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Pfizer, Samsung Research Group Details Second Gene Fusion Assay on Nanostring Platform

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A Pfizer research group, working with Seoul's Samsung Medical Center, has published a study demonstrating a multiplex method for detecting ALK, ROS1, and RET fusions in a single assay.

According to the group — which published a description of the method and its performance in the Journal of Molecular Diagnostics this month — the multi-fusion assay shows promise "as a more practical and cost-effective screening modality for detecting rare but targetable fusions in NSCLC."

The team — previously led by Pfizer's Mao Mao, who is now a senior vice president with a Chinese contract research organization — has been conducting research for several years on diagnostic methods for ALK fusions and other pharmacogenomic alterations in non-small cell lung cancer.

Pfizer's Xalkori (crizotinib) was approved by the US Food and Drug Administration in 2011 for patients confirmed to carry ALK fusions with a fluorescence in situ hybridization companion test developed by Abbott Molecular.

Though Abbott's FISH assay is the only FDA-approved companion diagnostic for Xalkori, issues have been raised in regard to the suitability of FISH as a method for widespread screening of the NSCLC population to identify those with ALK, or other mutations.

A 2012 study by University of Colorado researchers published in the British Journal of Cancer found, for example, that broadly testing all advanced NSCLC patients in order to identify the small subset of ALK-positive individuals who should be treated with Xalkori did not meet a cost-effectiveness bar of less than $100,000 per quality-adjusted life year gained. The researchers found that oncologists could decrease the cost per QALY gained to around $4,756 by applying an enrichment strategy, but that such an approach would miss some ALK-positive patients.

Other research has suggested that FISH may miss some rare ALK fusions that don't fit the FDA-approved test's inclusion criteria.

In its most recent study, the Pfizer/Samsung group validated a multiplex assay for ALK, ROS, and RET rearrangements in 295 NSCLC specimens. The test, which uses a molecular barcoding platform from Nanostring and combines detection of fusion-specific transcripts with measurement of 3' overexpression, showed 100 percent concordance with FISH and almost 98 percent concordance with immunohistochemistry in identifying ALK fusions, and 100 percent concordance with FISH for ROS1 and RET fusions, according to the authors.

The new study is not the first from the Pfizer/Samsung group to explore the Nanostring platform. In an earlier paper in JMD, the same team reported on a Nanostring-based assay to detect ALK fusions and measure overall ALK 3' mRNA expression, which was also concordant with both FISH and IHC results.

The group has also demonstrated a sequencing-based method using the Ion Torrent PGM to detect previously identified resistance mutations in patients who relapsed after treatment with crizotinib.

In the new study, the researchers explained that the newest ALK, ROS1, and RET test is an expansion of their earlier Nanostring-based ALK assay, and now utilizes 56 multiplex probe sets to cover the three targets.

The Nanostring platform's wide dynamic range allows for a single assay incorporating ROS1, RET, and ALK fusions, despite wide differences in expression levels among the three, and the method's incorporation of both known ALK fusions and 3' overexpression increases the sensitivity over testing methods focused only on known fusions, like FISH, according to the authors.

According to the group, the assay can work with as little as 50 to 100 nanograms of RNA from formalin-fixed paraffin-embedded slide sections, which is a boon to the lung cancer setting where samples are limited.

While Pfizer has told Pharmacogenomics Reporter previously that its research with the Samsung group does not reflect plans to develop a commercial ALK assay internally, the company undoubtedly stands to benefit from more sensitive detection of ALK fusions in clinical testing, a robust diagnostics market for ALK and other fusion detection, and the resulting identification of the most patients possible who could benefit from treatment with Xalkori.

In a statement provided this week, Pfizer told PGx Reporter that "in order to achieve the broadest testing to deliver the appropriate drug to each patient, we would like health care professionals around the world to have access to multiple testing options to minimize all barriers for testing. Our hope is that additional diagnostic options will increase the availability and access to reliable testing for patients who are ALK-positive.”

Mollie Roth, founder of personalized medicine and life sciences consulting firm PGx Consulting, told PGx Reporter this week that because targeted therapies have a smaller market than drugs approved for a broad population, pharmaceutical companies have a direct interest in identifying the fullest population that can benefit from their drugs.

"Even though crizotinib took [less time] to develop thereby saving [Pfizer] money, it still is a huge expense," Roth said. "In personalized medicine, you need to find every single one of the people who have, for example, an ALK mutation so you can get your drug to the entirety of a smaller market. You want to make sure your sensitivity and specificity is absolutely the best it can possibly be because you can't afford to miss even one of that five or seven percent of the population who have that mutation, so that's part of the research they are doing."

Moreover, Roth explained, a robust, well-populated diagnostic market is also necessary to ensure that all the patients who could benefit from a targeted drug like Xalcori, are identified.

"The best diagnostic markets have multiple tests," she said.

In addition, tests for lung cancer fusions other than ALK, like ROS and RET, could potentially expand the patient population who could be treated with Xalkori itself, or next-generation ALK inhibitors and other drugs being developed by Pfizer and others.

"Crizotinib was first in class, but of course [Pfizer is] working at next-generation drugs, and looking at other markers that indicate sensitivity either to crizotinib or to the next generation they are working on," Roth said.

According to the Pfizer study authors, some recent evidence, including a study published in the Journal of Clinical Oncology last year, has suggested that patients with NSCLC with ROS1 fusions may benefit from treatment with Xalkori.

Responses to Xalkori among patients with ROS1 rearrangements were so positive in an extension of the Phase I Study 1001 — which last year led to Xalkori's approval as a treatment for NSCLC patients with ALK rearrangements — that some academic medical oncologists have already incorporated screening for this molecular marker into clinical practice.

RET fusions, meanwhile, have been associated with response to tyrosine kinase inhibitors with anti-RET activity, such as Pfizer's Sutent (sunitinib).

Overall, Roth explained that a wide variety of highly-sensitive tests looking at an array of markers associated with response to crizotinib or other drugs in Pfizer's pipeline should benefit the company, as well as patients.

But, because Xalkori's label constrains it to patients with ALK mutations established by an FDA-approved diagnostic, and Abbott's FISH test is currently the only FDA-approved test for ALK fusions, Pfizer is limited in how it can pursue these benefits.

Although the Pfizer/Samsung team acknowledged in the study that its Nanostring-based method is not without limitations, it argued that the assay has the potential to be a more practical screening method for PGx-associated fusions in NSCLC than current methods, and said the test "shows promise for use as a prescreening tool in both research and clinical practice." Pfizer would not say whether it was considering advancing a Nanostring-based test as an FDA-okayed companion test for crizotinib.

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