A Sensitive ALK Immunohistochemistry Companion Diagnostic Test Identifies Patients Eligible for Treatment with Crizotinib.
The availability of high-quality, rigorously validated diagnostic tests that can be broadly implemented is necessary to efficiently identify patients with anaplastic lymphoma kinase (ALK)-positive NSCLC who can potentially benefit from treatment with crizotinib. Here we present data on the recently approved Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Tucson, AZ), the only immunohistochemistry (IHC)-based assay linked to treatment outcome.



NSCLC specimens prospectively tested for anaplastic lymphoma receptor tyrosine kinase gene (ALK) status by flourescent in situ hybridization (FISH) in the PROFILE 1014 clinical trial of crizotinib versus chemotherapy (N = 1018, including 179 ALK-positive and 754 ALK-negative specimens) were evaluated using the ALK (D5F3) CDx assay. Hazard ratios for progression-free survival comparing crizotinib and chemotherapy for ALK IHC-positive patients and ALK FISH-positive patients, as well as for concordance with the enrollment ALK FISH assay, were determined.



Results from both assays were obtained for 933 cases. Percent positive, negative, and overall agreement rates were 86.0% , 96.3%, and 94.3%, respectively. There were 53 discrepant cases, of which 25 were ALK FISH-positive/ALK IHC-negative and 28 were ALK FISH-negative/ALK IHC-positive. The hazard ratios using observed outcomes were 0.401 for ALK FISH-positive/ALK IHC-positive cases and 0.407 for all ALK FISH-positive cases tested with ALK IHC versus 0.454 for all ALK FISH-positive cases enrolled in the trial. Outcome data for ALK FISH-negative/ALK IHC-positive cases were not available for analysis. Between-reader agreement rates for ALK IHC involving three independent laboratories exceeded 98%.



The ALK (D5F3) CDx assay is a stand-alone companion diagnostic test for identification of patients for treatment with crizotinib. This automated assay provides an effective option to accurately and rapidly identify patients with ALK-positive NSCLC. The simple binary scoring algorithm results in high reader-to-reader precision.
Ventana Medical Systems, Tucson, Arizona. Electronic address: trish.thorne-nuzzo@roche.com.
Trish
T
Thorne-Nuzzo
Ventana Medical Systems, Tucson, Arizona.
Crystal
C
Williams
Ventana Medical Systems, Tucson, Arizona.
Alice
A
Catallini
Ventana Medical Systems, Tucson, Arizona.
June
J
Clements
Ventana Medical Systems, Tucson, Arizona.
Shalini
S
Singh
Laboratory Corporation of America Holdings, Shelton, Connecticut.
James
J
Amberson
Laboratory Corporation of America Holdings, Shelton, Connecticut.
Kim
K
Dickinson
Caris Life Sciences, Phoenix, Arizona.
Zoran
Z
Gatalica
Pfizer Oncology, La Jolla, California.
Steffan N
SN
Ho
Ventana Medical Systems, Tucson, Arizona.
Isabell
I
Loftin
Personal Genome Diagnostics, Baltimore, Maryland.
Abigail
A
McElhinny
Ventana Medical Systems, Tucson, Arizona.
Penny
P
Towne
D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism*; D000077547:Crizotinib; D018572:Disease-Free Survival; D005188:False Negative Reactions; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods*; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015588:Observer Variation; D018579:Patient Selection; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015203:Reproducibility of Results; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
ALK IHC; Anaplastic lymphoma kinase; Companion diagnostic assay; NSCLC; Targeted therapy