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Case Study Suggests FISH Test May Miss Some Patients Who Could Benefit from Crizotinib

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Researchers from the University of Colorado and Tel Aviv University have reported a case study that suggests fluorescence in situ hybridization-based testing may miss some ALK rearrangements in lung cancer patients who could benefit from Pfizer's Xalkori (crizotinib).

The team is involved in an ongoing study evaluating different ALK testing methods, including FISH, immunohistochemistry, and RT-PCR.

In the Journal of Thoracic Oncology last month, the researchers reported a case study of a patient who tested negative for the EML-4ALK fusion with Abbot's FISH test — approved by the US Food and Drug Administration as a companion diagnostic for Xalkori — but who tested positive for an ALK rearrangement by immunohistochemistry and later experienced remission after treatment with the drug.

The results suggest FISH testing may miss some patients with rare types of ALK fusions that don't fit Abbot's FDA-approved testing criteria. While it is still unknown how many patients may be overlooked with current methods, Fred Hirsch, one of the study's co-authors, said that refining the FISH testing criteria, or adding methods like immunohistochemistry or PCR to doctors' testing protocols might help identify more patients who could benefit from the drug.

"The bottom line is we want to help as many people as possible. And we don't want certain criteria, or a certain assay, to be a limitation. If others either by themselves or in combination can be more optimal selection criteria, that would be good for the patients," he told PGx Reporter.

EML4-ALK fusions occur in about 5 percent of non-small cell lung cancers, according to the study authors. Xalkori's label doesn't mention Abbott's ALK test by brand name, though, for the time being, Abbott has the only FDA-approved companion diagnostic in this setting.

At the same time, alternative tests have begun to crop up. Recently, Lab21, a UK-based clinical lab services and diagnostics company, began providing PCR-based testing services to help physicians determine which of their NSCLC patients harbor EML4-ALK translocations and therefore, are more likely to respond to ALK inhibitors like crizotinib (PGx Reporter 2/20/2012).

A few months ago, GE subsidiary Clarient Diagnostic Services garnered a worldwide, non-exclusive license from Insight Genetics enabling it to develop a PCR-based genetic test that gauges ALK expression. Pfizer has also said it is also exploring RT-PCR platforms for ALK testing (PGx Story 6/6/2012).

Hirsch said immunohistochemistry antibody methods that have been developed vary in their accuracy, but overall, they've shown "very good correlation" with Abbot's FISH test.

Hirsch and his University of Colorado colleagues are involved in a study that is pitting the FDA-approved FISH assay against immunohistochemistry and RT-PCR.

"We are studying a much larger number of cases, which are both FISH-positive and FISH-negative," he said. "And we are then doing immunohistochemistry and RT-PCR on blinded samples.

"For immunohistochemistry and PCR, the criteria for positive or negative is not standardized," Hirsch said. "The only standardized [method] is the FISH, so what we are trying is to see is whether other criteria may be applicable. And at the end of the day, when we correlate it to therapy response and outcome, would other criteria or other assays be more suitable than the current well-defined FISH assay."

In the recently published case report, the researchers retested a 43-year old male patient, who was deemed FISH-negative, using an immunohistochemistry approach created by Cell Signaling Technology — which has since been licensed to Ventana Medical systems — and confirmed the presence of an EML4-ALK mutation using next-generation sequencing in collaboration with Foundation Medicine.

Immunohistochemistry revealed that while the patient was FISH-negative, he did have EML4-ALK fusion proteins. Sequencing then revealed that the subject did have a fusion between EML4 and ALK, but in a much more complicated arrangement than is commonly seen.

The team hypothesized that the resulting fusion — involving small pieces, or "shards," of genomic material in a complex rearrangement — was different enough from typical EML4-ALK mutations that the FDA-approved FISH assay was unable to identify it as such. The authors wrote they believe the confounding shards of genetic material may be discarded during splicing, resulting in a functional EML4-ALK protein transcript.

Based on the immunohistochemistry results, the patient was treated with crizotinib and experienced improvement within two weeks and a negative PET scan after four months, the researchers reported.

"That really brings us to the question," Hirsh said. "Yes, the FDA has approved a test with certain criteria, but does it capture all the patients who could eventually benefit from crizotinib therapy?"

"This case indicates that there is more to the story than we know today. It is only the first case reported … but, my guess is that more will come," he said.

In the meantime, Hirsch's team will continue its larger comparison study. "Hopefully within three to six months we could have a very good picture of how the three assays are performing against each other," he said.

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