Personalized medicine benefits patients in early trials

Matching targeted therapies with gene mutations is associated with better outcomes, even in phase 1 studies


  • Carrie Printz

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As more and more targeted cancer therapies are being developed, patients are beginning to experience their benefits, even in early phase 1 clinical trials. Although phase 1 trials typically are reserved for testing the safety and toxicity of new drugs, researchers at The University of Texas MD Anderson Cancer Center in Houston were recently able to demonstrate additional results. Specifically, they found that matching targeted therapies with certain gene mutations in patients was associated with higher rates of response, survival, and failure-free survival than in nonmatched patients.

The study's principal investigator, Apostolia-Maria Tsimberidou, MD, PhD, and colleagues analyzed 1444 patients with advanced cancer who had received a median of 4 prior treatments. One or more gene alterations were identified in 460 patients in genes such as phosphoinositide-3-kinase, catalytic, alpha (PIK3CA); mammalian target of rapamycin (mTOR); BRAF; MEK; KIT; epidermal growth factor receptor (EGFR); and RET. For 175 patients with 1 aberration, the response rate was 27% with matched targeted therapy. In 116 patients treated with nonmatched therapy, the response rate was 5%. The median survival for patients treated with matched therapy was 13 months, compared with 9 months for patients who did not receive matched therapy. However, the researchers note that these preliminary results need further confirmatory, prospective studies.

A “Changing Landscape”

“Many patients don't derive direct benefit from phase 1 studies,” says Gary Lyman, MD, MPH, director of the comparative effectiveness and outcomes research program in oncology at Duke University in Durham, North Carolina. “This group has demonstrated to some extent that the picture is different with phase 1 studies of targeted therapies.” In phase 1 studies of targeted therapies, patients with particular alterations are selected, so they have a better chance of responding to the drug—although it is not always guaranteed to work, he adds.

Dr. Tsimberidou conducted further follow-up studies, including one that was published this past February that demonstrated that phase 1 trials of primarily targeted agents demonstrated low rates of toxicity and a 0.4% percent rate of death.1 “What they're showing is that for targeted therapies, the whole landscape has changed,” Dr. Lyman says. “You no longer have to tell patients, ‘You have a 5% chance of benefitting from a phase 1 study.’ ”

Instead, patients' chances with targeted therapies are already substantially better, because physicians know that their tumor cells contain the specific alteration that the drugs are targeting. At the same time, experts agree that the drug development process (from animals to early human studies to phase 3 trials) is being compressed due to this new ability to select the right patients for targeted studies. Instead of taking decades, the process likely will occur much more rapidly, says Dr. Lyman. “It's also much easier for patients to agree to go on a study and for physicians to recommend it when the numbers look better,” he says, adding that the majority of targeted therapies are most likely to work in combination with conventional therapies.

One example of a drug that quickly came to development was the anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor crizotinib, which demonstrated tremendous response in patients with advanced, ALKpositive nonsmall cell lung cancer, according to Pasi Jannë, MD, PhD, associate professor of medicine at the Dana- Farber Cancer Institute in Boston, Massachusetts. “Based on those responses, multiple other trials were initiated, and it was approved in a matter of years after starting phase 1,” he says.

Quicker to Trial

At Dana-Farber and other major cancer centers across the country, many patients now undergo genetic testing through their phase 1 clinical program and are enrolled in clinical trials based on their specific genetic subtypes. MD Anderson has launched an ambitious program to test many patients through its Institute for Personalized Cancer Therapy. Its goal over the next 5 years is to characterize the tumors and genomes of all patients who come to the cancer center. “It's both a challenge and an opportunity, as we see more than 30,000 new patients a year,” says Gordon Mills, MD, PhD, codirector of the institute.

At press time, scientists were testing tumors from more than 200 patients per month, and that number was expected to increase. Dr. Mills says that the center tests tumors for all events that are likely to be “actionable,” which means that the information they obtain would enable physicians to advise patients on changing their care to targeted therapies. “We will be testing for all genetic events for which there are drugs that are currently available, in clinical trials or in preclinical development,” he says, adding that the center already has tested more than 4000 patients.

Based on genetic testing results, some patients will be directed to standard-of-care personalized therapy (such as those individuals with human epidermal growth factor receptor 2 [HER2]-positive and estrogen receptor-positive breast cancers), whereas others will have 3 options:

  • 1)A clinical trial of a drug that is designed to target their specific molecular abnormality.
  • 2)A clinical trial of a drug that treats an abnormality in a signaling pathway (patients are not required to have the abnormality to participate in the trial).
  • 3)A more in-depth analysis of tumors in patients (approximately one-half of all patients) in whom an abnormality is not found through standard clinical testing.

Currently, the clinical laboratory analyzes the most important abnormalities in approximately 46 different genes. Conversely, the exploratory laboratory examines a full-length sequence of 200 genes with the goal of finding an abnormality that was not detected in the clinical laboratory. Researchers also are studying changes in copy number and the amount of DNA that is present. Soon, they also will be searching for gene rearrangements.

Findings are communicated to patients, who are then given the option of enrolling in a trial that targets the abnormality. These trials are generally phase 1 and phase 2 studies. Researchers also currently are evaluating the cost-effectiveness of such efforts. If cure rates are reduced even slightly, the medical system will experience enormous savings, says Dr. Mills.

The pilot program at MD Anderson, which began in March 2012, focuses on patients with cancers of the breast and colon, but leaders are anticipating adding most of the common disease sites by January 2013. “Our goal is to improve outcomes and more rapidly accrue to clinical trials, as well as see how often certain mutations occur across disease sites and how often there are co-mutations,” says Funda Meric-Bernstam, MD, medical director of the institute and breast disease section editor for Cancer.

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What they're showing is that for targeted therapies, the whole landscape has changed. You no longer have to tell patients, ‘You have a 5% chance of benefitting from a phase 1 study.’—Gary Lyman, MD, MPH

Previously, patients whose cancers were progressing were only tested when they were about to be enrolled in a trial, and the testing would take another 3 to 4 weeks to complete. If they were found to be ineligible, they would then have to be tested for another biomarker. Patients are now tested for multiple genomic alterations at once, says Dr. Meric-Bernstam. “We get a snapshot of the patient's molecular profile so we know early in the game which trials they are eligible for,” she says.

Ultimately, the hope is to be able to increasingly treat newly diagnosed patients at earlier stages in their disease, but that will take time, further research, and more available and effective drugs, she adds. “It's very challenging because there is a lot we don't know. It only matters [when] you do genotyping if you have a drug that works. Also, we're trying to figure out which of the abnormalities are relevant to the cancer.”