Elsevier

Lung Cancer

Volume 88, Issue 2, May 2015, Pages 231-234
Lung Cancer

Case report
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

https://doi.org/10.1016/j.lungcan.2015.02.005Get rights and content

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.

Section snippets

Case

Patient is a Caucasian female never-smoker who was diagnosed with stage IV non-small cell lung cancer (left hilar tumor primary and liver metastases) at age 51. Her tumor was found to be positive for ALK rearrangement by fluorescence in situ (FISH) at the time of diagnosis. She was started on crizotinib 250 mg twice daily but had grade 3 (>5 and ≤20 upper limits of normal) liver enzymes elevation after only 3 weeks of crizotinib and requiring discontinuation of crizotinib. During the subsequent

Discussion

This case report represents only the fifth case to date demonstrating that the ALK I1171 missense mutation is an acquired resistance mechanism to alectinib and the second case to date demonstrating ALK I1171 missense mutation is sensitive to ceritinib (Table 1) [2], [3], [4]. Currently, I1171 missense mutation has developed in both EML4-ALK variant 3 [3], [4] and HIP1-ALK [3] indicating I1171 acquired resistance mutation is independent of the ALK fusion partner (Table 1). To generate the

Conflict of interest statement

Sai-Hong Ignatius Ou and Barbara Gitlitz have received honorarium as a member of the Pfizer and Roche Speaker bureau and Advisory Board.

Joel Greenbowe, Siraj Ali, Jeffrey S. Ross, Phil J. Stevens, Vincent A. Miller and employees of Foundation Medicine Inc. and own stocks of Foundation Medicine Inc.

Ziad Khan and Michele Azada have no conflict of interest to declare.

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