Patricia Lorusso, DO
Less than a decade after the FDA set the ground rules for developing assays that pair molecular targets with new drugs, experts say there have been strides in personalizing anticancer therapies but that many hurdles remain before next-generation sequencing and other precision medicine advances are incorporated into the diagnostic paradigm.
As it stands now, FDA-approved companion diagnostics that stratify patients for particular therapies based on a molecular marker have been the path to targeted therapy drug approvals and a mechanism that helps ensure reimbursement from payers.
Amid a competitive drug development market and technological advances, however, experts throughout the oncology field—including FDA officials—are wondering aloud about how to take the next step from the “one drug, one test” model and embrace emerging diagnostics that offer more information about tumors.
“Today, it seems as though ‘per drug’ testing is rapidly becoming impractical, as multiple development efforts converge on the same targets, and multiple targets are recognized within a disease entity that was previously not easily subclassiï¬ed on a molecular basis,” according to Elizabeth A. Mansfield, PhD, who is the deputy director of personalized medicine in the Office of In Vitro Diagnostics and Radiological Health, which is part of the FDA’s Center for Devices and Radiological Health (CDRH).1
Mansfield noted that multiplex testing, which provides information on more than one molecular marker, and the use of gene expression signatures as biomarkers may help solve the immediate problem of having to conduct multiple genetic tests on the same patient sample. She said the FDA would be flexible in evaluating new approaches.
Looking forward, Mansfield cited the development of next-generation sequencing technologies, which she defines as high-throughput DNA or nucleic acid sequencing, as particularly promising. However, she said the detection of rare mutations of unknown significance through sequencing remains an unresolved scientific question that would complicate the use of such diagnostics.
Even as the recently announced US government initiative and innovative precision medicine oncology clinical trials propel personalized medicine in cancer care forward, leading researchers and pharmaceutical industry observers expect a long road ahead in diagnostics.
“I do believe personalized medicine is still in its infancy,” Patricia M. LoRusso, DO, a professor of medicine and associate director of Innovative Medicine at Yale Cancer Center, said in an interview with OncologyLive
The Current Landscape
As a therapeutic class, oncology leads the way in the development of personalized medicine. Approximately 36% of the nearly 140 approved products with pharmacogenomic information on the labels are for oncology or hematology medicines, according to the FDA.2
These biomarkers include germline or somatic gene variants, protein biomarkers used to select patients for therapies, and chromosomal abnormalities.
There also are several gene signature tests and sequencing assays that have been incorporated into treatment guidelines in evaluating patients for breast and ovarian cancers.
When it comes to pairing a particular drug with molecularly targeted therapies, however, there are specifically approved in vitro companion diagnostics, which the FDA defines as a “device that provides information that is essential for the safe and effective use of a corresponding therapeutic product.”3
Currently, the FDA has approved companion diagnostics for 15 anticancer drugs and one supportive care agent sometimes used for patients with myelodysplastic syndromes (Table)
. Those numbers are likely to increase markedly in the coming years, according to Joshua P. Cohen, PhD, a research associate professor at the Tufts Center for the Study of Drug Development in Boston.
Cohen said several dozen companion diagnostics are being developed in phase I and phase II oncology clinical trials, and that he expects 50% to 60% of newly approved cancer drugs to have a companion diagnostic within the next five years.
“There’s plenty of failure in any drug development process, so you’re not going to hear about those several dozen diagnostics nor the therapeutics that are linked to them,” Cohen said in an interview. “You’ll only hear about a few of them that make it through the process.”
Although progress in personalized medicine has not unfolded at the rapid pace once forecast when the human genome was sequenced in 2001, Cohen noted that the biopharmaceutical industry has significantly expanded its spending since 2010.