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Ref Type | Abstract | ||||||||||||
PMID | |||||||||||||
Authors | J. Hu N. Ding Y. Chen J. Liu J. Zhou X. Xu H. Bao Y. Song D. Zhang Y. Shao Y. Zhang | ||||||||||||
Title | MET and NF2 alterations confer early resistance to first-line alectinib treatment in ALK-rearranged non-small cell lung cancer | ||||||||||||
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URL | https://www.annalsofoncology.org/article/S0923-7534(22)02988-X/fulltext | ||||||||||||
Abstract Text | Background The second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), alectinib, has shown impressive efficacy in naïve ALK-rearranged advanced non-small-cell lung cancer (NSCLC). However, why tumors develop early resistance to the drug is incompletely understood. Methods Total 108 ALK-rearranged NSCLC patients had confirmed clinical relapse on alectinib within two years and had detectable genetic alterations from targeted sequencing of cancer-related genes. Of these, 52 received first-line alectinib treatment (1L) and 56 received alectinib after crizotinib resistance (2L). Genomic profiles of pre- and post-alectinib biopsies were compared. Results In the 1L cohort, acquired on-target alterations were found in 13 patients post-alectinib (25%), including ALK kinase domain mutations (KDMs) at G1202R (7, 13%), I1171N (3, 6%), L1196Q (2, 4%), V1180L (2, 4%), and L1196M (1, 2%) and one amplification. Eleven acquired MET alterations (21%) were found in mutual exclusivity with ALK KDMs (L1195F, Y1248H, kinase domain duplication, and 8 amplifications). NF2 (5/52, 10%) was another common off-target mutation, followed by PIK3CA, KRAS, NRAS, and BRAF. In contrast, in 2L, significantly more tumors gained resistance from various ALK KDMs (44/56, 79%, p<0.001), including G1202R (18, 32%), L1196M (15, 27%), G1269A (6,11%), I1171T/S (5, 9%), F1174L/V/S (5, 9%) and E1129V (2, 4%), and ALK amplifications (2, 4%). However, no MET amplification or NF2 mutation, but only one concurrent ALK G1201R/MET D1228H/L1195V was found after 2L (p<0.001). In 1L, acquired MET alterations was associated with shorter progression-free survival (PFS) (median 7.2m) than ALK alterations (median 11.1m) (HR 2.0, 95CI, 0.85-4.76; p = 0.11). Also, NF2-mutant patients only had a median PFS of 4 months, significantly poorer than those without (HR 11.1, 95CI 2.17-50; p<0.001). Conclusions By analyzing different mutational profiles of ALK-rearranged patients after alectinib treatment, we proposed MET and NF2 as putative mechanisms that conferred resistance to early resistance of first-line alectinib, which shone light on future tailored treatment for ALK-positive NSCLCs. |