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Multicenter Study
. 2019 Dec:138:13-18.
doi: 10.1016/j.lungcan.2019.09.023. Epub 2019 Oct 3.

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

E Thunnissen  1 , B I Lissenberg-Witte  2 , M M van den Heuvel  3 , K Monkhorst  4 , B G Skov  5 , J B Sørensen  6 , A Mellemgaard  7 , A M C Dingemans  8 , E J M Speel  9 , A J de Langen  10 , S M S Hashemi  10 , I Bahce  10 , M A van der Drift  11 , M G Looijen-Salamon  12 , J Gosney  13 , P E Postmus  14 , S M S Samii  15 , F Duplaquet  16 , B Weynand  17 , X Durando  18 , F Penault-Llorca  19 , S Finn  20 , A O Grady  21 , B Oz  22 , N Akyurek  23 , R Buettner  24 , J Wolf  25 , L Bubendorf  26 , S Duin  27 , I Marondel  28 , L C Heukamp  29 , W Timens  30 , E M D Schuuring  30 , P Pauwels  31 , E F Smit  32
Affiliations
Multicenter Study

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

E Thunnissen et al. Lung Cancer. 2019 Dec.

Abstract

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.

Keywords: alk; fluorescence in situ hybridisation; immunohistochemistry; non-small cell lung cancer; prognosis; treatment.

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