Format

Send to

Choose Destination
See comment in PubMed Commons below
Lung Cancer. 2015 May;88(2):231-4. doi: 10.1016/j.lungcan.2015.02.005. Epub 2015 Feb 12.

I1171 missense mutation (particularly I1171N) is a common resistance mutation in ALK-positive NSCLC patients who have progressive disease while on alectinib and is sensitive to ceritinib.

Author information

  • 1Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA 92868, United States; Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA 92868, United States. Electronic address: Ignatius.ou@uci.edu.
  • 2Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, United States.
  • 3Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA 92868, United States; Chao Family Comprehensive Cancer Center, University of California Irvine Medical Center, Orange, CA 92868, United States.
  • 4Foundation Medicine Inc., 150 Second Street, Cambridge, MA 02141, United States; Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY 12208, United States.
  • 5USC Norris Comprehensive Cancer Center and Hospital, Department of Medicine, Division of Medical Oncology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, United States.

Abstract

OBJECTIVES:

Acquired resistance mutations to anaplastic lymphoma kinase (ALK) inhibitors such as crizotinib and alectinib have been documented in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangement (ALK+). Of note I1171T/N/S mutations in the ALK kinase domain have recently been described by several groups to confer resistance to alectinib, a second-generation ALK inhibitor. Additionally one of these reports demonstrated one ALK+ NSCLC patient harboring an I1171T acquired mutation has responded to ceritinib, another second-generation ALK inhibitor.

MATERIALS AND METHODS:

We reported the presence of an ALK I1171N resistance mutation from comprehensive genomic profiling from a liver biopsy of a progressing metastatic lesion in an ALK+ patient on alectinib after an initial partial response. The patient then responded to ceritinib 750 mg orally once daily but required dose reduction to 600 mg once daily. She initially had grade 3 elevation of liver enzymes from crizotinib necessitating the original switch to alectinib but experienced no transaminase elevations with alectinib or ceritinib.

CONCLUSIONS:

This is the fifth patient case to date demonstrating that ALK I1171 mutation confers resistance to alectinib and the second reported case of ALK I1171 mutation being sensitivity to ceritinib. Substitutions of isoleucine at amino acid 1171 in the ALK kinase domain may distinguish which second generation ALK inhibitor will be effective after crizotinib failure. This case also provides evidence that transaminase elevations is likely a unique adverse event associated with crizotinib and unlikely a "class" effect involving all ALK inhibitors.

KEYWORDS:

ALK-rearranged non-small cell lung cancer; Alectinib; Ceritinib; Crizotinib; I1171 missense mutation; I1171N; I1171S; I1171T

PMID:
25736571
DOI:
10.1016/j.lungcan.2015.02.005
[PubMed - indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center