American College of Physicians: Internal Medicine — Doctors for Adults ®


In cancer treatment, targeted therapies are giving physicians and patients hope

New, focused drugs have produced dramatic results, but more challenges remain

From the December ACP Observer, copyright 2003 by the American College of Physicians.

By Margie Patlak

Ask radiation oncologist Marisa Weiss, MD, about cutting-edge oncology treatments, and she talks about one of her "miracle patients."

When Kathy, a 36-year-old mother of four young children, was diagnosed with breast cancer in June 2000, the disease had already spread to her bones, brain and liver. "I was there when she was first diagnosed," recalled Dr. Weiss, who specializes in breast cancer in suburban Philadelphia "It was a very somber and sad day. Kathy and her husband knew her life was counted in months, not years."

Within months of taking the new drug trastuzumab (Herceptin), however, Kathy's cancer lesions began to shrink, with some melting away altogether. And nine months after starting with trastuzumab, the crushing fatigue she felt before treatment had disappeared. Kathy's life returned to normal, replete with attending PTA meetings and doing the mounds of laundry her family generates each week.

Although the patient's bone metastases have recently acted up, Dr. Weiss said the drug has outperformed anyone's expectations. "We're already three years past a point we ever thought we'd be," she pointed out.

Trastuzumab is one of several novel "targeted treatments" for cancer that have recently entered the market. Instead of attacking all dividing cells—the strategy used by standard chemotherapy—targeted therapies take an approach that is molecularly more fine-tuned.

Put simply, these drugs try to counteract the specific biochemical defects that foster the runaway growth of cancer cells. (See "What aspects of cancer do new therapies target?") Because these designer drugs tend to target abnormalities housed only by cancer cells, they tend to produce less troublesome side effects than standard chemotherapy.

"Targeted therapy is all about knowing your enemy," said Louise B. Grochow, FACP, chief of the National Cancer Institute's investigational cancer drug program. "The reason for all the excitement is that some valid targets have been identified through molecular research, and they are what we call 'drug able' targets."

Works in progress?

Besides trastuzumab, several other targeted therapies have been approved to treat cancer. Imatinib (Gleevec), for instance, has been approved for chronic myelogenous leukemia and a rare type of stomach cancer, while gefitinib (Iressa) has been approved to treat lung cancer.

Several other targeted therapies are doing so well in clinical trials that they will likely be added to the cancer drug arsenal in the near future. Dozens more agents are in various stages of testing.

The drugs have clear theoretical advantages, and many have received considerable hype in the media. But experts caution that targeted therapies are still in their early stages of therapeutic use.

"One shouldn't be mesmerized by the words 'targeted therapy,' " said Richard Pazdur, FACP, director of the FDA's division of oncology drug products. "The science is wonderful and the agents are interesting, but there are ludicrous amounts of hype," Dr. Grochow added.

That caution stems from the fact that targeted treatments are far from perfect. As both researchers and practicing physicians have discovered, a number of problems plague this innovative approach to treating cancer.

Targeted therapies, for example, are typically not very effective when used singly or even in combination with standard chemotherapies. Although there are some stunning exceptions, researchers often see response rates on the order of between 10% and 20%.

Durable responses are even more rare. No one with advanced cancer has yet to be cured with targeted therapy, and researchers say it's debatable whether these designer drugs can cure patients facing earlier stages of their disease.

In part, targeted therapies produce limited results because they can help a relatively small subgroup of cancer patients. Tests to pinpoint those exact patients, however, do not exist.

Finally, the targets of many of these drugs are so narrow that cancer cells are likely to eventually find ways to bypass them.

"The value of a targeted therapy depends on how important the target is," explained oncologist Herbert I. Hurwitz, MD, of Duke University in Durham, N.C. "There will be some tumor types where there is one driving pathway alteration, and when that can be hit, there's a dramatic effect. But for more complicated tumors, the impact of hitting one target is likely to be incremental."

