Tumor agnostic comparison of immunohistochemistry and next-generation sequencing in detecting ALK fusions and assessment of ALK tyrosine kinase inhibitor efficacy

ABSTRACT

Background: Reliable methods to identify anaplastic lymphoma kinase (ALK) fusions are critical to matching patients to ALK tyrosine kinase inhibitors (TKIs) therapy, on or off trial. Various methods including FISH have been used, but immunohistochemistry (IHC) and next-generation sequencing (NGS) are most commonly employed. Evaluating the concordance of IHC and NGS is key, particularly in non-lung cancers where data is sparse. Method(s) NGS+ (MSK-IMPACT DNA hybrid capture NGS and/or RNA anchored multiplex PCR) and/or IHC+ (clone D5F3) patients with cancers of any histology were identified as ALK+. ALK IHC was scored as negative (0), equivocal (e 1+, 2+) or positive (3). Concordance of ALK detection (number of NGS+ and IHC+/total number of patients with NGS and IHC) was calculated. For patients with metastatic disease treated with any ALK TKI in the first-line (1L) setting, progression-free survival (PFS) was reported. Result(s) 347 ALK+ solid tumor patients were identified. As expected, the majority (96%, n=336) had lung cancer, however, 11 patients with 11 unique non-lung cancer histologies were found (3 gastrointestinal, 2 gynecologic, 1 breast, 1 thyroid, 1 primary brain tumor, 1 DLBCL, 1 PEComa, and 1 CUP). 57% had EML4-ALK fusions;36 non-EML4 ALK rearrangements were identified, including four novel fusions (PEKHA7-ALK, ZFPM2-ALK, TRIM24-ALK, ALK-MYO3B). ALK was evaluated by IHC alone in 83 patients (23.9%). The concordance rate between NGS and IHC was 85%. Among discordant cases, 11% (n=28) were IHC+/NGS-, 24% (n=63) were IHCe/NGS-, 3% (n=8) were IHCe/NGS+, and 0.4% (n=1) was IHC-/NGS+. The most frequent ALK TKIs were alectinib (n= 87, 58%) and crizotinib (n= 56, 38%). PFS on 1L ALK TKIs for patients with IHC+/NGS+ (n=134), IHC-/NGS+(n=1), IHC+/NGS- (n=8), IHCe/NGS+ (n=4), IHCe/NGS- (n=1) was 26 months, 26 months, 39 months, 41 months, 9 months respectively. Conclusion(s) In a population including multiple tumor types, NGS and IHC were highly concordant in ALK fusion detection. ALK TKI benefit may be observed in cases with discordant testing, in which only one assay detects a putative ALK fusion. Legal entity responsible for the study The authors. Funding(s) NIH Cancer Center grant P30CA008748. Disclosure M.G. Kris Financial Interests, Personal, Research Grant Boehringer Ingelheim, National Lung Cancer Partnership, Pfizer, PUMA, Stand up to Cancer;Financial Interests, Personal, Advisory Role Ariad, AstraZeneca, Bind Bioscience, Boehringer Ingelheim, Chug Pharma, Clovis, Covidien, Daiichi Sankyo, Esanex, Genentech;Financial Interests, Personal, Invited Speaker Boehringer Ingelheim, Novartis, Millenium, Pfizer, Roche. A. Drilon Financial Interests, Personal, Advisory Board Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millennium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, BeiGene, BerGenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem Oncology, MORE Health, AbbVie, 14ner/Elevation Oncology, Remedica Ltd, ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX, Amgen, Janssen, EcoR1, Monte Rosa;Financial Interests, Personal, Other, CME Medscape, Onclive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, PeerView Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences, Med Learning, Imedex, Answers in CME, Medscape, Clinical Care Options, AiCME;Financial Interests, Personal, Other, CME, Consulting Axis;Financial Interests, Personal, Other, Consulting Nuvalent, Merus, EPG Health, mBrace, Harborside Nexus, Ology, TouchIME, Entos, Treeline Bio, Prelude, Applied Pharmaceutical Science, Inc;Financial Interests, Personal, Invited Speaker Chugai Pharmaceutical, Remedica Ltd, RV More;Financial Interests, Personal, Stocks/Shares Treeline Biosciences;Financial Interests, Personal, Royalties Wolters Kluwer;Financial Interests, Personal, Other, stocks mBrace;Financial Interests, Institutional, Funding, Research funding: Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar;Finan ial Interests, Personal, Funding, Research Foundation Medicine;Non-Financial Interests, Personal, Member ASCO, AACR, IASLC;Other, Personal, Other, Food/Beverage Merck, PUMA, Merus;Other, Personal, Other, Other Boehringer Ingelheim. All other authors have declared no conflicts of interest.Copyright © 2023 European Society for Medical Oncology