Targeted Therapies Disrupt the Inner Workings of Cancer

By Rabiya S. Tuma, PhD

Gina Nati was diagnosed with metastatic colon cancer in February of 2003. Given the extent of the tumors in her colon and liver, the doctors told her it was unlikely they could operate, so they put her on a combination of 5-fluorouracil, Camptosar® (irinotecan), leucovorin and later Eloxatin® (oxaliplatin). Her tumors remained more or less under control while on these chemotherapy regimens, even shrinking a bit.

A week after the Food and Drug Administration approved Avastin® (bevacizumab) in February 2004 for first-line treatment of metastatic colorectal cancer, Nati’s doctors changed her chemotherapy regimen to include the new agent. After about six months her tumors had decreased in size enough that the doctors opted for surgery to try to completely remove the remaining tumors. Such responses to Avastin-based combinations are what doctors anticipated when developing targeted therapies.

Nati has had two surgeries to remove tumors and has one more to go. “I hope I’m close to going into remission, ” she says. “I have high hopes now.”

Although the of using agents that target particular pathways or molecules has been around for more than 40 years, doctors are witnessing a new era in cancer therapeutics. The increasing knowledge of cancer biology combined with an improved ability to develop agents that inhibit these molecular targets have resulted in an influx of novel targeted agents.

The new agents aren’t perfect, stress the experts, but they offer some advantages, including better disease control, especially when paired with traditional chemotherapies or other targeted drugs. And while the new drugs can potentially cause serious adverse reactions, they are not typically associated with familiar chemotherapy side effects, such as hair loss, nausea and fatigue.

The Advent of Targeted Drugs

In the 1970s, cancer therapy changed dramatically as researchers found they could slow and sometimes halt cancers using chemotherapies that kill rapidly dividing cells, a hallmark of most cancers. Unfortunately such “cytotoxic” drugs do not discriminate between healthy cells and cancerous ones. Targeted therapies, by comparison, are designed primarily to interact with only tumor cells. Over the years, scientists have uncovered specific molecular changes that turn healthy cells into cancerous ones. Targeted agents block or reverse the negative effects of those changes.

Because different types of mutations or cell changes cause different cancers, a targeted therapy must inhibit a specific mutation or pathway. For example, some of the drugs block signals that tell the cell to proliferate and grow, while others work by inducing cell death (see illustration).

The new drugs also come in various forms. Some are small molecules that can fit into the pocket of an enzyme and prohibit its activation much like a broken-off key in a lock prevents an intact key from opening a door. Others are monoclonal antibodies that bind to cell surface receptors and either prevent growth signals from reaching the cancer cells or recruit immune cells to target and kill the cancer cell.

Approved Agents: Hope for New Indications

Avastin—the drug that helped shrink Nati’s tumors to an operable size—and Erbitux® (cetuximab) are monoclonal antibodies that bind to the vascular endothelial growth factor (VEGF) receptor and the epidermal growth factor receptor (EGFR), respectively. They have both been approved for colorectal cancer, but now researchers are looking at other cancers that may respond to the drugs.

When activated, VEGF induces the formation of blood vessels, a process called angiogenesis. As tumors grow, they require additional blood vessels to supply oxygen and nutrients. By blocking angiogenesis, Avastin “starves” the tumor. In spring 2005, two large studies reported that the addition of Avastin to standard chemotherapy improves survival in metastatic breast cancer and advanced non-small cell lung cancer.

“We have been talking about anti-angiogenesis for years, but now it is a clinical reality for treating a number of major cancers,” says Roy Herbst, MD, PhD, chief of thoracic oncology at M.D. Anderson Cancer Center. This new trend is so important that Dr. Herbst describes anti-angiogenesis as the “fourth modality” of cancer therapy, fitting in with surgery, radiation and chemotherapy.

Unlike Avastin, Erbitux works directly on tumor cells by binding to EGFR and preventing the tumor cells from turning on the growth pathways. Researchers liken the drug to lifting up a stuck accelerator pedal in a car. Without the extra gas (or oxygen and nutrients), the car (or tumor) coasts to a halt.

As a supplement to the current indication for advanced colorectal cancer, the FDA is currently reviewing approval of Erbitux for head and neck cancer. In clinical testing, the drug improved two- and three-year survival when combined with radiation for the treatment of locally advanced disease, compared with radiation alone. The drug also improved response rates in metastatic or relapsed head and neck cancer that did not respond to platinum therapy.

