Analysis of circulating tumour DNA to identify patients with epidermal growth factor receptor-positive non-small cell lung cancer who might benefit from sequential tyrosine kinase inhibitor treatment

Eur J Cancer. 2021 May:149:61-72. doi: 10.1016/j.ejca.2021.02.031. Epub 2021 Apr 5.

Abstract

Background: Survival data support the use of first-line osimertinib as the standard of care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC). However, it remains unclear whether upfront osimertinib is superior to sequential first- or second-generation tyrosine kinase inhibitors (TKIs) followed by osimertinib for all patients. It is impossible to predict which patients are at high risk of progression, and this constitutes a major limitation of the sequential TKI approach.

Patients and methods: A total of 830 plasma samples from 228 patients with stage IV, EGFR-positive NSCLC who were treated with first-line TKIs were analysed by digital polymerase chain reaction (dPCR).

Results: The circulating tumour DNA (ctDNA) levels helped to identify patients with significantly improved survival rate, regardless of the treatment. Patients treated with first- or second-generation TKIs (N = 189) with EGFR mutations in plasma at a mutant allele frequency (MAF) <7% before treatment initiation (low-risk patients) or who were ctDNA negative after 3 or 6 months of treatment and with an MAF <7% at diagnosis (high responders) had two-thirds lower risk of death than patients in the opposite situation (adjusted hazard ratio [HR] = 0.38; 95% confidence interval [CI]: 0.23-0.64 and HR = 0.22; 95% CI: 0.12-0.42, respectively). The median overall survival (OS) for low-risk patients and high responders treated with first- or second-generation TKIs was 34.2 months and not reached, respectively, regardless of second-line treatment. There were no significant difference in OS between low-risk or high-responder patients treated upfront with osimertinib (N = 39) and those treated under a sequential approach with osimertinib (N = 60). Median OS was not reached in both cases.

Conclusions: Pre-treatment ctDNA levels identify low-risk patients, who may benefit from sequential TKI treatment. Information regarding EGFR mutation clearance can help to improve patient selection.

Keywords: EGFR; NSCLC; Osimertinib; TKI; ctDNA.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrylamides / therapeutic use
  • Aged
  • Aniline Compounds / therapeutic use
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics*
  • Carcinoma, Non-Small-Cell Lung / blood
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Circulating Tumor DNA / blood
  • Circulating Tumor DNA / genetics*
  • Clinical Decision-Making
  • Cross-Sectional Studies
  • DNA Mutational Analysis
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / blood
  • ErbB Receptors / genetics
  • Female
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Staging
  • Polymerase Chain Reaction
  • Predictive Value of Tests
  • Prospective Studies
  • Protein Kinase Inhibitors / therapeutic use
  • Spain
  • Time Factors
  • Treatment Outcome

Substances

  • Acrylamides
  • Aniline Compounds
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • Protein Kinase Inhibitors
  • osimertinib
  • EGFR protein, human
  • ErbB Receptors