Anaplastic Lymphoma Kinase (ALK) Kinase Domain Mutation Following ALK Inhibitor(s) Failure in Advanced ALK Positive Non–Small-Cell Lung Cancer: Analysis and Literature Review

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We analyzed anaplastic lymphoma kinase (ALK) kinase domain mutation in patients with advanced ALK-positive non–small-cell lung cancer who failed after treatment with ALK inhibitor(s). Secondary ALK domain mutation was found in 28% of the patients after crizotinib failure, in 78% of the patients after alectinib failure, and in 36% of the patients after ceritinib failure. Some mutations caused co-resistance to other ALK inhibitors. A re-biopsy for ALK mutation analysis might be suggested prior to second-line ALK inhibitor treatment.


Secondary anaplastic lymphoma kinase (ALK) mutation may occur in patients with advanced ALK-positive non–small cell lung cancer treated with ALK inhibitors, but its nature is not well-known.

Patients and Methods:

We analyzed tumor specimens after the failure of treatment with ALK inhibitor(s) (crizotinib, alectinib, and ceritinib) for secondary ALK kinase domain mutation, EGFR, K-ras, and PIK3CA mutations. The literature regarding acquired ALK-inhibitor(s) resistance was also reviewed.


Among 59 patients who received ALK inhibitor(s) during the period of December 2010 to April 2015, 7 had re-biopsied tumor specimens for analyses following ALK inhibitor(s) failure. One had G1202R after crizotinib and alectinib failure, and 6 were wild type. No EGFR, K-ras, or PIK3CA mutations were found. In our review of the literature and taken together with our patients, 25 of the 88 (28%) patients with crizotinib failure had secondary ALK mutation; L1196M mutation was most common (n = 11). Patients with secondary ALK mutation other than L1196M had a longer progression-free survival after crizotinib than patients with L1196M (median, 12.0 vs. 7.0 months; P = .04). Of the 9 patients with alectinib failure, 5 had I1171 mutation and 2 had G1202R. Of the 11 patients with ceritinib failure, 2 had G1202R, 1 had F1174C, and 1 had both G1202R and F1174V. I1171 mutation, G1202R, and F1174 mutations were also found in crizotinib-failed patients.


Some acquired ALK mutations may cause co-resistance to other ALK inhibitors. Re-biopsy for ALK mutation analysis might be suggested prior to choosing a second-line ALK inhibitor treatment.

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