whole disease.” Furthermore, he adds, it is important to generate evidence because this can help with reimbursement decisions. Insurers do not often pay for targeted therapies that are administered off label, because there is little evidence to suggest that the use of a particular drug leads to improved outcome. TAPUR will address that gap by shedding light on what works and what doesn’t. “If a certain drug for certain targeted therapy is not helpful, we would want to discourage physicians from writing off-label prescriptions,” Schilsky says.

TAPUR, which hopes to begin enrollment at 30 sites across the US this month, is designed to run as a three-year trial. At present, five pharmaceutical companies, including AstraZeneca and Pfizer, have signed up to provide 13 targeted drugs free of charge to trial participants. The hope, Schilsky says, is to enroll roughly 800 people. The study will record changes in tumor growth as part of its evidence-generating process, and use response rate in patients to determine the primary endpoint.

All trial participants will be treated with the targeted drug for 16 weeks initially, at which point researchers will assess their

Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO), have begun to launch large-scale projects to gather data that could enable clinicians and researchers to discern how well targeted therapies work for cancer. One group even hopes to serve as a long-term data-collection operation that could someday unite the other organizations working to generate evidence.

A major problem now is that the medical community as a whole, facing an increase in cancer-genome sequencing and the administration of targeted therapies, has no way of knowing how a given patient tolerated a prescribed treatment, explains Richard Schilsky, ASCO’s chief medical officer. To this end, the ASCO announced plans for Targeted Agent and Profiling Utilization Registry (TAPUR) at its annual conference in Chicago last June. “The advantage of doing larger-scale studies is to begin to collect information about groups of patients,” Schilsky says. “A published case report is truly an ‘n of 1’ case. There’s variability among case reports when it comes to the amount of data included [and] how representative the case is of the

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Group mentality:Determining if targeted treatments really work for cancerBy Shraddha Chakradhar

Personalized medicine has become a buzz phrase, and all the more so in the cancer field. In 2015, almost one-third of the 45 novel biologics and molecular therapeutics approved by the US Food and Drug Administration (FDA) were personalized-medicine drugs, which treat individuals who have specific biomarkers, such as genetic mutations. And of those 13 personalized, or targeted, therapies, five were for cancer.

But even as targeted therapy becomes commonplace for cancer, there are few large-scale data sets that connect the results of next-generation sequencing (NGS) tests—and the consequent targeted therapy—with patient outcome. Success stories are often isolated anecdotes confined to large academic centers, and there is no centralized database with information that spans multiple cancer types to help scientists to better understand which targeted therapy, if there is one, is most likely to yield a positive clinical outcome. Consequently, although genetic testing can reveal druggable mutations, doctors lack the robust evidence needed to make crucial treatment decisions.

To combat this issue, some major groups, including the American Association for

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tumors for shrinkage or response, known as a signal event. If the study coordinators observe two or more signal events in a cohort of ten people with the same mutation and tumor type who have received the same drug, 18 more patients will be added to the cohort and given the same treatment to see whether the same signal events occur. If, at this point, 25% of the total group responds to the treatment, the drug will be considered useful for those circumstances. “We’ll make this information known to the respective pharmaceutical companies,” Schilsky says. Although the data-sharing policy for TAPUR is still under development, the recorded data will be available to researchers outside TAPUR for secondary research, so that they could potentially delve into the mechanisms underlying a particular finding.

Gathering evidenceIn November, the AACR launched the Project Genomics Evidence Neoplasia Information Exchange (GENIE), a project aimed at collecting de-identified information from seven major cancer centers around the US, with the goal of creating a database that is accessible to researchers worldwide. “The goal of GENIE is to gather the evidence that NGS has clinical utility,” says Charles Sawyers, chair of Project GENIE’s steering committee, “and to create an open-source database that will allow precision medicine to develop more rapidly.” During the initial two-year pilot phase, GENIE will collate information from seven cancer-research centers around the world that already have their own

evidence-gathering databases: Memorial Sloan Kettering Cancer Center in New York; the Dana-Farber Cancer Institute in Boston; the Sidney Kimmel Comprehensive Cancer Center in Baltimore; the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee; the Center for Personalized Cancer Treatment in Utrecht, the Netherlands; the Institut Gustave Roussy in Villejuif, France; and the Princess Margaret Cancer Centre in Toronto.

As with TAPUR, Project GENIE aims to answer questions about the utility of administering personalized medicine to people whose tumors present specific molecular profiles. Unlike TAPUR, which offers treatment as part of its data-collection project, Project GENIE is purely about consolidating information from the seven cancer centers to create a searchable database. Because the seven centers have pre-existing databases, GENIE’s database already contains more than 17,000 records. The project team hopes to populate the database with at least another 50,000 records by the end of the pilot phase in 2017.

GENIE operates by helping researchers to answer specific questions. Researchers can query the database to find out how patients with a specific mutation and tumor type fared on a particular therapy, for instance. A dedicated team at each of the member institutions then pulls up patients’ de-identified records to supply the relevant information; these records include comprehensive mutation data, tumor type, drugs administered and the genetic tests that were performed. The GENIE database is currently accessible only to researchers in the founding group, but scientists outside of it will have access beginning in November 2016.

