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Aims: Osimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events., Methods: Comprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUC ss ) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis., Results: E-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUC ss ; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control., Conclusions: E-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

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.)