Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster session 14

1011P - MET and NF2 alterations confer early resistance to first-line alectinib treatment in ALK-rearranged non-small cell lung cancer


10 Sep 2022


Poster session 14


Translational Research;  Targeted Therapy;  Molecular Oncology

Tumour Site

Non-Small Cell Lung Cancer


Jie Hu


Annals of Oncology (2022) 33 (suppl_7): S448-S554. 10.1016/annonc/annonc1064


J. Hu1, N. Ding1, Y. Chen2, J. Liu2, J. Zhou1, X. Xu1, H. Bao2, Y. Song1, D. Zhang1, Y. Shao2, Y. Zhang1

Author affiliations

  • 1 Department Of Pulmonary Medicine, Zhongshan Hospital Affiliated to Fudan University, 200032 - Shanghai/CN
  • 2 Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., 210000 - Nanjing/CN


Login to access the resources on OncologyPRO.

If you do not have an ESMO account, please create one for free.

Abstract 1011P


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

Editorial acknowledgement

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.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.