NEWS

Combinations of Targeted Therapies Take Aim at Multiple Pathways

Bruce Goldman

First in a two-part series.

Novel targeted agents—compounds designed to hit either a single pathway or, in some cases, multiple pathways that control a cancer cell’s ability to grow and escape conventional therapy—are raising hopes that cancer can be treated with more precision and fewer side effects than has been possible with more conventional cytotoxic drugs.

However, "targeted" is a relative term. The old-line cytotoxics are "targeted," too. But their targets are, metaphorically speaking, the broad side of a barn; for instance, the drugs may target DNA in rapidly dividing cells, transformed and healthy alike. In contrast, targeted therapies are designed to preferentially destroy cancer cells by keying in on abnormalities essential to those cells’ survival and proliferation, thus shrinking tumors while sparing normal cells.

Cytotoxic drugs have been tested and used in various combinations for decades. So why not try it with the new ones? The rationale is simple enough. You increase your chances of truly eradicating disease when you catch tumors in the crossfire of two (or more) pathway-inhibiting agents. Different specificities mean, one hopes, non-overlapping toxicities. If it has been established preclinically that there is no overlap in side effects, then it is reasonable to assume that two such agents can be combined in clinical trials without reaping some unexpected cluster of severe adverse events. Several trials have found that combining targeted therapies can be successful, but there is no guarantee that they always will be. It is also a challenge to prove that both drugs in a combination contributed to a favorable result. In fact, from a feasibility standpoint, just setting up a trial combining two targeted therapies when both are still in development can be a tall order.

Many Approved Therapies

The growing list of already-approved targeted drugs includes small molecules such as Novartis’s Gleevec (imatinib mesylate) for chronic myeloid leukemia (CML), AstraZeneca’s Iressa (gefitinib) for lung cancer, and Millennium Pharmaceuticals’ Velcade (bortezumib) for multiple myeloma, as well as monoclonal antibodies such as Genentech’s Herceptin (trastuzumab) for breast cancer, and IDEC Pharmaceuticals’ Rituxan (rituximab) and ILEX Pharmaceuticals’ Campath (alemtuzumab) for lymphoma. Many more are in clinical trials.



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Several targeted drugs have been approved in the last few years, including Gleevec, Iressa, and Velcade. Although the drugs received approval as single agents, several clinical trials in progress are looking at whether the drugs prove more effective when used in combination. Gleevec is narrowly targeted to the defining abnormality of specific cancers; Iressa is targeted to a growth receptor important to the proliferation of cancer cells. Velcade targets an organelle common to all cells but especially crucial to the function of cancer cells. (Images top to bottom courtesy of Novartis, AstraZeneca, and Millennium Pharmaceuticals.)

 
None of these new agents are cookie-cutter cures. Even monoclonals—often thought of as exquisitely targeted—can cause trouble if the targets they are aimed at are also found in healthy tissue. For example, Genentech’s Herceptin, directed at HER2—a member of a class of growth hormones that is overexpressed in some breast cancers—has on occasion caused cardiac toxicity, apparently because the receptor it targets has an important function in maintaining heart-muscle elasticity and pumping strength.

The poster product of targeted therapy is Gleevec, a small molecule precisely targeted to the defining abnormality of CML, the so-called Bcr/Abl fusion protein. Yet at high doses, there are side effects. Gleevec has efficacy limits, too. Major cytogenetic responses (significant drops in the percentage of chromosomes harboring the defining Bcr/Abl translocation) in newly diagnosed patients are initially around 75%. But molecular responses, as monitored by a much more sensitive PCR assay, are less than 5%, noted Brian Druker, M.D., Howard Hughes Medical Investigator at the Oregon Health and Science University Cancer Institute, Portland. Whereas the relapse rate at 18 months is only 3% for patients with chronic phase disease, Druker said, it is as high as 50% to 80% at 1 and 2 years, respectively, among patients with advanced disease.

