Longitudinal Analyses of Circulating Tumor DNA for the Detection of EGFR Mutation-Positive Advanced NSCLC Progression During Treatment: Data From FLAURA and AURA3.

Introduction: EGFR tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma through circulating tumor DNA (ctDNA). Circulating tumor DNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection.
Methods: This was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced NSCLC with EGFR mutations and on-study PD (RECIST [Response Evaluation Criteria in Solid Tumors]), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD and the first subsequent treatment (FLAURA only).
Results: Circulating tumor DNA PD preceded or co-occurred with RECIST-defined PD in 93 out of 146 patients (64%) in FLAURA and 82 out of 146 patients (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (mo) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, the median time from ctDNA PD to the first subsequent treatment (mo) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70).
Conclusions: Among patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD.
Competing Interests: Disclosure Dr. Gray reports participation on the board of directors for IASLC; consulting or advisory fees from AbbVie, AstraZeneca, Blueprint Medicines, Daiichi-Sankyo, EMD Serono, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Novartis, OncoCyte, Spectrum ODAC, Takeda, and Triptych Health Partners; research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co., Novartis, and Pfizer; employment with Moffitt Cancer Center; holding a leadership role as SWOG Lung Committee Chair and ASCO Education Committee Ex-Chair; and payments/honoraria from AbbVie, AstraZeneca, Blueprint Medicines, Daiichi-Sankyo, EMD Serono, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Novartis, OncoCyte, Spectrum ODAC, Takeda, and Triptych Health Partners. Dr. Markovets reports employment with AstraZeneca. Dr. Reungwetwattana reports honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Takeda, Yuhan, and Zuellig; and research grants from AstraZeneca, Novartis, Roche, and Yuhan. Dr. Majem reports honoraria from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Helsinn Therapeutics, Immedica, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and Takeda; research grants from AstraZeneca, Bristol Myers Squibb, and Roche; and travel support from AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Pfizer and Roche. Dr. Cho reports an advisory role for Bridge Biotherapeutics, Inc., Cyrus Therapeutics, Inc., Guardant Health, Joseah BIO, and KANAPH Therapeutic, Inc.; participation on boards of directors for Gencurix, Inc. and Interpark Bio Convergence Corp.; consulting fees from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Medpacto, Merck Sharp & Dohme, Novartis, Ono Pharma Co., Ltd., Pfizer, Roche, Takeda, and Yuhan; employment with Yonsei University College of Medicine; being a founder of DAAN Biotherapeutics; grants or funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, Dizal Pharmaceutical Co., Ltd., Dong-A ST, Eli Lilly, GI Innovation, Interpark Bio Convergence Corp., Janssen, Medpacto, Merck Sharp & Dohme, MOGAM Institute, Novartis, Ono Pharma Co., Ltd., and Yuhan; royalties from Champions Oncology; and stock or stock options with Bridge Biotherapeutics, Inc., Cyrus Therapeutics, Inc., Gencurix, Inc., KANAPH Therapeutic, Inc., Interpark Bio Convergence Corp., and TheraCanVac, Inc. Dr. Chewaskulyong reports honoraria and research grants from AstraZeneca. Dr. John reports consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead Sciences, Inc., Ignyta, Merck Sharp & Dohme, Merck KGaA, Novartis, Pfizer, PharmaMar, Roche/Genentech, and Specialised Therapeutics; honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche/Genentech; and travel support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche. Dr. Sebastian reports participation on an advisory board for Amgen; consulting fees from Amgen, AstraZeneca, Boehringer lngelheim, Bristol Myers Squibb, GSK, Johnson & Johnson, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Roche, and Takeda; grants or contracts from AstraZeneca; honoraria from Amgen, AstraZeneca, BioNTech, Boehringer lngelheim, Bristol Myers Squibb, CureVac, Daiichi-Sankyo, GSK, Johnson & Johnson, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, and Takeda; and travel support from Bristol Myers Squibb and Pfizer. Drs Todd, Rukazenkov, Barrett, and Chmielecki report employment and holding stock or stock options with AstraZeneca. Dr. Ramalingam reports personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, GSK, Merck, Takeda, and Tesaro and other non-financial support from AstraZeneca. Dr. Hartmaier reports being an inventor on patent US11066709B2, and employment and holding stock or stock options with AstraZeneca. The remaining authors declare no conflict of interest.
(Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)