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    The ARIA Study:activity of next-generation ALK TKIs based on ALK resistance mutations detected by liquid biopsy in ALK positive NSCLC patients

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    Authors
    Mezquita, L.
    Swalduz, A.
    Auclin, E.
    Carter, Mathew
    Steendam, C.
    Aldea, M.
    Scheffler, M.
    Corral, J.
    Viteri, S.
    Segui, E.
    Barba, A.
    Dubbink, E.
    Planchard, D.
    Vasseur, D.
    Reyes, R.
    Caramella, C.
    Recondo, G.
    Saintigny, P.
    Blackhall, Fiona H
    Dingemans, A.
    Besse, B.
    Show allShow less
    Affiliation
    Hospital Clinic, Medical Oncology Department, Barcelona; Medical Oncology Department, Gustave Roussy Cancer Campus, Villejuif, France, Spain/ES,
    Issue Date
    2021
    
    Metadata
    Show full item record
    Abstract
    Introduction: Detection of resistance mechanisms to tyrosine kinase inhibitors (TKI), in particular ALK mutations (ALKm), could help to select the subsequent treatment in ALK-positive NSCLC patients. Liquid biopsy can identify these ALKm from ctDNA in up to 29% of patients after 2nd-generation TKI-failure. We assessed the activity of next-gen TKIs based on the presence of ctDNA ALKm. Methods: Patients with ALK-positive advanced NSCLC pretreated with 1st and/or 2nd-generation ALK-TKI were selected in 9 European centers. Liquid biopsy was collected immediately before starting brigatinib or lorlatinib. ALKm were defined by commercial or homemade next-generation sequencing run on ctDNA and covering ALK exon 22/23/25. We correlated the activity of brigatinib or lorlatinib based on three ctDNA molecular groups: presence ALKm (if one: single; if 2: complex); other mutations and no detectable mutations. We assessed progression-free survival (PFS), objective response rate (ORR), intracranial ORR according to the clinical routine of each center and overall survival (OS). Results: 62 patients were identified, 58 evaluable at cutoff data (Jul-20): 16 before brigatinib and 42 before lorlatinib. Median age was 53 [27-80], 64% were female, 67% nonsmoker; 97% with adenocarcinoma; 7% and 10% with isolated thoracic and brain disease, respectively. The median (m) number of TKIs was 3 [2-7]; 90% received 2nd-generation TKIs. The mFU since liquid biopsy was 24.8 months. ALKm were detected in 28% (3 brigatinib; 13 lorlatinib), 9 single and 7 complex; others were detected in 17% (n¼10) and none in 55% (n¼32). The most common mutation was G1202R (7 before lorlatinib), followed by G1269A and F1174L in 3 cases each, all pretreated with 2nd-generation TKIs. The TKI outcomes according to the ctDNA molecular groups is summarized in table 1. In the ALKm group, lorlatinib showed an ORR of 46% and 56% of intracranial ORR with mPFS of 6.5 months (7¼single/ 6¼complex) while no responses were observed in the 3 cases treated with brigatinib, with mPFS of 3.5 months (2¼single/1¼complex). Those 7 cases harboring the G1202Rmut (4¼complex) had an ORR of only 14% but an intracranial ORR of 50%; mPFS was 3.6 mo. No differences were observed among ctDNA molecular groups. Conclusion: In our study, lorlatinib showed activity in heavily-pretreated patients with ALK-positive NSCLC, regardless the ctDNA molecular groups. Poor outcomes were observed for brigatinib in 3 heavily-pretreated patients with ctDNA ALKm. The recent use of 2ndgen TKI upfront calls for similar studies to confirm if ctDNA may be a biomarker for guiding the sequential therapy.
    Citation
    Mezquita L, Swalduz A, Auclin E, Carter M, Steendam C, Aldea M, et al. P84.01 The ARIA Study: Activity of Next-Generation ALK TKIs Based on ALK Resistance Mutations Detected by Liquid Biopsy in ALK Positive NSCLC Patients. Journal of Thoracic Oncology. 2021 Mar;16(3):S655.
    Journal
    Journal of Thoracic Oncology
    URI
    http://hdl.handle.net/10541/623986
    DOI
    10.1016/j.jtho.2021.01.1200
    Additional Links
    https://dx.doi.org/10.1016/j.jtho.2021.01.1200
    Type
    Meetings and Proceedings
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.jtho.2021.01.1200
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