Unfortunately, many of the more common solid tumors—those that occur in the breast, colon and lung—tend to fall in the category of "more complicated tumors," at least by the time most are detected, Dr. Grochow noted. Physicians may eventually have to combine several targeted treatments to achieve cures or durable responses for these cancers.

That strategy is akin to the multidrug combination therapies that have proven so effective for HIV infection. "In 20 years, we've seen AIDS converted from a disease that will kill people in weeks to months to a disease that may now go on for decades with combination therapy," said oncologist Roger B. Cohen, MD, director of the phase I clinical trials program at Philadelphia's Fox Chase Cancer Center. "That clearly is a model."

Combination therapy with targeted treatments may offer another advantage: slowing down—or completely eliminating—the development of drug resistance. Most of the clinical trials now being done with targeted therapies are trying to delineate the benefit achieved when a targeted therapy is combined with standard chemotherapy. But several trials are testing the effects of combining two innovative targeted treatments together.

"There's tremendous promise here," said the FDA's Dr. Pazdur. "But there's also a tremendous amount of work ahead."

Here is a look at several targeted therapies, as well as what experts say are the therapies' pros and cons:

  • Trastuzumab. Approved by the FDA in 1998, trastuzumab was one of the first targeted treatments for cancer to hit the market. When women with breast cancers that produced excessive amounts of the HER2/neu protein take the drug, between 20% and 40% see their tumors shrink.

    Some women—like Dr. Weiss' patient, Kathy—experience long-term results. On average, however, trastuzumab gives most women an extra six to 12 months of life.

    When trastuzumab is used in combination with standard chemotherapy, it boosts survival rates by 25%. The drug rarely causes side effects—although it is standard practice to combine it with standard chemotherapies, whose side effects can significantly impair quality of life.

    Oncologists say trastuzumab's results are remarkable, because HER2/neu positive cancers are extremely aggressive and often kill women within weeks or months. One of the drug's limitations, however, is that it works with a fairly small subgroup of cancer patients. While the FDA approved trastuzumab for HER2/neu positive metastatic breast cancer, only about one-quarter of women with metastatic breast cancer are HER2/neu positive.

    Another downside, pointed out Fox Chase's Dr. Cohen: Most patients eventually stop responding to trastuzumab, presumably because they develop resistance to the drug.

  • Imatinib. In February 2002, the FDA approved the oral drug imatinib (Gleevec) to treat a rare type of stomach cancer. Later that year, the drug received FDA approval as first-line treatment for chronic myelogenous leukemia (CML).

    When given to early-stage CML patients, imatinib is amazingly effective, making it the poster child for targeted treatment. Researchers think its remarkable success hinges on its ability to target the initial genetic trigger that causes CML.

    Nearly all CML patients respond to imatinib. In a study of more than 1,000 patients newly diagnosed with CML, complete responses were seen in 76% of subjects taking imatinib. By comparison, only 15% of patients using conventional therapy had complete responses.

    The study, published in the March 13, 2003, New England Journal of Medicine, also found that imatinib produced significantly fewer side effects than conventional therapy (interferon combined with a low-dose standard chemotherapy drug).

    But imatinib isn't a free ride for many patients who take it. Half of them experience edema, and almost as many experience some nausea. About one-third experience muscle cramps and/or diarrhea.

    "Targeted therapies generally are better tolerated than conventional chemotherapies," said Dr. Grochow. "But the likelihood that targeted therapies will be nontoxic or minimally toxic is vanishingly small. None of these drugs is acetaminophen."

    Even more troubling are relapse rates for patients taking the drug. After two years, about 13% of patients with early-stage CML relapse. An even higher number of patients with advanced CML (in blast crisis)—90%—relapse.

    Like breast cancer patients taking trastuzumab, patients with CML continue to take imatinib even after experiencing a complete response to the drug because it is not known yet what the effects of stopping it might be. Researchers have shown that some patients develop resistance to the drug over time.

