and prevent 1000 deaths of women in the United States.
- Future studies are determining whether other targeted therapies and combinations of targeted therapies are effective for metastatic and earlier stage breast cancer.
Last Updated: April 03, 2006
Colorectal Cancer
Targeted therapies have been successful in the treatment of metastatic colorectal cancer. Previously patients diagnosed with metastatic colorectal cancer (cancer that has spread outside the colon and rectum) could expect to survive about six to eight months. With chemotherapy, survival steadily improved to 15 to 20 months, and the addition of bevacizumab (Avastin), a targeted therapy, increased survival to about 21 months when combined with fluorouracil (5-FU)/irinotecan (Camptosar) chemotherapy.
"This result was startling at the time," said Richard M. Goldberg, MD, Professor of Medicine and Associate Director for Clinical Research at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill. "It was the longest time to progression ever recorded in patients on a colon cancer trial for advanced disease, and that translated into a survival benefit."
In 2004, bevacizumab was approved by the U.S. Food and Drug Administration (FDA) to treat metastatic colorectal cancer in combination with chemotherapy. Bevacizumab works by blocking the action of vascular endothelial growth factor (VEGF), which helps new blood and lymph vessels form. It also makes the blood vessels "leaky," meaning that chemotherapy cannot reach the tumor. When used with chemotherapy, bevacizumab causes the new blood vessels to shrink and allows the existing blood vessels to function normally, which in turn, allows chemotherapy to be delivered to the tumor.
Because bevacizumab targets blood vessel formation, it may cause blood vessel-related side effects, such as high blood pressure and dangerous blood clots. People who have had a stroke or heart attack are at a higher risk for these side effects.
Another pathway being studied in colorectal cancer is the epidermal growth factor receptor (EGFR) pathway. This pathway influences tumor growth, invasion, and metastasis. Cetuximab (Erbitux) is a monoclonal antibody that blocks the action of the EGFR, somewhat like a plug in a socket. Cetuximab was approved in 2004 by the FDA to treat metastatic colorectal cancer.
A phase II clinical trial testing the use of both bevacizumab and cetuximab in patients with advanced refractory colorectal cancer (meaning that 5-FU/irinotecan chemotherapy is no longer effective) is an example of testing a combination of two targeted therapies. The results of this clinical trial showed that the combination caused tumors to shrink in 23% of the patients. "This may seem like a small step in terms of the response rate, but we expect that we'll see even better results inuntreated patients and patients who have just had surgery for colorectal cancer," said Dr. Goldberg.
Furthermore, results of this study supported a previous study showing that the targeted therapy, cetuximab, made the irinotecan chemotherapy effective again.
Many targeted therapies for colorectal cancer are in development. "There are many opportunities for targeted therapies in colorectal cancer, and hopefully some of these drugs will result in clear advances for patients," said Dr. Goldberg.
Facts About Colorectal Cancer- Colorectal cancer is the second leading cause of cancer-related death for both men and women in the United States.
- An estimated 150,000 new cases occur each year in the United States, and 800,000 new cases occur worldwide.
Targeted Therapy Summary for Colorectal Cancer- Two approved therapies, bevacizumab and cetuximab, are currently used to treat metastatic colorectal cancer.
- Researchers are testing combinations of these targeted therapies with the hope of eventually eliminating the need for chemotherapy.
- Many other targeted therapies are in development or are being tested in clinical trials.
- Targeted therapies are also being tested for use as adjuvant therapy (therapy after surgery).
Last Updated: April 03, 2006
Kidney Cancer
One of the most interesting breakthroughs for the treatment of metastatic kidney cancer is the recent approval of two new drugs, sorafenib (Nexavar) and sunitinib (Sutent). These therapies focus on stopping angiogenesis (the process of forming new blood vessels), which is an important part of how kidney cancers grow and spread. Both of these drugs block angiogenesis and are in the form of pills that can be taken by mouth.
"These new therapies are exciting because there is no effective systemic treatment for patients with metastatic kidney cancer," said Robert Motzer, MD, Attending Physician, Genitourinary Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center in New York City. Previously, patients were treated with high-dose interleukin-2 (aldesleukin [Proleukin]) or interferon-a (Roferon), which are therapies that stimulate the immune system. However, these drugs only work in a small number of patients and cause many unpleasant side effects.
