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ASCO Launches Trial to Study Benefit of Off-Label Cancer Rx for Advanced Patients Using Genomic Info

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CHICAGO – The American Society of Clinical Oncology is launching a trial through which doctors and researchers can collect real-world safety and efficacy data when off-label drugs are prescribed based on the genomic characteristics of advanced cancer patients who are out of treatment options.

New marketed precision medicine drugs are indicated for smaller and smaller subsets of patients. For example, HER2 targeted breast cancer therapies are intended for one in five patients whose tumors overexpress the HER2 protein. And ALK inhibitors are approved for around 5 percent of non-small cell lung cancer patients who harbor ALK rearrangements, and there is data showing that these drugs may also work for the 1 percent of patients with ROS1 fusions.

Given the rarity of genetic biomarkers associated with drug response, it has been challenging for the oncology field to quickly translate gene-drug associations into new marketed drugs and indications. Although studies have shown that between 30 percent and 80 percent of advanced solid tumors are characterized by potentially druggable genomic markers, there is often scant evidence demonstrating that patients would actually benefit from drugs administered based on these markers.

"It's increasingly difficult to do clinical trials in these rare subsets of patients, simply because they are rare, and it's difficult to find enough patients to actually open a trial," Richard Schilsky, ASCO chief medical officer, said at ASCO's annual meeting today discussing the project. Schilsky, who led the planning of the Targeted Agent and Profiling Utilization Registry (TAPUR), noted that with the study ASCO is hoping to increase patients' access to drugs when they lack standard treatment options with the help of genomic testing.

In TAPUR, ASCO plans to enroll cohorts of advanced cancer patients with different types of solid tumors, multiple myeloma, or B-cell non-Hodgkin lymphoma, and prescribe them drugs based on genomic markers that target them or markers that can predict which patients are likely to benefit from treatment. ASCO estimates that between 40 percent and 70 percent of the time genomic tumor profiling pinpoints a drug that has been shown in the literature to potentially target a genomic alteration in a patient's tumor.

A recent report by the Tufts Center for the Study of Drug Development noted that the proportion of marketed drugs with pharmacogenomic information in their labels grew from 10 percent in 2010 to 13 percent today. So, chances are that such testing will identify off-label treatment options.

After genomic testing suggests an off-label drug might benefit a patient, "the question that the doctor and patient then face is, 'How do I get the drug?'" Schilsky said. Patients could try to enroll in a traditional drug trial, but only around 3 percent of cancer patients participate in clinical trials. A study may not even be an option for many patients since trials enrolling participants with really rare genetic abnormalities are expensive.

Given the high price tag of targeted agents, payors also don't usually pay for drugs prescribed off-label without evidence of their efficacy. "There's lots of phone calls being made to insurance companies and pharmaceutical companies, begging and pleading for the drug," Schilsky said. "Even if the patient can receive the drug, we have no mechanism right now to learn from the experience of patients, how they did, whether they responded or not, had side effects or not. "

To get around these difficulties, researchers participating in TAPUR will record the patients' responses to the off-label drugs they receive (objective tumor response, duration of treatment, and progression-free and overall survival) and the toxicities they experienced. This information will be prospectively stored in a registry that ASCO is planning to launch.

Doctors can order tests from labs that are CLIA certified and accredited by the New York Department of Health and College of American Pathologists. Another TAPUR registry will record the genomic tests physicians use to guide treatment decisions.

Also, the study will have a "generous" enrollment criteria, to ensure patients with different types of cancer situations can participate in the study. ASCO has also partnered with five drug firms (AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, and Pfizer) that will provide drugs for the trial for free. So far, drug partners have agreed to provide 13 drugs that target more than 15 unique genomic variants for the study. Although patients will not have to pay for the drugs they are prescribed through TAPUR, ASCO expects that the patients' insurers will pick up the tab for routine clinical care costs.

A molecular tumor board will consider drug/target combinations and suggest which ones to include in the trial for doctors to prescribe. The trial will have groups based on a particular tumor type, variant, and drug, and researchers hope to enroll eight patients per group. If there is at least one response, then another 16 patients will be enrolled. If there are five or more responses in a group then that tumor type-variant-drug arm will be further studied.

ASCO has also formed a data and safety monitoring board that will track patients' adverse events to determine when enrollment should be stopped for a cohort. If there are no responses in a group, then researchers will stop studying that arm. If a patient has a molecular profile that doesn't fit with any group in TAPUR, the physician could discuss the case with the tumor board for additional guidance. ASCO is planning to publish the findings from TAPUR, and hopes that pharma companies will inform development programs based on the signals seen in the project.

The association will submit its study protocol to a central institutional review board in July, and begin enrolling patients in the fourth quarter. So far, the study sites that have signed on to participate in TAPUR include the Michigan Cancer Research Consortium, the Cancer Research Consortium of West Michigan, and the Carolinas Healthcare System. However, ASCO plans to expand TAPUR on a national scale and will involve community-based programs, where the majority of people get treated, and help community oncologists interpret genomic tests. Patient advocate Jane Perlmutter will lead efforts to recruit and educate other advocates for the study.

Syapse will automate the process for capturing patient data from the EMRs of participating practices using its Precision Medicine Platform, and the molecular tumor board will have access to Illumina's NextBio knowledge base platform for its case review work.

Another technology firm SAP is working with ASCO to develop and launch the first version of its health IT platform CancerLinQ, slated for launch this fall. ASCO is hoping to make CancerLinQ the platform that oncologists in the US will use to harness patients' real-world data, including patients' molecular information, and guide personalized cancer treatment decisions and inform research. 

The association unveiled the platform at the annual meeting and announced that 12 oncology practices in the US have agreed to use the first version, which will draw around 500,000 deidentified patient records from the EMRs at these practices and involve some 350 physicians.

However, TAPUR and CancerLinQ are distinct projects. "Our goal for CancerLinQ is for it to be fully integrated into the practices of our members and others nationwide. And until that day comes, we think there is a pressing need to learn what's happening with molecularly targeted treatments in every day practice right now," Memorial Sloan Kettering Cancer Center's Clifford Hudis said at the meeting. "We still have a lot of work to do and progress to make in the meantime ... [but] TAPUR is a microcosm of what CancerLinQ hopes to become."

ASCO is also sharing data from TAPUR with the Netherlands Center for Personalized Cancer Treatment, a group conducting a similar trial. There are now a number of trials like TAPUR where government researchers, pharmaceutical companies, and diagnostic firms are looking at cancer patients' outcomes when drug prescribing is guided by genomic information.

The US Government has launched several precision cancer medicine trials, such as NCI-MATCH, which will begin enrolling patients in July (see related story). Drugmakers, such as Genentech and Novartis, have also launched their own efforts to look at drug activity according to molecular tumor markers.

Foundation Medicine reported at the meeting results from a study where researchers genomically profiled more than 300 metastatic cancer patients with its next-generaiton sequencing FoundationOne test. Using this approach, 95 percent of patients had one or more clinically targetable genomic alterations. Among the 110 patients who were given a pathway-matched therapy, median overall survival was 10.8 months, compared to 7.5 months for the 65 patients who received a non-matched therapy. 

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