So not even Gleevec has been fully successful in eradicating cancer all by itself. "It’s somewhat naïve to think that a cancer cell will roll over and die if one single pathway is affected," said David Schenkein, M.D., vice president for clinical oncology at Millennium. Indeed, cancer cells may have recourse to multiple pathways for sustaining every facet of tumor development: growth, proliferation, metastasis, and evolution of resistance to immune detection.



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Dr. David Schenkein

 
Combination Trials

Several combination trials of U.S. Food and Drug Administration-approved targeted therapies are in progress. Carlos Arteaga, M.D., director of the breast cancer program at the Vanderbilt-Ingram Cancer Center, Nashville, Tenn., is principal investigator on a 120-patient phase II trial of a Herceptin–Iressa combination for women with HER2–positive breast cancer. German researchers have been reporting encouraging results in early clinical trials of a combination of the monoclonal antibodies Rituxan and Campath, which are directed at two different B-cell surface antigens that are co-expressed in a substantial number of patients with lymphoma.

"We’re participating—and many other companies and academics are participating now—in both preclinical and clinical experiments combining two novel agents," said Schenkein. "Over the next 12 to 24 months, we’ll see a wave of results come out along these lines."

Targeted agent combinations are fine—if they work. A clear preclinical rationale, including solid safety data, and methodical early-phase trials are essential.

What’s more, you have to be able to prove they work. "The biggest problem," said Druker, "is designing a trial that will let you determine whether a combination has any benefits over either of the single agents. The way to do that, optimally, would be to do a randomized trial of a single agent versus the combination. But before you’d run a randomized trial like that, you want to get a hint of whether or not the combination has activity over a single agent."

One such hint came about when Druker met Zihai Li, M.D., Ph.D., a researcher at the University of Connecticut’s Center for Immunotherapy of Cancer and Infectious Diseases. Druker was impressed by data from a pilot study of a vaccine being developed by Antigenics Inc. that employs heat-shock proteins (HSPs). In Li’s pilot study, eight CML patients resistant to Gleevec received a course of several injections of the vaccine, AG-858, which is composed of HSPs extracted from their own leukemic cells. Seven patients showed cytogenetic improvement, and two tested negative for leukemic DNA in a PCR assay, indicating that the Bcr/Abl-positive cells had been eliminated from their blood.

"I’d already been thinking for some time about an immune-based approach," Druker said. He concluded that a trial combining Gleevec with AG-858 would be "an excellent setting for testing such an approach, because you’d be getting people at minimal residual disease," when immune-based therapy is most likely to work. So he signed on as principal investigator for a now up-and-running multicenter phase II Gleevec/AG-858 trial in which 60 to 120 patients with sub-optimal responses to Gleevec will receive several weekly injections of AG-858 and will be assessed for cytogenetic improvement.

"From historical controls we know that the likelihood of having improved responses with longer-term exposure to Gleevec is relatively low," said Druker. "So if we do see a response, we have a pretty good idea that it’s the vaccine doing the work, rather than longer-term exposure to Gleevec." Recruiting is going well, he added. "As far as I can see, there’s no downside to participating in the study. You stay on your stable dose of Gleevec and you get the vaccine, which has been extremely well tolerated." Results are expected sometime next year.

The Gleevec/AG-858 clinical trials were possible only because Gleevec is already approved, so it can be obtained for such uses without the express consent of Novartis. Antigenics, which has a similar HSP-based vaccine in late-phase trials as a single agent in renalcell carcinoma and advanced metastatic melanoma, is also looking to combine its investigational therapy with antiangiogenic and immunotolerance-inhibiting agents in new trials. This will not be easy, though, because the drugs in these categories are all still investigational, too.

"As the new-generation targeted therapeutics become available in the marketplace—for any indication—so you can get your hands on them, there is going to be a proliferation of activity with combinations that were never possible before," said Garo Armen, Ph.D., CEO of Antigenics.

In the next issue: When an investigator wants to combine two not-yet-approved drugs, especially if the two are owned by different companies, setting up the trial can be difficult.


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