Fusion detection and longitudinal circulating tumor DNA (ctDNA) profiling in ALK+ non-small cell lung cancer (NSCLC) patients.

Le résumé fourni par la source

e21031 Background: Therapeutic response in ALK+ NSCLC is driven by heterogeneous mechanisms of resistance. Liquid biopsy (LB) offers a non-invasive approach to study the tumor genomic landscape under therapy. However, the potential of LB for fusion detection and disease monitoring in ALK+ patients is poorly understood. Methods: LB was performed at diagnosis (n = 10), at each radiologic evaluation (n = 75) and at the time of progressive disease (PD) (n = 34) in 35 FISH/RNAseq confirmed ALK+ NSCLC patients, treated with ALK-TKI. EML4-ALK fusions (variants v1, v2, v3), and a 36–gene panel were investigated in LB using the Inivata InVisionFirst amplicon-based ctDNA NGS assay. Results: Preliminary results show that an EML4-ALK fusion was detected in 4/6 (67%) patients at diagnosis (2 v1, 1 v2 and 1 v3). The 2 patients for whom an ALK-fusion was not detected in LB had intrathoracic disease only. LB collected at the 1st radiographic evaluation under therapy revealed complete clearance of the fusion and associated TP53 mutations in all patients experiencing partial response. ALK resistance mutations were detected in samples collected at PD under crizotinib (L1196M+C1156Y), ceritinib (F1174L), brigatinib (F1174V, F1174L+G1202R, D1203N, R1192P) and lorlatinib (F1174L+G1202R). TP53 and CDKN2A mutations were detected in 41% of the samples. In patients with slow brain PD, fusion and resistance mutations were undetectable, possibly due to low ctDNA release. Among patients with PD, a striking difference in PFS was observed in patients harboring ALK secondary mutations (n = 6) versus those who did not (n = 13) with a median progression-free survival of 4.5 [95%CI: 3-12] vs. 22 [95%CI: 13-30] months respectively (log-rank p-value = 0.0002). Results for the remaining samples will be presented at the meeting. Conclusions: ctDNA profiling is a promising non-invasive alternative for the management of ALK+ NSCLC patients, from the identification of the fusion variant, to the monitoring of response to treatment and to the characterization of resistance mechanisms. Our results suggest heterogeneity in tumor biology regarding acquisition of resistance mechanisms.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.