  • Bevacizumab. At the American Society of Clinical Oncology meeting last June, Dr. Hurwitz's report on a large clinical trial with bevacizumab (Avastin) generated considerable excitement.

    Researchers combined bevacizumab with standard chemotherapy as a first-line treatment for patients with metastatic colorectal cancer. Although the drug boosted response rates by only 10%, median survival rates rose 30% (five months) compared to standard chemotherapy alone.

    Bevacizumab was also remarkably well-tolerated. Researchers were able to control the most common side effect of the drug—high blood pressure—with standard antihypertensive drugs.

    "The results of our study are proof of the principle that targeted therapy for cancer is able to make an impact on critical outcomes like survival," Dr. Hurwitz explained. "A handful of patients had dramatic responses that were maintained for several years."

    Although some may scoff at the fact that the median added survival benefit of bevacizumab was measured in months, not years, adding months of life can be meaningful to cancer patients.

    "We're not taking into account that a five-month improvement in survival could include a high school graduation, a birth of a grandchild or a trip overseas," Dr. Cohen explained. "As cancer patients are quick to remind you, you can be amazed how much living you can do in six weeks, let alone a year, if someone gives that time to you."

    The FDA is currently considering approving bevacizumab to treat metastatic colorectal cancer.

  • Gefitinib. More discouraging, however, were the results of the targeted therapy gefitinib (Iressa) when used in combination with standard chemotherapy as a first-line treatment for patients with lung cancer. In two randomized, placebo-controlled studies, the drug offered no additional survival benefit or boost in response rate.

    Researchers have hypothesized that gefitinib may have counteracted the effects of the standard chemotherapy drugs, or vice versa. "You hope that if A, B and C work, then together you get a cumulative effect," said the FDA's Dr. Pazdur. "But these drugs may be working against each other."

    Even on its own, gefitinib shrinks tumors in only 10% of lung cancer patients compared to supportive care that no longer responds to standard chemotherapy. Despite that relatively low response rate, the FDA approved gefitinib in May 2003 to treat non-small cell lung cancer patients who don't respond or can't tolerate standard chemotherapy. (Gefitinib is well-tolerated. An acne-like rash is the most common side effect.)

    While a 10% benefit may seem low, Dr. Pazdur said that it gives hope to patients whose lives are immediately threatened by lung cancer. "This isn't like treating hypertension or pneumonia, where a majority of people see a response to a drug," he said.

    And the fact that it works at all in patients with advanced lung cancer is amazing, Dr. Cohen added. "For the advanced solid tumors I treat, like breast, lung, and colon, we're really thrilled if things stop growing" he said. "If there's a partial response, we couldn't be happier."

  • Cetuximab and erlotinib. Cetuximab (Erbitux) and erlotinib (Tarceva)—two drugs with a similar mechanism of action as that of gefitinib—have shown promising results in treating colorectal, lung or ovarian cancer in small clinical studies.

    The drugs have produced response rates of 10% when used by themselves, and between 20% and 40% when used with standard chemotherapy. (Like gefitinib, the most common side effect of these drugs is an acne-like rash.) But researchers have yet to document the durability of those responses.

    Dr. Cohen has a 50-year old lung cancer patient who has been taking erlotinib for more than a year and is living a completely normal life. "I did not make her lung cancer go away in her bones or her lungs, but she has no symptoms whatsoever from the disease, or from taking Tarceva," he said. "She looks like a million bucks. You would not know she has metastatic lung cancer."

Needed: targeted tests

With targeted therapy, the trick is figuring out which patients will respond. While physicians can use tests to determine which patients will benefit from a drug like trastuzumab, there are no tests to identify the subgroup of patients who will benefit from bevacizumab, gefitinib, erlotinib or cetuximab.

