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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.)

Comprehensive genotyping is necessary to identify therapy options for patients with advanced cancer; however, many cancers are not tested, partly because of tissue limitations. Next-generation sequencing (NGS) liquid biopsies overcome some limitations, but clinical validity is not established and adoption is limited. Herein, clinical bridging studies used pretreatment plasma samples and data from FLAURA (NCT02296125; n = 441) and AURA3 (NCT02151981; n = 450) pivotal studies to demonstrate clinical validity of Guardant360 CDx (NGS LBx) to identify patients with advanced EGFR mutant non-small-cell lung cancer who may benefit from osimertinib. The primary end point was progression-free survival (PFS). Patients with EGFR mutation as identified by NGS LBx had significant PFS benefit with first-line osimertinib over standard of care (15.2 versus 9.6 months; hazard ratio, 0.41; P < 0.0001) and with later-line osimertinib over chemotherapy (8.3 versus 4.2 months; hazard ratio, 0.34; P < 0.0001). PFS benefits were similar to the original trial cohorts selected by tissue-based EGFR testing. Analytical validation included accuracy, precision, limit of detection, and specificity. Analytical validity was established for EGFR mutation detection and pan-tumor profiling. Panel-wide limit of detection was 0.1% to 0.5%, with 98% to 100% per-sample specificity. Patients with EGFR mutant non-small-cell lung cancer by NGS LBx had improved PFS with osimertinib, confirming clinical validity. Analytical validity was established for guideline-recommended therapeutic targets across solid tumors. The resulting US Food and Drug Administration approval of NGS LBx demonstrated safety and effectiveness for its intended use and is expected to improve adherence to guideline-recommended targeted therapy use., Competing Interests: Disclosure Statement J.E.G. served on advisory councils or committees for AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Daiichi Sankyo, Inc (DSI), EMD Serono–Merck KGaA, Inivata, Janssen Scientific Affairs, LLC, Merck, and Novartis; received consulting fees from AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, DSI, EMD Serono–Merck KGaA, Inivata, Janssen Scientific Affairs, LLC, Merck, and Novartis; and received grants or funding from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G 1 Therapeutics, Merck, Novartis, Pfizer, and Ludwig Institute of Cancer Research. J.-Y.H. served on advisory councils or committees for Novartis, MSD Oncology, AstraZeneca, Lilly, and Takeda; received honoraria from Roche, AstraZeneca, and Takeda; and received grants or funding from Roche, Pfizer, and ONO. A.T.-K., X.H., A.K., R.H., Y.R., J.C., and J.C.B. are employees and shareholders of AstraZeneca. C.R.E., M.L., and J.I.O. are employees and shareholders of Guardant Health. Y.-L.W. participated on speaker's bureau for AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Sanofi, and Roche; and received institutional financial research grants from AstraZeneca, BMS, Pfizer, and Roche. S.S.R. received honoraria from Amgen, BMS, Merck, Genentech, Tesaro, Takeda, Glaxo SmithKline, and AstraZeneca; and grants or funding from Amgen, Advaxis, AstraZeneca, BMS, Merck, Tesaro, Takeda, and Genmab; and nonfinancial support from AstraZeneca., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis., Patients and Methods: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points., Results: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm., Conclusions: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib., Clinical Trials Number: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981., Competing Interests: Disclosures VAP has declared honorarium from F Hoffman-La Roche; advisory or consultancy fees from Nektar Therapeutics, Astra Zeneca Pharmaceuticals, Arrys Therapeutics, Merck & Co, LOXO Oncology, Araxes Pharma, F. Hoffman–LaRoche Ltd, Janssen Research Foundation, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly & Co, Novartis Pharmaceuticals Corp., Takeda Pharmaceuticals, AbbVie, TRM Oncology, Tesaro, Exelixis, Gritstone, Leeds Biolabs, IDEAYA, Bolt Therapeutics, and G2 Innovation; and research funding from Eli Lilly & Co, Novartis, Merck, Astra Zeneca Pharmaceuticals, F Hoffman-La Roche, Nektar Therapeutics, Janssen, Bristol-Myers Squibb, Checkmate, and Incyte. TSM has declared honoraria from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Celgene, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate, Hengrui Therapeutics, Ignyta, Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo Oncology, Merck Serono, MSD, MORE Health, Novartis, OncoGenex Pharmaceuticals, OrigiMed, PeerVoice, Pfizer, PrIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Pharmaceuticals HK, Vertex Pharmaceuticals, and Yuhan Corporation; advisory or consultancy fees from ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, AstraZeneca, Bayer, Boehringer Ingelheim, Blueprint Medicines Corporation, Bristol-Myers