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1363P Genomic heterogeneity of ALK rearrangements and acquired resistance pathways in ALK+ Advanced non-small cell lung cancer (NSCLC) treated with upfront alectinib: Preliminary results of GALILEO project

2023; Elsevier BV; Volume: 34; Linguagem: Inglês

10.1016/j.annonc.2023.09.2396

1569-8041

Emanuele Vita, Federico Monaca, J. Russo, Alessandro Di Stefani, Q. Zhang, Mariantonietta Di Salvatore, Rocco Trisolini, Filippo Lococo, Alessandra Cancellieri, Giampaolo Tortora, Emilio Bria,

Lung Cancer Diagnosis and Treatment

Longitudinal genomic evaluation of ALK+ ANSCLC patients treated with 1L alectinib is poorly explored in clinical practice. GALILEO (Genomic ALteratIons and cLonal EvOlution in ALK+ NSCLC) is national observational prospective cohort study on ALK+ ANSCLC pts treated with new generation ALK-TKIs. Comprehensive genomic profiling was performed on pre-treatment FFPE tissue of ALK+ ANSCLC identified by using FISH and/or IHC. At the time of progression, DNA-based NGS was repeated on newly obtained tissue (if feasible) or blood ctDNA (FM1 CDx/Liquid®). In this preliminary analysis, 30 ALK+ ANSCLC pts who started 1L alectinib by Dec 2020 were evaluable. In pre-treatment samples, NGS identified 26 (86.6%) EML4-ALK fusion (V1: 9, V2: 2; V3: 11; NOS: 4), 6 (20%) non canonical fusions (1 alone, 5 conc. with EML4-ALK), 8 (30%) ALK Internal/Intrachromosomal rearrangements (4 intron 19, 2 exon 19, 1 intron 18, 1 C2orf44; 2 alone, 6 conc. with ALK-fusions); in one case, any ALK-alteration was detected. As the data cut-off (median FU: 37 mo.), 14 pts had radiological progression (PD). Among 11 alectinib-responder pts (CR/PR or SD > 6 mo.), 4 patients presented de-novo ALK-SNV [G1202R (50%); E1210K (25%); I1171N/T (25%)], 4 pts had no ALK-SNV (DNMT3A M+: 3 pts; SEDTD2 M+: 2 pts, TP53 M+: 2 pts), 1 pt had oncogene-switch (EGFR); 2 pts failed ctDNA-NGS (low purity). Among 8 pts who received 2L lorlatinib, we observed 3 PR in ALK SNV+ pts, 2 SD ≥6 mo. and 3 PD in pts without ALK-SNV. In post-lorlatinib NGS-assay, 2 pts had ALK-compound mutations, while 4 pts had newly off-target alterations (CDKN2A/B CDKN2B loss, NF1 deletion, DNMT3A/ARID1A/CHECK2 M+). Implementation of longitudinal genomic assessment is required in order to provide an extensive overview of resistance mechanisms and clinical outcomes according to current ALK-inhibitors treatment sequences.