Experts say that the missing piece is a deeper appreciation of the disease process itself. Once researchers understand the growth and spread of tumors at a molecular level, experts say, they will be able to identify the patients these drugs can help.

"There are signs that we have our hands on agents that do something, and now the challenge is to figure out which patients to give them to," Dr. Cohen said. It's not enough, he added, to know that cancer has something to do with invasion or blood vessel growth or cellular motility.

"What we really need to know is what's the driver of this particular patient's cancer at this particular time," Dr. Cohen explained. "There are no assays for that."

But he is optimistic that targeted assays to match targeted cancer therapies will soon be developed that will dramatically change the effectiveness of these treatments.

"If you had talked to me in 1978 and I had just given tamoxifen to a few dozen women with advanced breast cancer, I would have told you it doesn't seem to work most of the time," he pointed out. "That's because it was being given to everybody, but the only people who were going to respond to it were the ones who had estrogen receptors on their cancers." Studies now show that most women with estrogen-positive tumors benefit by taking tamoxifen.

Most experts agree that targeted therapies are still too early in their infancy for doctors to make a judgment call on their effectiveness. As Dr. Hurwitz explained, "I'm encouraged by the progress made to date, but I'm not naive. First of all, we're not done, and second of all, most of the battle has yet to be fought."

Margie Patlak is a freelance science writer in Elkins Park, Pa.

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.

What aspects of cancer do new therapies target?

Targeted therapies are an exciting option in cancer treatment because they focus on treating narrow aspects of the disease. Here's an overview of how several of the newest drugs work.


The genesis of this drug can be traced to the discovery of the human version of a specific gene (HER2/neu) that caused cancer in mice. Researchers later discovered large amounts of it in aggressive breast tumors.

The more copies of this gene a tumor has, the faster the disease spreads in patients, discovered Dennis J. Slamon, MD, director of the Revlon/UCLA women's cancer research program at the University of California, Los Angeles. When he convinced a biotech firm to make monoclonal antibodies to block the actions of the protein expressed by the aberrant gene, trastuzumab was born.

Trastuzumab stops the actions of a HER2/neu protein, which is a tyrosine kinase. Most of the new targeted treatments for cancer inhibit these kinds of enzymes, which are the workhorses for growth factors that signal cells to grow and divide.


Like trastuzumab, imatinib targets a tyrosine kinase. Through a series of fortuitous events, researchers discovered that the chromosomal swap that triggers chronic myelogenous leukemia (CML) causes the production of an abnormally active tyrosine kinase called BCR-ABL.

This kinase is responsible for the excessive growth of blood cells that typify CML. Imatinib blocks the actions of BCR-ABL.

Cetuximab, erlotinib and gefitinib

A major thrust in the targeted treatment arena has been the development of drugs that thwart the effects of the epidermal growth factor receptor (EGFR). Closely related to the receptor that relies on HER2/neu to carry its tumor-fostering signals to the cell nucleus, EGFR is overproduced in the solid tumors of many patients with common cancers like colorectal, breast, ovarian, prostate and lung cancers. That overproduction is linked to a poorer prognosis.

When EGFR is activated, it allows a number of cellular feats that fuel the development or progression of solid tumors. They include proliferation, migration and the development of blood vessels (angiogenesis).

Like most growth factor receptors, EGFR is lodged in the cell membrane. A portion of the receptor juts outside of the cell, while another section extends inside.

While growth factors latch on to the external portion, they rely on another mechanism to carry their "messages" to the cell nucleus: Tyrosine kinases provide a phosphate plug into the pouch of the portion of the receptor that is inside the cell.

With that in mind, researchers have pursued two tactics to block EGFR. One solution is to develop an antibody that prevents EGFR from making contact with the circulating growth factors that trigger its activation. This is how cetuximab works.

Another solution is to block the pouch part of the receptor on the inside of the cell where tyrosine kinases place their phosphate triggers of activation. This is how erlotinib and gefitinib work.


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