National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
May 17, 2011 • Volume 8 / Number 10

A Closer Look

Combining Targeted Cancer Therapies: Much Promise, Many Hurdles

Scientists at work in a research laboratory Obstacles can prevent researchers from testing combinations of investigational targeted agents in clinical trials

A major advance in the treatment of cancer over the past decade has been the introduction of drugs such as imatinib (Gleevec) that target specific abnormalities in cancer cells. But when these drugs are given as single agents, cancer cells often find ways to overcome their anticancer effects. If cancer-promoting signals from one signaling pathway are blocked, for example, tumors activate another.

Evidence from laboratory studies suggests, however, that using combinations of targeted agents to block multiple pathways simultaneously may prevent or slow the development of drug resistance. In some cases, combinations of two investigational targeted agents have had synergistic antitumor effects, even if one or both drugs showed little or no anticancer activity alone. 

However, major obstacles can prevent researchers from testing combinations of investigational targeted agents in clinical trials. The drug development system in the United States is designed to test single agents; first in trials to assess safety, and then in larger studies to evaluate effectiveness. Only after an agent has been approved by the Food and Drug Administration (FDA) can it be tested in combination with a different investigational agent.

Another set of barriers can occur when researchers want to test two investigational agents that belong to different pharmaceutical companies. A situation like that "raises business, legal, liability, and intellectual property issues so thorny no one wants to touch them," said Dr. Michael Caligiuri, director of the NCI-designated Comprehensive Cancer Center at Ohio State University.

Earlier this month, Dr. Caligiuri hosted the Cancer Drug Development Roundtable that brought together representatives of NCI, the FDA, the pharmaceutical industry, and other cancer organizations to develop recommendations for overcoming obstacles to the co-development of two or more promising investigational anticancer agents. The group's recommendations will be announced later this year.

Drafting Guidance

One concern about the co-development of investigational drugs is that the process will provide less information about the safety and effectiveness of these agents than if each were developed and tested individually, according to Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research.

However, she continued, the benefit of getting more effective drug combinations for patients may outweigh this concern. For this reason, a draft guidance published by the FDA in December 2010 proposes allowing clinical trials of two or more investigational agents for use in combination only when:

  • A compelling biological rationale exists for use of the combination—for example, the agents block different targets in the same molecular pathway, block multiple pathways, or block the target in ways that decrease resistance or permit lower doses to be used, thus minimizing toxicity;
  • Preclinical or preliminary clinical studies suggest that the combination provides greater than additive activity or a more durable response compared with using the agents alone; and
  • A compelling reason argues against development of the agents individually—for example, single-agent therapy would lead to resistance or one or both agents would likely be ineffective on its own.

Adaptive Trial Design

The sheer numbers of new targeted agents that could be used in combination challenge the capacity of the current system for developing drugs, explained several speakers at the multi-agency roundtable. Dr. Eric Rubin, vice president for oncology clinical research at Merck Research Laboratories, estimated that testing every possible combination of 10 new drugs in sequential clinical trials would take about 90 years.

With multiple targets, multiple cancers, and multiple active pathways within tumors, we really need to think about how to design trials efficiently.

—Dr. Janet Woodcock

"We can't keep doing one-off trials of single agents that take years to complete," said Dr. Woodcock. "With multiple targets, multiple cancers, and multiple active pathways within tumors, we really need to think about how to design trials efficiently."

Dr. Rubin cited two recent trials as models of the type of "adaptive" trial design needed to address these complexities. In the BATTLE trial, tumor samples from patients with non-small cell lung cancer were tested for specific biomarkers; based on that analysis, the patients were enrolled into one of the trial's four treatment arms, each of which tested a different targeted therapy.

Another trial, called I-SPY2, is using biomarkers to identify women with early-stage breast cancer who might benefit from new investigational drugs that are given along with standard chemotherapy prior to surgery. Participants in that trial have a high risk of recurrence as determined by factors such as estrogen receptor and HER2 status.

Model Agreement

A template developed by NCI's Cancer Therapy Evaluation Program (CTEP) may serve as a model for resolving the intellectual property concerns that often hinder co-development of investigational targeted agents owned by different pharmaceutical companies, said Dr. James H. Doroshow, director of NCI's Division of Cancer Treatment and Diagnosis (DCTD), which oversees CTEP.

Under the CTEP model agreement, all collaborators receive fully paid, nonexclusive, royalty-free licenses to any intellectual property that emerges from combination drug studies. NCI currently holds such collaborative development agreements with more than 80 industry partners for more than 100 investigational agents. CTEP has recently proposed extending such agreements to biomarker studies.

Eleanor Mayfield

Addressing the Scientific Challenges of Co-Developing Targeted Agents

NCI is creating resources for the research community to address some of the scientific challenges to developing combination targeted therapies.

Until now, for example, there haven't been any standardized assays for assessing the clinical effects of targeted therapies. NCI is currently developing more than 50 assays for evaluating the mechanisms of action of molecularly targeted agents. Once validated, these assays will be made available to the research community at no charge.

NCI has also developed "combo plates" specially formatted for researchers to use in testing new compounds in combination with commercially available anticancer drugs. A plated set of about 100 FDA-approved oncology drugs is now available without charge to the research community. Information about this resource and how to obtain it can be found on the DCTD Developmental Therapeutics Program Web site.

Until recently, Dr. Doroshow said, the Department of Health and Human Services' Office of General Counsel prohibited NCI from purchasing or synthesizing patented agents for research purposes. But that policy changed in 2009, and NCI has acquired more than 300 investigational agents for in vitro testing. A program is being established to allow investigators to submit requests for in vitro studies of the effects of specific combinations of investigational agents.

NCI scientists are also modeling estimates of the effectiveness of combining investigational and approved agents in a variety of concentrations across the institute's Human Tumor Cell Line Screen, which includes 60 human cancer cell lines and is used to screen potential anticancer compounds. These data will be publicly available within a year. The most promising combinations will then be studied in animal models to identify those that should progress to clinical trials.