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Pfizer, Collaborators Developing NanoString ALK Test as Lower-Cost Alternative to FISH, IHC

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Using NanoString's nCounter technology, researchers from Pfizer and Seoul National University have developed an ALK test they hope will be as accurate as the gold standard fluorescence in situ hybridization test for identifying patients who could benefit from Pfizer's Xalkori (crizotinib) and other ALK inhibitors used to treat non-small cell lung cancer, but at a lower cost.

The group recently tested the method, which uses NanoString's transcript profiling platform to detect the presence or absence of ALK fusions and overall ALK 3' mRNA expression, on 66 archival NSCLC samples.

The team published the results in The Journal of Molecular Diagnostics last week, showing the method was highly concordant with both FISH and immunohistochemistry results. According to a Pfizer researcher involved with the study, the company has no immediate plans to commercialize the NanoString test to gauge best responders to Xalkori, but is hoping the publication will encourage labs and other groups to consider performing the test.

Pfizer collaborated with Abbott Molecular to launch Xalkori last year with Abbott's Vysis ALK Break Apart FISH Probe Kit, the FDA-approved companion diagnostic for the drug. Abbott officials have previously told PGx Reporter that the company charges labs less than $170 per patient for the test. After factoring in lab costs, Medicare reimbursement is around $440 on average (PGx Reporter 3/28/2012).

Mao Mao, a researcher at Pfizer Oncology and a co-author of the study, told PGx Reporter that in general, the cost of a NanoString assay is "a fraction" of a FISH test, though he didn't provide specific cost estimates. "On the reagent side, NanoString is roughly 10-fold less costly than FISH. It also offers a digital reading, so there is no need for a pathologist to grade the result," he said.

Dong-Wan Kim, another co-author of the new study and a researcher at Seoul National University Hospital, told PGx Reporter in an email that his team's experience participating in the Phase I, II, and III clinical trials of Xalkori led them to believe a cheaper and easier ALK testing method was necessary.

"We found that ALK FISH [testing] is quite complex and expensive as a screening tool and we wanted to have a more handy method to screen ALK-positive patients," he wrote.

"FISH is the gold standard but is difficult to perform and to interpret. IHC needs highly sensitive antibodies and is also difficult to interpret. RT-PCR needs fresh tissue and multiple reactions. We chose NanoString's platform because it is easy to interpret and can be done with FFPE tissue samples," he added.

Pfizer's Mao said that having a more cost-effective test could make it cheaper to screen patients for ALK fusions, potentially catching more patients who could benefit from Xalkori and other ALK inhibitors.

"When a diagnostic test is costly and the incidence is low, then [identifying] eligible patients for the drug is going to be very expensive," Mao said.

"There are also additional oncogenic fusions identified in lung cancer recently, but their incidence is only 1 percent, so using a FISH test would really be too expensive," he added.

An analysis published earlier this year in the British Journal of Cancer found that broadly testing all advanced NSCLC patients by FISH 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. However, Abbott has challenged the findings of this paper, asserting that the researchers' cost assumptions were overblown (PGx Reporter 3/21/2012).

Studies have also found that FISH may miss some NSCLC patients who might benefit from Xalkori. Researchers from the University of Colorado and Tel Aviv University reported a case study earlier this year highlighting a complex rearrangement that FISH testing missed in a patient that in fact did respond to crizotinib (PGx 12/12/2012).

The NanoString test that the Pfizer group created is made up of two independent but complementary assays, Mao explained. One looks at the overexpression of ALK 3' mRNA and the other is directly hybridized to the fusion junction.

According to Mao, looking at both known ALK fusions and the overall ALK 3' mRNA expression increases the sensitivity of the test.

"If we only used the fusion probes, it would only detect known fusions. The 3’ overexpression aspect of the assay does not require upfront knowledge of the fusion partner," he said. "By combining both assays, the test can pick up the presence of unknown variants while also measuring known variants specifically, he explained.

Mao said the NanoString technology is a good fit for this approach because it allows multiplexing without adding significantly to the cost of the assay.

"If you have a few additional probes, it's not that much of a difference in cost," he said. "So the current assay has about 20 probes – eight expression probes, seven fusion probes, and also housekeeping gene probes."

In the trial, the group evaluated the NanoString test on 66 archival samples from two separate cohorts with previously established FISH, and in some cases IHC, results. Overall, the test results were 93 percent concordant with the established FISH or IHC ALK scores. In samples where IHC and FISH scores themselves agreed, the NanoString assay was 100 percent concordant with that result, the group wrote.

In the first set of samples — six ALK-positive and 13 ALK-negative NSCLC samples from the Seoul National University Hospital — the researches found that all the NanoString results were concordant with FISH.

In the second sample set — 19 ALK-positive and one ALK-negative NSCLC sample from the Samsung Medical Center — the group found that all but two were concordant.

In the two discordant results, patients positive by FISH were found to be ALK-negative according to the NanoString test. According to the researchers, both of these patients showed no response to Xalkori, suggesting the initial FISH results were likely false positives.

According to Mao, the researchers are now working on a larger validation study, which has already examined 100 ALK-positive and 100 ALK-negative subjects. In the ongoing [investigation,] the concordance between NanoString and FISH or IHC has been greater than 95 percent, he said.

Mao noted that Pfizer does not have plans to commercialize the test. "For me as a scientist, we just put the data out there so labs, especially reference labs, can try the test. If they like it, then they can run it as clinical service … We want [this testing] to be more cost-effective. I think we achieved that goal," he said.

Pfizer has also said it is investigating RT-PCR methods for ALK testing (PGx 6/6/2012). Mao confirmed that this is still ongoing.

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