The Impact of Clinical Factors, ALK Fusion Variants, and BIM Polymorphism on Crizotinib-Treated Advanced EML4-ALK Rearranged Non-small Cell Lung Cancer.

Yen-Ting Lin,Yi-Nan Liu,Jin-Yuan Shih

doi:10.3389/fonc.2019.00880

Abstract

Patients' clinical factors and genetics factors such as anaplastic lymphoma kinase (ALK) fusion variants and BIM (Bcl-2-like 11) polymorphism were reported to be associated with clinical outcome in crizotinib-treated advanced non-small cell lung cancer (NSCLC). However, the results were still controversial. We analyzed outcome of 54 patients with known ALK fusion variants who received crizotinib for advanced NSCLC. Thirty of them had successful BIM polymorphism analysis and 6 (20%) had a BIM deletion. Multivariate Cox regression analysis found that previous anticancer therapy [adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI), 1.04–1.76 for each additional line of therapy, p = 0.025] and Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (aHR 8.35, 95% CI, 1.52–45.94, p = 0.015) were independent factors for progression-free survival (PFS). Only ECOG performance status ≥2 (aHR 7.20, 95% CI, 1.27–40.79, p = 0.026) was an independent factor for overall survival (OS). Neither ALK fusion variants nor the presence of a BIM deletion was associated with crizotinib PFS or OS. After adjusting with clinical factors, different ALK variants and BIM polymorphism might not be independent factors for crizotinib PFS or OS in advanced NSCLC with ALK rearrangement.

Highlights

In 2007, the echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) gene rearrangement was first discovered as a driver oncogene for non-small cell lung cancer (NSCLC) [1]
We found that clinical factors such as prior anticancer therapy and Eastern Cooperative Oncology Group (ECOG) performance status were independent factors for crizotinib progression-free survival (PFS) in advanced NSCLC bearing EML4–ALK fusion, TABLE 2 | Progression-free survival: univariate and multivariate analysis (n = 54)
AALK variants other than variants 1, 2, or 3a/b. bAs a reference compared to other ALK variants

Summary

Introduction

In 2007, the echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) gene rearrangement was first discovered as a driver oncogene for non-small cell lung cancer (NSCLC) [1]. Inversion in chromosome 2p fused the N-terminal domain of EML4 to the intracellular kinase domain of ALK, causing constitutive activation of tyrosine kinase, leading to uncontrolled cell growth and proliferation. During the following 10 years, targeting ALK with tyrosine kinase inhibitors (TKIs) has achieved great success. The first-generation ALK TKI crizotinib had better progression-free survival (PFS) (10.9 vs 7.0 months) and a better overall response rate (ORR) (74 vs 45%) than chemotherapy in treating naïve ALK rearranged {ALK positive [ALK(+)]} NSCLC in the PROFILE 1014 study [2]. Crizotinib has been approved by the US Food and Drug Administration (US FDA) as first-line treatment for ALK(+) advanced NSCLC [3].

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