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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
Journal Vol Issue Date Pages Journal Short Title
Annals of Oncology 33 Supplement 7 Sep 10, 2022
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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK rearrange ALK F1174S lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK F1174S was identified in a patient with non-small cell lung cancer harboring an ALK rearrangement after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK F1174V lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK F1174V was identified in a patient with non-small cell lung cancer harboring an ALK rearrangement after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK E1129V lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK E1129V was identified in 4% (2/56) of patients with non-small cell lung cancer harboring an ALK rearrangement after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK I1171T lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK I1171T was identified in a patient with non-small cell lung cancer harboring an ALK rearrangement after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK I1171N lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK I1171N was identified in 6% (3/52) of patients with non-small cell lung cancer harboring an ALK rearrangement after disease progression on first-line Alecensa (alectinib) treatment (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK G1202R lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK G1202R was identified in 13% (7/52) of patients with non-small cell lung cancer harboring an ALK rearrangement after disease progression on first-line Alecensa (alectinib), and in 32% (18/56) patients who responded to second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK L1196Q lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK L1196Q was identified in 4% (2/52) of patients with non-small cell lung cancer harboring an ALK rearrangement after progression on first-line Alecensa (alectinib) treatment (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK I1171S lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK I1171S was identified in a patient with non-small cell lung cancer harboring an ALK rearrangement after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK L1196M lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK L1196M was identified in one patient with non-small cell lung cancer harboring an ALK rearrangement after progression on first-line Alecensa (alectinib) and in 27% (15/56) of patients after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK amp lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK amplification was identified in a patient with non-small cell lung cancer harboring an ALK rearrangement after progression on first-line Alecensa (alectinib) treatment and in 4% (2/56) of patients after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK V1180L lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK V1180L was identified in 4% (2/52) of patients with non-small cell lung cancer harboring an ALK rearrangement after disease progression on first-line Alecensa (alectinib) treatment (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...
ALK rearrange ALK F1174L lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a clinical study, ALK F1174L was identified in a patient with non-small cell lung cancer harboring an ALK rearrangement after progression on second-line Alecensa (alectinib) treatment following Xalkori (crizotinib) resistance (Ann of Oncol (2022) 33 (suppl_7): S448-S554). detail...