The next question for Erbitux will be if it is active in the front-line setting of previously untreated colorectal cancer patients. “A 22 percent response rate as a third- or fourth-line therapy is a pretty high percentage and suggests this could be an active drug in the front line,” says Leonard Saltz, MD, a colorectal cancer specialist at Memorial Sloan-Kettering Cancer Center. “Studies are being done to answer the question, but it will take time.”

In the same receptor family as EGFR is HER2, the target of Herceptin® (trastuzumab). Kristie Naines was 35 when she was diagnosed with stage 3 breast cancer. Her cancer was HER2 positive, which is often associated with a particularly aggressive form of the disease, but one that responds to Herceptin.

The FDA approved Herceptin in 1998 for treatment of metastatic breast cancer in the approximately 20 percent of patients whose tumors overexpress HER2. Edith Perez, MD, a breast cancer specialist at the Mayo Clinic in Jacksonville, Florida, and colleagues immediately designed a three-arm trial to test whether the addition of Herceptin to traditional chemotherapy would prolong disease-free survival in patients with local disease following surgery.

Naines joined that trial in early 2003 following a double mastectomy. In one arm, patients received adjuvant chemotherapy with Taxol® (paclitaxel). In the other two arms, patients received adjuvant chemotherapy with Taxol plus Herceptin, which was given either with Taxol or following four cycles of Taxol. When researchers unveiled a joint analysis of the trial and a similar one in the New England Journal of Medicine in late 2005, both showed overwhelmingly positive results in women who received Herceptin with surgery and standard chemotherapy. The combined study results showed that among patients taking Herceptin, 85.3 percent were alive and free of disease at four years compared with 67.1 percent in the control group. “The results completely exceeded my expectations,” says Dr. Perez.

Naines says she prayed every day that she wouldn’t be in the Taxol-alone arm. “But I also thought that if the study wasn’t in existence I would be getting the traditional chemotherapy anyway,” she says. “And at that time, people really didn’t know if Herceptin made a difference or not.”

Luck was with her, and she was randomized to an arm that had Herceptin. She continues to be disease free and is participating in the follow-up study with Dr. Perez. Because Herceptin has been associated with increased risk of heart problems, patients with a history of heart disease must be carefully monitored while taking the drug. Reports indicate Herceptin will be filed for the additional indication in the adjuvant breast cancer setting in early 2006.

Investigational Agents

Affecting the Immune System

It took Kaete Angel, a realtor from Redding, Connecticut, three years and ultimately a bone marrow biopsy to be properly diagnosed with myelodysplastic syndrome (MDS), a rare cancer of the blood that requires frequent blood transfusions. After an initial diagnosis from her primary care physician in 2002, Angel learned how serious the disease was and scheduled an appointment for a second opinion at Memorial Sloan-Kettering Cancer Center. Angel began receiving blood transfusions almost immediately followed by monthly transfusions for one year. In between transfusions, Angel says life was difficult because of frequent fatigue and shortness of breath.

During the time of Angel’s diagnosis, a French trial of Revlimid® (lenalidomide) for MDS showed favorable results. “My doctor called me and she was so excited,” says Angel, who credits her doctors for getting her on the Revlimid trial. “For over two years, I have been taking this drug and have not had a blood transfusion since October 2003.” With Revlimid, Angel has her energy back and she’s started exercising again. “I can now walk 2 miles a day if I want to and I don’t have to stop and gasp for air.”

Angel is not alone in her positive response to Revlimid. In a single-arm phase II trial involving nearly 150 MDS patients, 64 percent achieved transfusion independence, and more than half of those are still responding to treatment after 58 weeks.

Because Angel participated in the Revlimid trial, she was asked to speak to the FDA’s Oncologic Drugs Advisory Committee in September 2005 about her response to Revlimid. “Before this miracle drug, my life was ruled by how long I could last between needing a transfusion,” Angel told ODAC. In addition to encouraging clinical trial results, the committee ultimately recommended the drug to the FDA, which is currently evaluating Revlimid for treatment of patients like Angel who have low to intermediate-1 risk MDS with a partial deletion of chromosome 5q and who are dependent on blood transfusions to stave off serious anemia. A final approval decision is due by January 2006.

Revlimid also has activity in patients with refractory or relapsed multiple myeloma. According to data from two phase III studies, response rates more than doubled in the Revlimid-dexamethasone arm compared with patients treated with dexamethasone alone. Disease progression also appeared to be delayed in patients in the combination therapy arm.