Squibb, Celgene, Cirina, CStone Pharmaceuticals, Eli Lilly, Fishawack Facilitate, GeneDecode, Hengrui Therapeutics, Ignyta, Incyte Corporation, InMed Medical Communication, IQVIA, Janssen, Loxo-Oncology, Merck Serono, MSD, MORE Health, Novartis, OncoGenex Pharmaceuticals, OrigiMed, PeerVoice, Pfizer, PrIME Oncology, Roche/Genentech, Sanofi-Aventis R&D, SFJ Pharmaceutical, Takeda Pharmaceuticals HK, Vertex Pharmaceuticals, and Yuhan Corporation; leadership roles for AstraZeneca and Hutchison Chi-Med; research funding from AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, MSD, Novartis, Pfizer, Roche, SFJ, and Xcovery; shareholdings in Hutchison Chi-Med, and Sanomics; stock options in Clearbridge BioMedics (now Biolidics), Loxo-Oncology, OrigiMed, and Virtus Medical Group; and officer or director for AstraZeneca, Hutchison Chi-Med (remunerated), American Society of Clinical Oncology (ASCO), Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Chinese Society of Clinical Oncology (CSCO), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), and International Association for the Study of Lung Cancer (IASLC; term ended on 30/4/19 [non-remunerated]). J-YH has declared honoraria from Roche, AstraZeneca, Bristol-Myers Squibb, MSD, and Takeda; advisory or consultancy fees from AstraZeneca, Bristol-Myers Squibb, MSD, Takeda, Pfizer, Novartis, and Lilly; research funding from Roche, Pfizer, Ono Pharmaceutical, and Takeda. M-JA has declared advisory or consultancy fees from AstraZeneca, MSD, Ono Pharmaceutical, and Lilly; and speaker fees from AstraZeneca, MSD, Ono Pharmaceutical, Lilly, Roche, Alpha Pharmaceutical, and Takeda. SSR has declared honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, and Tesaro; advisory or consultancy fees from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Roche/Genentech, Loxo, Nektar, and Tesaro; and research funding from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck, Tesaro, Advaxis, and Takeda. SWK has declared advisory or consultancy fees from AstraZeneca; and research funding from AstraZeneca. FAS has declared advisory or consultancy fees from AstraZeneca; research funding from AstraZeneca; and shareholdings in AstraZeneca. JL has declared honoraria from Roche, AstraZeneca, and Pfizer; and research funding from Roche, Boehringer Ingelheim, Pfizer, and AstraZeneca. HA has declared honoraria from AstraZeneca, Chugai, Pfizer, and Boehringer Ingelheim; and advisory or consultancy fees from AstraZeneca and Pfizer. W-CS has declared travel, accommodation, or expenses from Bristol-Myers Squibb and Boehringer Ingelheim. TJ has declared advisory or consultancy fees from Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda, Boehringer Ingelheim, and Pfizer. MS has declared honoraria from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD; advisory or consultancy fees from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD; and speaker fees from AstraZeneca, Pfizer, Roche, Boehringer Ingelheim, Novartis, Celgene, Takeda, Lilly, Bristol-Myers Squibb, and MSD. Y-LW has declared honoraria from AstraZeneca, Roche, Eli Lilly, Pfizer, MSD, Bristol-Myers Squibb, and Boehringer Ingelheim; advisory or consultancy fees from AstraZeneca and Roche; and research funding from AstraZeneca and Roche. HM, MM, GL, and YR are employees of and have shareholdings in AstraZeneca. AD, YH, and WSMET have declared no conflicts of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Introduction: Currently, the role of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as adjuvant therapy for early-stage non-small-cell lung cancer after complete surgical tumor resection remains under investigation. We present the rationale and study design for the ADAURA (ClinicalTrials.gov identifier, NCT02511106) trial, a multicenter, double-blind, randomized, placebo-controlled study., Patients and Methods: Study entry will be limited to adults aged ≥ 18 years (and in Japan and Taiwan, age ≥ 20 years) with primary nonsquamous stage IB-IIIA non-small-cell lung cancer with central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be randomized 1:1 to receive osimertinib 80 mg once daily or placebo once daily until disease recurrence, a treatment discontinuation criterion is met, or patients achieve the maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival. Secondary endpoints include the disease-free survival rate at 2, 3, and 5 years, overall survival, overall survival rate at 5 years, and safety and tolerability. Health-related quality of life and pharmacokinetics will also be evaluated. The exploratory objectives include assessment of osimertinib efficacy in patients with a confirmed baseline T790M mutation status and postrecurrence outcomes, health resource use, and a comparison of plasma-derived circulating tumor DNA EGFR mutation status at baseline and at disease recurrence., Results: Study enrollment began in August 2015, and results are expected in the third quarter of 2021 (depending on the actual event rate)., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)