In a phase III clinical trial of 800 patients with metastatic kidney cancer that wasn't responding to standard treatment, half of the patients received sorafenib and the other half received a placebo (an inactive treatment) because there are no standard treatments for this disease. Preliminary results show that sorafenib increased progression-free survival (the time it took for the kidney cancer to grow or spread) from a median of 2.8 months to 5.5 months. Sorafenib also shrank tumors in about three quarters of the patients. The results were good enough that patients who originally received the placebo were allowed to receive sorafenib. The overall survival data for sorafenib is not yet available.
Sunitinib was studied in two, phase II single-arm clinical trials, which means that all patients receive the new drug. The patients in these trials also had metastatic kidney cancer that didn't respond to the standard treatment. Results from both clinical trials show that sunitinib shrank tumors in about 40% of patients and the median progression-free survival was about eight months. Based on these promising results, a phase III clinical trial comparing sunitinib with interferon-a was begun.
Each drug has some side effects, though not as serious as those that can occur with the standard therapy. Sunitinib can cause fatigue. Both sunitinib and sorafenib can cause a rash on the hands and feet, called hand-foot syndrome. Some patients also experience nausea and vomiting.
Another targeted therapy, CCI-779 (temsirolimus), has shown promise in early clinical trials. This therapy is given intravenously. Because this therapy blocks a different protein in the angiogenesis process, it might be used in combination with these other therapies. A phase III clinical trial studying whether CCI-779 is more effective than interferon-a is ongoing.
Facts About Kidney Cancer- Renal cell carcinoma is the most common type of kidney cancer and occurs in about 38,000 people each year in the United States.
- Many patients with kidney cancer develop metastases (tumors in other areas of the body), which make this disease difficult to treat.
Targeted Therapy Summary for Kidney Cancer- For the first time, effective, approved second-line therapies (therapy that is given if or when the first therapy no longer works) are available for patients with metastatic kidney cancer.
- These therapies have fewer side effects than interleukin-2 or interferon-a therapy.
- Phase III clinical trials comparing targeted therapy with interferon-a for the initial treatment of metastatic kidney cancer are underway.
Last Updated: April 03, 2006
Lung Cancer
Targeted therapy is changing the treatment of lung cancer. Before targeted therapy, treatment for advanced non-small cell lung cancer (NSCLC) was limited to chemotherapy. "Today, many targeted therapies are being studied for lung cancer, both for early and late stage cancer," said Roy S. Herbst, MD, PhD, Chair, ASCO Cancer Communications Committee and Professor of Medicine, Department of Thoracic/Head and Neck Medical Oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Lung cancer and epidermal growth factor
A primary target for new lung cancer therapies is the epidermal growth factor receptor (EGFR), which is a protein that helps cells grow and multiply, including some cancer cells. Several targeted therapies for lung cancer work by blocking the activity of EGFR.- Gefitinib (Iressa) is a pill that is taken by mouth. The U.S. Food and Drug Administration (FDA) approved gefitinib in 2004 to treat patients with advanced NSCLC that continued to grow despite chemotherapy. However, follow-up data from a clinical trial showed that gefitinib did not improve survival for most patients, and the FDA-approved indication changed in June 2005. This means that gefitinib can only be given to patients currently or previously on the drug, or those participating in clinical trials.
- Erlotinib (Tarceva) is also a pill taken by mouth and targets an EGFR protein on the surface of cancer cells called human epidermal growth factor receptor 1 (HER-1/EGFR). The FDA approved erlotinib in 2004 for locally advanced and metastatic NSCLC. The side effects of erlotinib include rash and diarrhea.
Lung cancer and angiogenesis
An exciting development in lung cancer is with bevacizumab (Avastin), a targeted therapy that blocks angiogenesis (the formation of new blood vessels). Results from a large clinical trial in 2005 showed that the one-year survival rate of patients with advanced lung cancer could be improved by 50% with the addition of bevacizumab to chemotherapy.
One of the concerns of the use of bevacizumab for treating lung cancer is the risk of bleeding. Because the lungs don't have as much tissue as the colon or kidney, when a lung tumor shrinks, it can pull away from the blood vessel, causing bleeding. In clinical trials of bevacizumab, the risk of bleeding was about 2%.
