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Clinical Utility of Paradigm's Cancer Sequencing Test Supported in Indiana University Study

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NEW YORK (GenomeWeb) – As cancer sequencing tests continue to gain ground in clinical practice, they still face some hurdles in proving their merit — convincing clinicians and insurers that they are worth the costs involved and that they actually improve patient outcomes compared to clinical decision-making made in their absence.

Results from an independent study by researchers from Indiana University — published in the journal Oncotarget last week — have provided some of this important utility evidence for one of this new breed of tests, Paradigm Diagnostics' PCDx.

The study tracked results from clinical use of the PCDx test by IU's Health Precision Genomics Program from April 2014 to October 2015. Overall, the investigators enrolled 168 patients presenting with metastatic tumors that had progressed on at least one line of standard therapy and sent their samples to Paradigm for analysis.

Of the larger tested cohort, 101 patients had enough clinical follow-up for outcome analysis, half of whom were treated with a genomically directed therapy, and half of whom were not, due to either a lack of an appropriate target, a lack of access to the appropriate drug or clinical trial, or based on a physician's choice not to treat based on the genomic test results.

Looking at the outcomes of these two groups, the researchers calculated that genomically guided therapy (informed by the PCDx test) improved progression-free survival significantly more than therapy not guided by the genomic results.

Launched in 2014, PCDx is a comprehensive targeted NGS test — run on Thermo Fisher Scientific's Ion Torren PGM — which detects cancer-associated alterations in DNA and also analyzes mRNA and protein expression. 

Paradigm's test has a rapid turnaround time of four to five days. The company also said it sequences to a much higher average depth of coverage than some other assays, about 5000x, according to its current parameters.

David Mallery, Paradigm's president and co-founder, told GenomeWeb that IU was an early and enthusiastic adopter of the test, attracted by its comparatively short turnaround time and its broad approach including RNA and protein analyses.

"This was a very much arms-length, IU-driven study where they were able to collect outcomes on their own patients," he said. "We weren’t surprised [by the results.] But we were more pleasantly surprised," he added.

Because of the design of the IU trial — instead of comparing a group of genomically tested patients to a control arm of patients without genomic testing, it looked at outcomes within a cohort where all patients received testing and compared patients who received a genomic therapy versus those who didn't — there remain important questions that the results do not answer.

Namely, the analysis does not speak to whether genomic testing, overall, including the patients for whom it successfully directs therapy and also those for whom it does not successfully direct therapy, offers improved outcomes over care given in the absence of genomic information. 

The results do, however, speak to the promise of genomic analysis when it is successful.

"It certainly would be great to have a randomized controlled trial, but I think what this does speak to is something we have seen in the past. … What it says really is that in advanced cancer, a physician's [non-molecularly informed] drug choice is inferior to [a choice informed by] molecular profiling," David Loesch, Paradigm's medical director of oncology services, told GenomeWeb.

Based on the IU team's report, patients who were sequenced and whose results were acted upon had better outcomes on average than those who either had no actionable genomic results, or who had results that were not acted upon.

To demonstrate this benefit from genomically-guided treatment the IU investigators calculated a ratio of patients' progression-free survival (PFS) after receiving sequencing results relative to the PFS for their prior line of treatment.  Based on this analysis, patients whose post-genomic testing PFS ratio was greater than 1.3, or at least 30 percent longer, were deemed to have a meaningful improvement.

Of the 101 patients that were included in the IU team's final analysis, 19 of 44 (about 43 percent) who were treated with genomically guided therapy attained a ratio greater than or equal to 1.3. In contrast, only 3 of 57 (about 5 percent) of those treated with non-genomically guided therapy had a PFS ratio of 1.3 or more. 

The authors cautioned that because of the structure of the trial, it is possible that the differences in survival could be a result of differences in prognosis rather than a measure of the added value of genomically targeted treatment. There is no way to rule out in this small study the possibility that those patients who didn't have actionable targets simply had a more biologically aggressive or resistant disease and that’s possibly why they had poorer PFS ratios.

However, the findings join an "evolving body of literature that demonstrates superior outcomes for patients who receive genomically guided therapy," the authors wrote.

Not all results from molecularly guided therapy trials have been positive, however.

For example, the SHIVA trial, published last year in The Lancet Oncology— which, unlike the IU study, did randomize patients — found that the use of molecularly targeted agents did not improve progression-free survival compared with a physician's choice of therapy in heavily pretreated patients with cancer.

According to Mallery, Paradigm's more comprehensive approach, coupling targeted DNA sequencing with mRNA and protein expression analyses, could be a factor in the more positive result that the IU investigators achieved.

Other studies utilizing comprehensive genomic analyses like whole-genome and transcriptome sequencing have also shown much clearer added value over standard therapeutic decision making than very simple or limited genomic sequencing tests.

For example, in the British Columbia Cancer Agency's ongoing Personalized OncoGenomics (POG) clinical trial, researchers have been sequencing the whole genomes and transcriptomes of participants with advanced cancer to inform personalized treatment and also comparing the results of more targeted sequencing panels. In an analysis of the first 100 patients in the trial, researchers found that panel results were rarely actionable, and the greater information offered by whole-genome and transcriptome sequencing was necessary to yield meaningful results. Other groups have also had similar findings.

Formed initially as a non-profit, Paradigm is now a for-profit company headquartered in Phoenix, Arizona.

"We are now in our third year of commercial offering," Mallery said. "And we are taking more of a white-label data-sharing approach, where we co-brand with an oncology practice … and help them generate custom reports."

Apart from IU, Mallery said that the company has about five or six large customers with whom it has pursued this "white-label" model. Though he could not provide details on these customers, he said that it is a fairly even mix between academic medical centers and community oncology practices.

Since the company consolidated in Phoenix, it transitioned to a barcoding system that allows it to multiplex 30 patient samples at once. The firm also has seen about 50 percent year-over year growth in test volume in its three years of operation, said Mallery.

Paradigm is following the emerging trends in liquid biopsy cancer testing, according to Mallery, but for the near term, the company feels that "there is still a lot of room for improvement in solid tumors," and so it's main focus is on advancing and refining its current, tissue-based testing approach.

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