Open AccessLongitudinal monitoring by next‐generation sequencing of plasma cell‐free DNA in ALK rearranged NSCLC patients treated with ALK tyrosine kinase inhibitors
Author(s) -
Kwon Minsuk,
Ku Bo mi,
Olsen Steve,
Park Sehhoon,
Lefterova Martina,
Odegaard Justin,
Jung HyunAe,
Sun JongMu,
Lee SeHoon,
Ahn Jin Seok,
Park Keunchil,
Ahn MyungJu
Publication year - 2022
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.4663
Subject(s) - crizotinib , ceritinib , alk inhibitor , anaplastic lymphoma kinase , medicine , lung cancer , oncology , cancer research , tyrosine kinase , receptor , malignant pleural effusion
Background Patients with ALK‐ rearranged non‐small cell lung cancer ( ALK+ NSCLC) inevitably acquire resistance to ALK inhibitors. Longitudinal monitoring of cell‐free plasma DNA (cfDNA) next‐generation sequencing (NGS) could predict the response and resistance to tyrosine kinase inhibitor (TKI) therapy in ALK+ NSCLC. Methods Patients with ALK+ NSCLC determined by standard tissue testing and planned to undergo TKI therapy were prospectively recruited. Plasma was collected at pretreatment, 2 months‐post therapy, and at progression for cfDNA‐NGS analysis, Guardant 360. Results Among 92 patients enrolled, circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%): 43 ALK fusions (62.3%) and two ALK mutations without fusion (2.8%). Two patients showed ALK ‐resistance mutations after ceritinib; G1202R, and co‐occurring G1202R and T1151R. Eight patients developed ALK resistance mutations after crizotinib therapy; L1196M ( n = 5), G1269A ( n = 1), G1202R ( n = 1), and co‐occurring F1174L, G1202R, and G1269A ( n = 1). Absence of ctDNA at baseline was significantly associated with longer progression‐free survival (PFS; median 36.1 vs. 11.4 months, p = 0.0049) and overall survival (OS; not reached vs. 29.3 months, p = 0.0200). ctDNA clearance at 2 months ( n = 29) was associated with significantly longer PFS (25.4 vs. 11.6 months, p = 0.0012) and OS (not reached vs. 26.1 months, p = 0.0307) than those without clearance ( n = 22). Patients with co‐occurring TP53 alterations and ALK fusions at baseline ( n = 16) showed significantly shorter PFS (7.28 vs. 13.0 months, p = 0.0307) than those without TP53 alterations ( n = 25). Conclusions cfDNA‐NGS facilitates detection of ALK fusions and resistance mutations, assessment of prognosis, and monitoring dynamic changes of genomic alterations in ALK + NSCLC treated with ALK‐TKI.