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.
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.
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).
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.
Clinical trial identification
Legal entity responsible for the study
Ethics Committee of Zhongshan Hospital, Fudan University.
Has not received any funding.
Y. Chen, J. Liu, H. Bao, Y. Shao: Other, Institutional, Full or part-time Employment: Nanjing Geneseeq Technology Inc. All other authors have declared no conflicts of interest.