ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib

Thunnissen, E.; Lissenberg-Witte, B.I.; Heuvel, M.M. van den; Monkhorst, K.; Skov, B.G.; Sorensen, J.B.; ... ; Smit, E.F. (2019)

Article / Letter to editor

Objective: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH +). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC) +). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases.Materials and methods: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH.Results: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC + /FISH +) and 16 discordant (ALK IHC + /FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR = 4.5; 95% CI = 1.2-15.9; p = 0.010.Conclusion: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

• non-small cell lung cancer
• alk
• immunohistochemistry
• fluorescence in situ hybridisation
• treatment
• prognosis

• All authors: Thunnissen, E.; Lissenberg-Witte, B.I.; Heuvel, M.M. van den; Monkhorst, K.; Skov, B.G.; Sorensen, J.B.; Mellemgaard, A.; Dingemans, A.M.C.; Speel, E.J.M.; Langen, A.J. de; Hashemi, S.M.S.; Bahce, I.; Drift, M.A. van der; Looijen-Salamon, M.G.; Gosney, J.; Postmus, P.E.; Samii, S.M.S.; Duplaquet, F.; Weynand, B.; Durando, X.; Penault-Llorca, F.; Finn, S.; Grady, A.O.; Oz, B.; Akyurek, N.; Buettner, R.; Wolf, J.; Bubendorf, L.; Duin, S.; Marondel, I.; Heukamp, L.C.; Timens, W.; Schuuring, E.M.D.; Pauwels, P.; Smit, E.F.
• Date: 2019-12-01
• Journal: Lung Cancer
• Volume: 138
• Pages: 13 - 18
• DOI: doi:10.1016/j.lungcan.2019.09.023