Researchers could also use information in the GENIE database to generate leads on novel targets or to suggest previously unconsidered therapies for patients with mutations observed in cancer types different than the one a patient has. “We’re certainly going to find out some things that will lead to changes in practice,” Sawyers says. He adds that the GENIE group has already received requests from other US and international institutions to join the project. The main qualification to be a part of the founding group was to have a pre-existing database. “We hope to open it up to others,

however,” he says. Yet another group with similar goals is the

Oncology Research Information Exchange Network (ORIEN), founded jointly in

2014 by the Moffitt Cancer Center in Tampa, Florida, and the Ohio State University’s Comprehensive Cancer Center (OSUCCC). OR I E N , w ho s e network now consists of 11 US-based cancer centers in total, also has a database of mutation, tumor, c l in ica l -

outcome and genetic-testing information from de-identified patient records, which researchers can query for help. In a departure from the approach to TAPUR and AACR, however, ORIEN operates a clinical trial matching service, which is open to patients who are eligible on the basis of their cancer’s molecular profile. In addition, individuals who are no longer receiving treatment at an ORIEN member institution can agree to be contacted about future trials. “We have 130,000 patients who have come on board,” says Michael Caligiuri, a founding member of ORIEN at the OSUCCC. “It’s the single largest database of its kind in the world.”

Whereas those researchers and clinicians at the 11 member institutions have free access to the ORIEN database, non-member institutions, including pharmaceutical companies, can subscribe to a database run by the network’s for-profit arm, operated by

“The key issue is whether these databases can agree on a core set of data sets to enable better data sharing.”

Consortium chief: Dane Dickson, CEO of Med-C.

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Generating evidence: Project GENIE's Charles Sawyers.

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Med-C standard can participate, Dickson thinks that Med-C will capture more number of patients than do groups engaged in similar efforts. Although he declined to specify any names, Dickson says that a handful of the country’s major insurance companies have agreed to pay for such uniform lab testing in order to begin to

populate the registry. Med-C is still largely

in the planning phase. The pilot sites have been identified, according to Dickson, and the consortium is working out how to bring these sites on board. The team hopes to begin collecting data from the first few patients by June 2016 and to expand the cohort by July or August.

In his January announcement of a “moonshot” plan to help to cure cancer, US Vice President Joe Biden said that one focus of his plan is to “break down silos and bring all the cancer fighters together—to

work together, share information and end cancer as we know it.” Creating such databases “is a way to break down these silos to determine whether a therapy is a go or no-go,” Caliguiri says. “It could be that we’d have to merge with say, GENIE, but we don’t know what’s going to prove to be beneficial to patients.”

“No database will ever capture the data on every patient,” Schilsky says. “The key issue is whether these databases can agree on a core set of data sets to enable better data sharing.”

Taken together, these efforts could shed light on which targeted therapies offer the best hope for people who are seeking personalized treatment for cancer. And although results from these studies will not be available for a while, all of these groups think that the collection of such data is vital to achieve the final goal.

“If we’re going to cure cancer, we have to understand what’s happening in its different layers,” Dickson says. “Big data is the only way to find a cure.”

Shraddha Chakradhar is Nature Medicine’s assistant news editor based in Cambridge,

Massachusetts.

Med-C. “So this consortium was created to bring together the different stakeholders.”

Much like the TAPUR study and Project GENIE, Med-C hopes to generate evidence that links mutations and targeted treatment with patient outcomes. Unlike the others, however, Med-C will ensure that the genomic information included in the database is obtained using the same methods. There is no consensus in the genomic-testing space over which panel or sets of panels might be most useful for a patient, Dickson explains. The sensitivity and specificity of genetic tests vary from company to company, and this makes it difficult to figure out the exact nature of a mutation. “Physicians are not equipped to understand the complexity of these data readouts,” he says. Whether a mutation is a point mutation or a translocation, and even a mutation’s allele frequency, can determine whether a targeted therapy will work. Physicians are entirely dependent on what the lab tells them, Dickson explains; even if a particular mutation is not present in all of a person’s tumor cells, physicians will still place the patient on the drug that corresponds to the mutation. This runs the risk of wasting time on a treatment that ultimately had a very low chance of efficacy.

To alleviate confusion, a steering committee will develop a standard algorithm for labs to follow. This method will ensure that all patients who are entered into the Med-C’s database, called the N1 Registry, have been tested using the same protocol. “The participating labs will have to provide tests that have the same sensitivity and specificity as a neighboring lab,” Dickson says. Any discrepancies will be adjusted to ensure uniformity in standards. The hope is that by standardizing testing and recording patient outcomes, Med-C can tease out what information in a lab report is actually clinically relevant for physicians to know. Based on what they find, Med-C hopes to create a system that provides easily understandable genetic testing readouts to clinicians.

Given that any lab willing to follow the

M2Gen, a health-informatics subsidiary of the Moffitt Cancer Center. In one instance, Caligiuri recalls, a research team from Italy approached ORIEN with a case: a small group of patients with multiple myeloma, whom the team had treated with a drug known as lenalidomide, seemed to have a high incidence of subsequent malignancies after treatment. The researchers wanted to know whether this phenomenon had been observed in others treated with lenalidomide, or whether their cohort was exceptional (Blood 124, 413, 2014). “We looked at about 1,200 patients in the ORIEN database and couldn’t confirm this finding,” Caligiuri says. It was a quick way to determine whether there was a large enough trend to warrant further investigation into the drug—and given their finding, he adds “it’s nice for both patients, as well as the makers of the drug, to know that the drug wasn’t the culprit.”

Coalescing coalitionsTo harmonize the different efforts to bring clarity to the targeted cancer–therapy space, a group of scientists, physicians and policy researchers formed the Molecular Evidence Development Consortium (Med-C) in April 2015 as a nonprofit organization, funded by donors that include Genentech, Roche and Eli Lilly. “There wasn’t a place for everyone in personalized medicine to come together under an umbrella to look at the strengths of the individual groups to figure out the best way forward,” says Dane Dickson, CEO of

“There wasn’t a place for everyone in personalized medicine to come together under an umbrella to look at the strengths of the individual groups to figure out the best way forward. So this consortium was created to bring together the different stakeholders.”

Collating results: Richard Schilsky, who is with the TAPUR study.

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