Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRAS G12C -Mutated NSCLC Treated With Sotorasib.

Autor:	Ernst SM; Department of Respiratory Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands., van Marion R; Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands., Atmodimedjo PN; Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands., de Jonge E; Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands., Mathijssen RHJ; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands., Paats MS; Department of Respiratory Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands., de Bruijn P; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands., Koolen SL; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands; Department of Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands., von der Thüsen JH; Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands., Aerts JGJV; Department of Respiratory Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands., van Schaik RHN; Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands., Dubbink HJ; Department of Pathology, Erasmus University Medical Center, Rotterdam, The Netherlands., Dingemans AC; Department of Respiratory Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands. Electronic address: a.dingemans@erasmusmc.nl.
Jazyk:	angličtina
Zdroj:	Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2024 Jul; Vol. 19 (7), pp. 995-1006. Date of Electronic Publication: 2024 Apr 12.
DOI:	10.1016/j.jtho.2024.04.007
Abstrakt:	Introduction: For patients with KRAS G12C -mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression. Methods: Patients with KRAS G12C -mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1. Results: Pretreatment KRAS G12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRAS G12C had inferior progression-free survival (hazard ratio [HR] 2.13 [95% confidence interval [CI]: 1.06-4.30], p = 0.031) and overall survival (HR 2.61 [95% CI: 1.16-5.91], p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 [95% CI: 1.65-7.74], p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations. Conclusions: Our data suggest detectable pretreatment KRAS G12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions. Competing Interests: Disclosure Dr. Mathijssen reports receiving institutional fees for investigator-initiated trials from Astellas, Bayer, Boehringer-Ingelheim, Cristal Therapeutics, Deuter Oncology, Nordic Pharma, Novartis, Pamgene, Pfizer, Roche, Sanofi, and Servier, outside the current work. Dr. Paats reports receiving institutional fees from AstraZeneca, Bayer, Eli Lilly, Janssen, Novartis, Pfizer, Roche, and Takeda, outside the current work. Dr. Koolen reports receiving speaker fees from Promise Proteomics, outside the current work. Dr. von der Thüsen reports receiving advisory board and speaker fees from Eli Lilly, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Bayer, Janssen, and Pfizer, outside the current work. Dr. Aerts reports receiving advisory board and speaker fees from Eli Lilly, Bristol-Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Bayer, and Amphera and is a stock owner of Amphera, outside the current work. Dr. Dubbink reports receiving translational research funding and support from AstraZeneca, Merck Sharp & Dohme, and Illumina; advisory board fees from AbbVie, AstraZeneca, Bayer, Janssen, Lilly, Merck Sharp & Dohme, and Pfizer; honorarium from AstraZeneca, Lilly, Novartis, and Pfizer; and consultant fees from Bayer. Dr. Dingemans reports receiving institutional fees from Roche, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Janssen, Chiezi, Amgen, Pfizer, Bayer, Takeda, Pharmamar, Sanofi, and Daiichi, outside the current work. All other authors report no disclosures. (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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