“I don’t want to overstate the case, but in myeloma patients who do respond to Revlimid, which is about one-third of patients, they can enjoy very durable disease control on the agent,” says Paul Richardson, MD, clinical director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute.

Revlimid directly attacks myeloma by modulating the patient’s immune response to the tumor. Myeloma is a notoriously adaptive disease because it has multiple mechanisms of resistance, says Dr. Richardson, so Revlimid targets not only the tumor but also its environment, making it less hospitable to the cancer cells. The treatment gains of Revlimid do come at a cost, with thrombocytopenia and neutropenia occurring in about half of patients.

Researchers are now testing Revlimid with Velcade® (bortezomib), and “the combination has a manageable side effect profile and the response rate is very promising,” says Dr. Richardson, who has worked extensively with both drugs and leads the phase I combination trial.

Hitting Multiple Targets

Nexavar® (sorafenib) and Sutent® (sunitinib) are tyrosine kinase inhibitors designed to block one or more pathways that promote cell growth. Although similar in a general sense, they each inhibit a different profile of tyrosine kinases, which are enzymes the cell uses to pass on signals. The differences will likely make tyrosine kinase inhibitors more useful in different disease settings or drug combinations.

In early 2005, Ronald Bukowski, MD, director of the Experimental Therapeutics Program at the Cleveland Clinic Taussig Cancer Center, and colleagues reported interim results from a large phase III trial comparing Nexavar to a placebo and best supportive care in patients with relapsed or refractory metastatic kidney cancer. Patients taking Nexavar remained disease free for an average of 12 weeks longer than those on a placebo, doubling the time to disease progression. Updated data released in late 2005 showed a 39 percent improvement in survival for patients receiving Nexavar compared with placebo. Side effects included fatigue, diarrhea, skin rash and hand-foot syndrome.

“This is really the first time in renal cell cancer that we have had a drug that can produce this kind of benefit for patients, especially one that is very easy to take and has a reasonable toxicity profile,” says Dr. Bukowski. FDA approval for Nexavar in kidney cancer is expected by early 2006. Meanwhile, the drug is being tested in previously untreated kidney cancer patients, although it is too early to know the results.

Phase II trials using Sutent to treat relapsed metastatic kidney cancer showed activity. Researchers are also testing Sutent in breast cancer, non-small cell lung cancer and neuroendocrine tumors. It has already shown benefit in patients with gastrointestinal stromal tumors (GIST) who have relapsed or are refractory to Gleevec® (imatinib). The FDA is currently reviewing Sutent for approval in GIST and kidney cancer. The agency will make a decision by early 2006.

Numerous combinations are being developed using Sutent or Nexavar with standard chemotherapy or other targeted agents, such as Avastin, which itself has shown activity in kidney cancer.

A Dual Inhibitor

HER2, one of many growth factors on cancer cells, is part of the same receptor family as EGFR. One of the normal functions of HER2 is to bind to other cancer cell receptors. “It’s thought that the normal function of HER2 is to bind proteins like EGFR and control the normal growth and differentiation of the cell,” says Harold Burstein, MD, PhD, an assistant professor of medicine at Harvard Medical School. “In HER2-positive breast cancers, these proteins are deranged, or abnormal. The thinking is that by going after two pieces of this abnormal growth pathway, you might accomplish more than by just going after one half of it.”

A new oral drug called Tykerb® (lapatinib) inhibits both HER2 and EGFR. While it is being tested in a variety of tumor types, Dr. Burstein says the new agent has shown the most promise in HER2-positive breast cancer. Researchers still don’t know if the drug is going to be a clinical improvement over Herceptin therapy, but trials testing Tykerb alone and in combination with Herceptin offer an early hint at the answer.

A phase I trial of heavily pretreated HER2-positive metastatic breast cancer patients given Tykerb plus Herceptin resulted in six of 27 patients having their tumors shrink by at least 30 percent, while an additional 10 patients had stable disease. A phase II study with a planned enrollment of 130 patients will test Tykerb alone as first-line therapy in HER2-positive locally advanced or metastatic breast cancer. Early results presented at the 2005 San Antonio Breast Cancer Symposium reported that of the first 40 patients to receive treatment, 14 had their tumors shrink by at least 30 percent and another 14 had stable disease. “These results argue that the drug has substantial activity,” says Dr. Burstein. “It doesn’t say it’s better than Herceptin, but it definitely has activity.”

Given the important role of EGFR in a variety of solid tumors, Dr. Burstein says, “Where it’s going to shake out for lapatinib is whether there’s activity just in breast cancer or whether it will have a wider spectrum of activity in tumors like colon or lung.”

