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Observational Study
. 2024 Jul;19(7):995-1006.
doi: 10.1016/j.jtho.2024.04.007. Epub 2024 Apr 12.

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRASG12C-Mutated NSCLC Treated With Sotorasib

Sophie M Ernst  1 , Ronald van Marion  2 , Peggy N Atmodimedjo  2 , Evert de Jonge  3 , Ron H J Mathijssen  4 , Marthe S Paats  1 , Peter de Bruijn  4 , Stijn L Koolen  5 , Jan H von der Thüsen  2 , Joachim G J V Aerts  1 , Ron H N van Schaik  3 , Hendrikus J Dubbink  2 , Anne-Marie C Dingemans  6
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Free article
Observational Study

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRASG12C-Mutated NSCLC Treated With Sotorasib

Sophie M Ernst et al. J Thorac Oncol. 2024 Jul.
Free article

Abstract

Introduction: For patients with KRASG12C-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 KRASG12C-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 KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C 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 KRASG12C 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.

Keywords: Biomarker; NSCLC; Sotorasib; ctDNA.

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Conflict of interest statement

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.

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