FISHing for a Better Assay in ALK-Positive Lung Cancer

The phase III ALEX trial did more than demonstrate that the ALK-inhibitor alectinib (Alecensa) could significantly reduce the risk of progression or death compared with crizotinib (Xalkori) for the first-line treatment of adults with ALK-positive, advanced non—small cell lung cancer (NSCLC). It provided clear guidance on which of 2 assays evaluated could provide stronger guidance on which patients would respond to ALK-specific therapy.

Both fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) tests were used to screen patients for inclusion in the study.

ALEX results provided the confirmatory data for the December 2015 FDA accelerated approval of alectinib for patients with ALK-positive NSCLC following progression on crizotinib, and last week the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended approval of alectinib (Alecensa) for the first-line treatment of adults with ALK-positive, advanced NSCLC, also based on the phase III ALEX results.

FISH and IHC are the most commonly used assays to determine ALK positivity, but clinical outcomes data linked to specific methods are limited. Data upon which such an analysis could be performed was available from the ALEX trial of alectinib versus crizotinib, and the data were particularly useful for evaluating relative significance of IHC-positive/FISH-negative results.

The review of FISH and IHC assay performance based on ALEX data revealed that when it comes to evaluating patients for ALK positivity, IHC testing is markedly better, with fewer false negatives, according to data presented this week at the IASLC 18^th World Conference on Lung Cancer (WCLC) in Yokohama, Japan. Furthermore, IHC testing had fewer limitations on applicability, meaning that a broader volume of samples could be tested without rejection based on quality or other factors.

Investigators used the Ventana ALK (D5F3) CDx Assay (IHC) as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit.

Investigators said 303 patients with ALK IHC-positive NSCLC were enrolled in the trial, and of those, 203 had positive FISH results, and 39 patients had FISH-negative results. For 61 patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained because of an “uninformative” FISH result (10.9%) or the poor quality of and lack of tissue available (9.2%). This led to the finding that Ventana IHC staining success rates were higher than those from the Vysis FISH testing.

An exploratory analysis of progression-free survival (PFS) in patients with a FISH positive result showed consistency with the results obtained in the Ventana ALK IHC-positive population (median not reached alectinib versus 12.7 months crizotinib; HR, 0.40; 95% CI, 0.27—0.61; P <.0001). Overall, 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.

“While progression-free survival of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment,” investigators wrote.

Where targeted agents must be matched to patients for best outcomes, and there is a critical need both for reliable assays and guidance on which assays are most reliable, the ALEX analysis on FISH versus IHC testing has demonstrated that IHC is “a robust testing approach” which may identify more patients who can benefit from ALK tyrosine kinase inhibitor treatment, investigators concluded. Additionally, FISH-negative results should not be interpreted as a conclusive sign that ALK inhibitors will not be effective, they said.

The helpful findings from the assay comparison build upon the continuing success story as ALK inhibitors continue to evolve and demonstrate improved potential for combatting ALK-positive NSCLC disease burden. More data on these developments are expected to emerge during the WCLC conference.

Mok T, Peters S, Camidge DR. Patients with ALK IHC-positive/fish-negative NSCLC benefit from ALK TKI treatment: response data from the global ALEX trial. Presented at: the IASLC 18^th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Poster MA 07.01.

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