Circulating Cell-free DNA as a Prognostic Biomarker in Patients with Advanced ALK+ Non-small Cell Lung Cancer in the Global Phase III ALEX Trial

Clin Cancer Res. 2022 May 2;28(9):1800-1808. doi: 10.1158/1078-0432.CCR-21-2840.


Purpose: We retrospectively assessed prognostic value of circulating cell-free DNA (cfDNA) using data from the phase III ALEX study in treatment-naïve, advanced ALK+ non-small cell lung cancer (NSCLC).

Patients and methods: Patients were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151). cfDNA was quantified from baseline plasma samples, with patients stratified into ≤median and >median cfDNA biomarker-evaluable populations (BEP). Effect of cfDNA concentration on outcomes was analyzed using a Cox regression model with treatment group as covariate, and in multivariate analyses.

Results: Median cfDNA concentration in the BEP was 11.53 ng/mL (n = 276). A positive correlation was found between cfDNA concentration and number of lesions, organ lesion sites, and tumor size (sum of longest diameter; all P < 0.0001). In both treatment arms, patients in the >median BEP were more likely to experience disease progression than the ≤median BEP [alectinib adjusted HR = 2.04; 95% confidence interval (CI), 1.07-3.89; P = 0.0305 and crizotinib adjusted HR = 1.83; 95% CI, 1.11-3.00, P = 0.0169]. Median progression-free survival was longer with alectinib than crizotinib in both ≤median and >median BEPs (P < 0.0001). Overall survival data remain immature; survival probability was lower in the >median versus ≤median BEP in both treatment arms (alectinib HR = 2.52; 95% CI, 1.08-5.88; P = 0.0333 and crizotinib HR = 2.63; 95% CI, 1.27-5.47; P = 0.0096).

Conclusions: These data suggest that plasma cfDNA concentration may have prognostic value in advanced ALK+ NSCLC. Prospectively designed studies are warranted to investigate this finding.

Trial registration: NCT02075840.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase / genetics
  • Carbazoles / therapeutic use
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Cell-Free Nucleic Acids*
  • Crizotinib
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use
  • Retrospective Studies


  • Carbazoles
  • Cell-Free Nucleic Acids
  • Protein Kinase Inhibitors
  • Crizotinib
  • Anaplastic Lymphoma Kinase

Associated data