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Cancer trials aim to shore up 'precision medicine's' base of evidence

Precision, personalized or individualized medicine: By any name, it's going to take big clinical trials

Officials of the National Cancer Institute joined cancer scientists on Monday to announce the launch of three ambitious clinical trials designed to bolster research undergirding President Obama's precision medicine initiative.

The national trials are expected to help clarify whether and how precision medicine -- also called personalized or individualized medicine -- can improve the diagnosis and treatment of cancer by tailoring therapies to the unique genetic makeup of individual patients and their malignancies. 

The trials are set to begin enrolling participants immediately and over the coming months, although the largest of the three won't start until July. Most of the studies' participants will be cancer patients whose malignancies are in advanced stages and who have been treated with standard therapies that failed to slow or halt their cancer's progress.

In all three trials, genomic sequencing of a participant and his or her malignancy will dictate the choice of medication -- some already in wide use, others still considered experimental. Although their participants' identities are to be strictly protected, the trials will, for the first time, create large and comprehensive registries of patients, their cancer types, the treatments offered and their responses to those treatments.

In oncology practices especially, physicians have already begun to prescribe medications that target the specific genetic mutations seen in patients' malignancies. But Dr. James H. Doroshow, the National Cancer Institute's deputy director, said Monday that those pioneering efforts to save patients are not guided by a solid base of clinical research, and that the responses of those patients are not being systematically collected and analyzed.

Speaking from a meeting of the American Society of Clinical Oncology in Chicago, Doroshow called the biggest of the trials -- the National Cancer Institute's Molecular Analysis for Therapy Choice, or NCI-MATCH for short -- "the largest, most rigorous physician-run oncology trial that's ever been attempted." He expressed hope it would flesh out how physicians can most effectively tailor treatment to the genetic makeup of patients and their cancers.

With a price tag at "around $30 [million] to $40 million," according to Doroshow, the NCI-MATCH trial will enroll as many as 3,000 participants in its first wave starting next month. Starting with 10 separate "arms," or groups of patients getting different therapies, the MATCH trial will enroll adults with advanced solid tumors and lymphomas that are no longer responding, or that never responded, to standard cancer therapies and that have begun to grow.

Researchers will first harvest biopsy specimens of those patients' tumors and send them to one of three certified genetic-testing laboratories. Using genetic-sequencing techniques that only a decade ago cost millions of dollars and took months to perform, those labs will conduct genetic assays on those samples in 14 days or less, looking for over 4,000 commonly seen cancer variants in about 143 genes.

The findings of those assays, in turn, will guide researchers' choices for a patient's subsequent treatment. A wide range of medications -- some newly developed, some that have long been available for other diseases -- will target either the genetic variations that give rise to an individual's cancer (such as the BRCA-1 and BRCA-2 "germline variations" that greatly raise a carrier's lifetime of breast or ovarian cancer) or the genetic mutations observed in the cancerous tissue itself.

By the time the trial is complete, NCI officials expect that 20 to 25 drugs will have been tested as treatments for cancers, each in a different arm of the MATCH trial.

Scientists believe that an approach in which medicines are "matched" to the genetic makeup of the patients they treat and the cancers they attack will change the practice of oncology -- and eventually other medical specialties -- for good.

The location or origin of a malignancy -- breast, prostate, pancreas, lungs -- has long dictated treatment choices for cancer patients. Increasingly, cancer doctors are expected to look to an individual's genetic makeup, as well as the genetic mutations that drive his or her cancer, to drive the choice of medicine.

First, however, they will have to discern which of the many mutations seen in malignancies are bystanders and which are driving the out-of-control growth of cells.

That is among the goals of a second, smaller clinical trial also announced Monday in Chicago. Starting this year, the Targeted Agent and Profile Utilization Registry (TAPUR) is expected to facilitate and track the choice of therapy after a cancer patient has had a genomic analysis performed, and to collect information about outcomes.

A collaboration of the American Society of Clinical Oncology, several genetic testing firms and five pharmaceutical companies, the TAPUR study will enroll cancer patients whose options for further treatment are limited. Prospective participants must have had some genomic testing conducted already. But medications thought to target the genetic signatures of their cancers will be provided, free of charge. From there, TAPUR researchers will record their side effects, response and disease course and create a registry of participant outcomes. 

One of the TAPUR trial's key draws for participants will be its ability to make often prohibitively costly new drugs available to patients whose cancers are deemed likely to respond. Currently, some of the 30 commercially available medications thought to target malignancies' genetic signatures are not FDA-approved for the kinds of cancer they might be used to treat. And insurers have been resistant to paying for some of these drugs in the absence of better evidence they are effective.

"Drugs are being introduced into practice right now with far less information than has ever been had before," said Dr. Richard L. Schilsky, one of TAPUR's principal investigators. "We need to learn how these drugs are being used in the real world community," and how well they work.

Advancing the aims of precision medicine was also the subject of a third experimental study unveiled Monday -- this one to test the potential benefits of a prototype electronic medical record, the CancerLinQ, to track the medical odysseys of cancer patients. The comprehensive electronic document not only tracks standard-care treatments given and genomic testing performed over time, but also flags safety issues and possible next steps in a patient's care.

"At its heart, CancerLinQ is a quality-improvement program," said Dr. Allen S. Lichter. The CancerLinQ Demo project -- undertaken by the American Society of Clinical Oncology's commercial spinoff, the Institute for Quality -- will be introduced this year at 15 oncology practices across the country -- from small private practices to comprehensive cancer centers housed in large academic medical institutions.

All told, the first group of patients expected to have their care tracked by CancerLinQ is expected to number 500,000.

Generating large stores of data will be key to realizing the potential of precision medicine. If researchers are to find better, more targeted treatments for cancer, they will have to flesh out the roles of potentially thousands of relevant gene variants in driving patients' cancers. They must then divine which medications are most likely to attack those cancers along vulnerable links in their progression, and test their effectiveness.

Given the extent of genetic variance seen across cancer patients, it will take huge numbers of trial participants -- and careful maintenance and analysis of their data -- to lead researchers to conclusions about which therapies will work best in individual patients.

Precision medicine? Personalized medicine? Individualized medicine? Whatever you call it, I'm following it. Follow me on Twitter @LATMelissaHealy and "like" Los Angeles Times Science & Health on Facebook.

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