Anaplastic Lymphoma Kinase Variants and the Percentage of ALK-Positive Tumor Cells and the Efficacy of Crizotinib in Advanced NSCLC

Clin Lung Cancer. 2016 May;17(3):223-31. doi: 10.1016/j.cllc.2015.09.002. Epub 2015 Sep 21.

Abstract

Background: Anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer patients exhibited heterogeneous magnitude of response and duration time to criztotinib treatment. This study explored ALK variants and the percentage of ALK-positive cells using fluorescent in situ hybridization (FISH) on clinical efficacy of crizotinib.

Patients and methods: A total of 120 patients with ALK rearrangement who were treated with criztotinib were enrolled. ALK variants were clarified in 61 patients, and ALK percentages were evaluated using FISH in 114 ALK-positive patients. Retrospectively, objective response rate, and progression-free survival (PFS) were evaluated.

Results: A total of 61 patients with specific ALK variants were divided into 3 subgroups, echinoderm microtubule-associated protein like 4 (EML4)-ALK variant 1 (n = 22), EML4-ALK variant 3a/b (n = 18), and other ALK variants (n = 21). Median PFS in the 3 subgroups was 11.0 months (95% confidence interval [CI], 5.5-16.5), 10.9 months (95% CI, 5.9-15.8), 7.4 months (95% CI, 3.2-11.6), respectively, and no significant difference (P = .795) existed among them. The percentage of ALK-positive cells in FISH analysis was weakly correlated with PFS (rs = 0.235; P = .015). Additionally, it was also weakly correlated with best response to crizotinib (rs = 0.288; P = .003). Overall, there were 45, 49, and 26 patients receiving first, second, and third or further-line crizotinib, respectively. Median PFS in the first-line setting (10.5 months; 95% CI, 8.6-12.4) was significantly longer than that in the second-line setting (8.3 months; 95% CI, 4.7-12.0; P = .020).

Conclusion: Anaplastic lymphoma kinase variants might have no correlation with clinical response to crizotinib. The percentage of ALK-positive cells might correlate with the extent of benefit from crizotinib treatment.

Keywords: Anaplastic lymphoma kinase variants; Crizotinib; Non–small-cell lung cancer; Percentage of ALK-positive cells; Progression-free survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anaplastic Lymphoma Kinase
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Pharmacological / analysis
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Crizotinib
  • Female
  • Follow-Up Studies
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / mortality
  • Male
  • Middle Aged
  • Neoplasm Staging
  • Polymorphism, Genetic
  • Pyrazoles / therapeutic use*
  • Pyridines / therapeutic use*
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Survival Analysis
  • Treatment Outcome
  • Young Adult

Substances

  • Antineoplastic Agents
  • Biomarkers, Pharmacological
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases