Cell‐Free Plasma DNA‐Guided Treatment With Osimertinib in Patients With Advanced EGFR‐Mutated NSCLC

Introduction: Osimertinib is standard treatment for patients with advanced EGFR T790M‐mutated non–small‐cell lung cancer who have been pre‐treated with EGFR–tyrosine kinase inhibitors (TKIs). We studied whether cell‐free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. Methods: From April 2015 to November 2016, we included 119 patients with advanced EGFR‐mutated non–small‐cell lung cancer who had progressed under treatment with an EGFR‐TKI. The T790M mutation status was assessed in cell‐free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. Results: T790M mutations were detected in 85 (93%) patients by analyses of cell‐free plasma DNA and in 6 (7%) plasma‐negative patients by tumor re‐biopsy. Eighty‐nine of 91 T790M‐positive patients received osimertinib. Median progression‐free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1–12.1). Median survival was not reached and the 1‐year survival was 64%. The response rate was 70% in T790M‐positive patients (n = 91) in the intention‐to‐treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number (<10 copies/mL) (hazard ratio for PFS = 1.72, 95% CI: 0.92–3.2, p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89–5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. Conclusion: Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first‐line EGFR‐TKI therapy for treatment with osimertinib.

[1]  N. Rosenfeld,et al.  Osimertinib benefit in EGFR-mutant NSCLC patients with T790M-mutation detected by circulating tumour DNA , 2017, Annals of oncology : official journal of the European Society for Medical Oncology.

[2]  S. Toyooka,et al.  Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. , 2010, The Lancet. Oncology.

[3]  R. Pirker.  What is the best strategy for targeting EGF receptors in non-small-cell lung cancer? , 2015, Future oncology.

[4]  P. Peng,et al.  Circulating cell-free DNA as a prognostic and predictive biomarker in non-small cell lung cancer , 2016, Oncotarget.

[5]  P. Jänne,et al.  Detection of T790M, the Acquired Resistance EGFR Mutation, by Tumor Biopsy versus Noninvasive Blood-Based Analyses , 2015, Clinical Cancer Research.

[6]  M. Ladanyi,et al.  Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based Assay , 2011, Clinical Cancer Research.

[7]  William Pao,et al.  AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. , 2014, Cancer discovery.

[8]  T. Mok,et al.  Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. , 2009, The New England journal of medicine.

[9]  T. Mok,et al.  Single-Molecule Detection of Epidermal Growth Factor Receptor Mutations in Plasma by Microfluidics Digital PCR in Non–Small Cell Lung Cancer Patients , 2009, Clinical Cancer Research.

[10]  P. Jänne,et al.  Plasma ctDNA Analysis for Detection of the EGFR T790M Mutation in Patients with Advanced Non–Small Cell Lung Cancer , 2017, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[11]  T. Jiang,et al.  Role of circulating-tumor DNA analysis in non-small cell lung cancer. , 2015, Lung cancer.

[12]  A. Gemma,et al.  F1000 highlights , 2010 .

[13]  C. Paweletz,et al.  Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  J. Neal,et al.  Rociletinib in EGFR-mutated non-small-cell lung cancer. , 2015, The New England journal of medicine.

[15]  J Carl Barrett,et al.  EGFR mutation detection in ctDNA from NSCLC patient plasma: A cross-platform comparison of leading technologies to support the clinical development of AZD9291. , 2015, Lung cancer.

[16]  M. Rodriguez-Ruiz,et al.  Total and mutated EGFR quantification in cell-free DNA from non-small cell lung cancer patients detects tumor heterogeneity and presents prognostic value , 2016, Tumor Biology.

[17]  E. Smit,et al.  Incidence of T790M mutation in (sequential) rebiopsies in EGFR-mutated NSCLC-patients. , 2014, Lung cancer.

[18]  Jun Ma,et al.  Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. , 2011, The Lancet. Oncology.

[19]  T. Mitsudomi,et al.  Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. , 2016, The Lancet. Oncology.

[20]  Yi-Lin Chen,et al.  Real‐world outcomes of NSCLC patients receiving tissue or circulating tumor DNA‐guided osimertinib treatment , 2019, Cancer medicine.

[21]  Suzanne E Dahlberg,et al.  Prospective Validation of Rapid Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced Lung Cancer. , 2016, JAMA oncology.

[22]  M. Erlander,et al.  A Highly Sensitive and Quantitative Test Platform for Detection of NSCLC EGFR Mutations in Urine and Plasma , 2016, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[23]  E. Felip,et al.  Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. , 2012, The Lancet. Oncology.

[24]  Chun-Ming Tsai,et al.  Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  P. Jänne,et al.  AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. , 2015, The New England journal of medicine.

[26]  Jingyun Shi,et al.  T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients. , 2014, Lung cancer.

[27]  J. Zavadil,et al.  Circulating free DNA concentration is an independent prognostic biomarker in lung cancer , 2015, European Respiratory Journal.

[28]  U. Lehmann,et al.  Molecular Analysis of Circulating Cell-Free DNA from Lung Cancer Patients in Routine Laboratory Practice: A Cross-Platform Comparison of Three Different Molecular Methods for Mutation Detection. , 2017, The Journal of molecular diagnostics : JMD.

[29]  Y. Ohe,et al.  LBA2_PROsimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA , 2017 .

[30]  Kyung-A Lee,et al.  Selecting short length nucleic acids localized in exosomes improves plasma EGFR mutation detection in NSCLC patients , 2019, Cancer Cell International.

[31]  Haikuo Zhang,et al.  Overcoming EGFR T790M and C797S resistance with mutant-selective allosteric inhibitors , 2016 .

[32]  William Pao,et al.  Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR-Mutant Lung Cancers , 2013, Clinical Cancer Research.

[33]  M. Ahn,et al.  Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer , 2017, The New England journal of medicine.

[34]  E. Giovannetti,et al.  Feasibility of cell-free circulating tumor DNA testing for lung cancer. , 2016, Biomarkers in medicine.

[35]  C. Paweletz,et al.  Noninvasive Detection of Response and Resistance in EGFR-Mutant Lung Cancer Using Quantitative Next-Generation Genotyping of Cell-Free Plasma DNA , 2014, Clinical Cancer Research.

[36]  M. Filipits,et al.  The potential of liquid biopsies , 2016, Current opinion in oncology.

[37]  W. Pao,et al.  Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models. , 2015, Cancer research.

[38]  Aleksandra Markovets,et al.  Acquired EGFR C797S mediates resistance to AZD9291 in advanced non-small cell lung cancer harboring EGFR T790M , 2015, Nature Medicine.

[39]  Kikuya Kato,et al.  Quantitative Detection of EGFR Mutations in Circulating Tumor DNA Derived from Lung Adenocarcinomas , 2011, Clinical Cancer Research.