Side effects of Tykerb include itching, rash and diarrhea. Early estimates indicate Tykerb will be filed for FDA approval in breast cancer in late 2006 or early 2007.

Obstructing the mTOR Pathway

Several signaling pathways are at work within a cell—both normal and abnormal—that regulate its growth and division. Most of these pathways begin at the cell surface with the binding of a growth factor to the receptor. “mTOR (mammalian target of rapamycin) is a protein that is involved several layers down in the cascade in regulating how the cell responds to treatment,” says Dr. Burstein. “This deeper step invites the possibility for a broadly useful target in cancer treatment.”

Rapamycin was found more than 30 years ago in soil bacteria on Easter Island in the South Pacific. Several rapamycin derivatives that inhibit the mTOR protein are undergoing testing in solid tumors and hematological malignancies.

Temsirolimus (CCI-779) showed benefit in phase II trials for breast cancer, kidney cancer, mantle cell lymphoma and glioblastoma multiforme, and it is now in phase III testing. The FDA granted fast-track status to temsirolimus in late 2004 for the potential indication of first-line kidney cancer therapy. The drug’s developer plans to file for approval in kidney cancer in late 2006.

The FDA fast-tracked another mTOR inhibitor called AP23573 for treatment of soft-tissue and bone sarcomas. The intravenous agent is also being studied in breast cancer, prostate cancer and lymphoma. Early data from an ongoing phase II trial in sarcoma patients showed 51 of 188 patients responded to the drug. In addition, the six-month progression-free survival in patients receiving the drug in the first stage of the trial was 22 percent. Early results of a phase I trial using an oral formulation of AP23573 show the drug can be administered safely and has anti-tumor activity.

Everolimus (RAD001) is an oral mTOR inhibitor undergoing testing in endometrial cancer, lung cancer, breast cancer and leukemia. Everolimus had a good safety profile in phase I studies, and phase II trials are now testing the drug’s effectiveness.

Dr. Burstein says testing targeted therapies like mTOR inhibitors requires time to locate the molecular pathways critical for the tumor cell’s survival. “We check that the biology is relevant to the particular tumor and then find anti-tumor therapies that are likely to be helpful. That’s ultimately a higher yield than trying to go after all tumors with relatively focused drugs.” Side effects of mTOR inhibitors can include fatigue, rash and mucositis.

When and How to Use Targeted Therapies

Identifying active agents is only part of the task in front of cancer researchers. The other part is deciphering when and how best to use the drugs.

An important illustration of that comes from the use of Avastin in metastatic breast cancer. The first phase III trial testing the drug was in women whose disease had already progressed on several chemotherapy regimens. In that trial, the addition of Avastin did not prolong disease-free survival or overall survival. By contrast, more recent results in newly diagnosed metastatic breast cancer patients demonstrate significant benefit from the drug.

Experts emphasize that finding such limitations is just part of the process of using targeted therapies. As cancers progress, they tend to accumulate more and more mutations. That means a therapy that induced a response or regression at one time may not later, which is the crux of the problem with drug resistance. Dr. Richardson points out, however, that although drug resistance can be a problem with targeted therapies, just like it is with traditional therapies, the dilemma seems to be a bit different. For one thing, doctors are finding that a patient who no longer responds to a drug in one combination might respond to it in another one.

“This is a new way of thinking in tumor biology,” says Dr. Richardson. “Traditionally we have always been taught that if a patient has received a drug and progressed on it, under no circumstances should you revisit the drug.” That dogma is changing with the advent of targeted therapies.

The list of targeted agents is impressive, and more are in various stages of development from early laboratory studies to clinical trials. The catch, however, is that while many improve patient outcomes, most of them haven’t lived up to the original promise of targeted therapies: standard chemotherapy replacements with less toxicity. “ ‘Targeted therapies’ is a popular buzzword and it sounds so great,” says Dr. Saltz. Patients are better off with the targeted agents than without them, but he emphasizes, “We really need to keep our efforts going to come up with something better.”

[Editor’s note: At the time of publication, numerous drugs discussed in this article were pending approval by the FDA. Nexavar was approved on Dec. 20 for advanced kidney cancer. Revlimid was approved on Dec. 28 for low to intermediate-1 risk MDS with a partial deletion of chromosome 5q and who are dependent on blood transfusions. Sutent was approved on Jan. 26 for both advanced kidney cancer and GIST.]