Combining targeted therapies
The advantage of combining targeted therapies is that cancer cells are destroyed in two different ways, which may be more effective for treating cancer. In a phase II clinical trial, combining erlotinib and bevacizumab resulted in a median survival of about 12 and a half months for patients with recurrent NSCLC.
"There are many good advances in lung cancer," said Dr. Herbst. "Now we have to take these drugs back to the laboratory and understand who these drugs work best in, so we can develop the right combinations and integrate these drugs into the treatment plan."
Facts About Lung Cancer- Lung cancer is the leading cause of cancer death for both men and women in the United States.
- Lung cancer is one of the most challenging cancers to treat because it has usually spread by the time it is diagnosed.
- Non-small cell lung cancer (NSCLC) is the most common type of lung cancer.
Targeted Therapy Summary for Lung Cancer- Several targeted therapies for lung cancer inhibit the epidermal growth factor receptor (EGFR).
- A combination of targeted therapies is being tested in recurrent lung cancer.
- New therapies that affect the vascular endothelial growth factor (VEGF), a protein involved in angiogenesis, are in development for lung cancer.
Last Updated: April 03, 2006
Non-Hodgkin Lymphoma
One of the most exciting developments in non-Hodgkin lymphoma (NHL) is the use of rituximab (Rituxan) to treat diffuse large B-cell lymphoma. This subtype of lymphoma represents about 30% of all cases of NHL and is considered an aggressive form of NHL. When combined with chemotherapy, rituximab significantly improves survival without additional severe side effects.
"We are looking at differences in cure rates in the range of 10% to 20%, which represents a major advance in the treatment of this disease," said Sandra J. Horning, MD, ASCO President and Professor of Medicine in the Division of Medical Oncology and Blood and Marrow Transplantation at Stanford University in Palo Alto, California. Recently, the U.S. Food and Drug Administration (FDA) approved the use of rituximab along with chemotherapy for the treatment of diffuse large B-cell lymphoma.
Rituximab is a monoclonal antibody that destroys B cells by attaching to a protein on the surface of the B cell called CD20, which is present on more than 90% of B-cell lymphomas. It was first approved to treat follicular lymphoma, a slow-growing type of B-cell NHL that tends to recur (come back after treatment). Recent clinical trial data indicate that combining rituximab and standard chemotherapy greatly improves event-free survival (a measure of how long a patient lives without experiencing symptoms) in patients with follicular lymphoma.
"We are beginning to see a survival benefit in patients with follicular lymphoma who have been treated with a combination of rituximab and chemotherapy—a result I find exciting," said Dr. Horning.
Radioimmunotherapy
Another way to target and kill B cells is to attach a radioactive substance to the monoclonal antibody. This is called radioimmunotherapy. The FDA has approved two such therapies, tositumomab (Bexxar) and ibritumomab (Zevalin). Recent clinical studies show that tositumomab can extend remission (when there are no signs or symptoms) in patients with follicular lymphoma. The effectiveness of these therapies for the initial treatment of patients with follicular or diffuse large B-cell lymphoma is being studied in clinical trials.
Mantle cell lymphoma
Mantle cell lymphoma is an aggressive lymphoma and does not respond well to chemotherapy. Bortezomib (Velcade) is a targeted therapy that was approved by the FDA in 2003 for the treatment of multiple myeloma, a cancer of the plasma cells in the bone marrow, and is given as an injection. Cancer cells live longer than they should, so bortezomib helps cancer cells die. Data from a phase II clinical trial appear promising for this type of cancer, and other clinical trials are ongoing.
Facts About Non-Hodgkin Lymphoma- In the United States, about 56,000 people are diagnosed with NHL each year, and an estimated 19,000 people die of the disease annually.
- NHL is cancer of the lymph system, which fights infection and disease and carries lymph, a colorless fluid containing lymphocytes (white blood cells). Lymphocytes fight germs in the body.
- There are approximately 30 subtypes of NHL, which can make diagnosis and treatment difficult.
- B-cell lymphoma is the most common type of lymphoma.
Targeted Therapy Summary for Non-Hodgkin Lymphoma- Rituximab has greatly improved treatment options for patients with B-cell lymphoma and improved the cure rate.
- Radioimmunotherapy is an effective way to deliver radiation to B cells and is an effective treatment for some types of B-cell lymphoma.
- Clinical trials testing other targeted therapies are underway.
Last Updated: April 03, 2006
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