Clinical utility of circulating tumor DNA in patients with advanced KRASG12C-mutated non-small cell lung cancer treated with sotorasib.

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 pre-treatment and on-treatment circulating tumor DNA (ctDNA), as well as treatment-emergent alterations upon disease progression. Methods Patients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected prior to sotorasib treatment, at first response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency (VAF) analysis. Tumor response and progression-free survival (PFS) was assessed per RECIST v1.1. Results Pre-treatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior PFS (HR 2.13 [95% CI 1.06 – 4.30], p=0.031) and overall survival (OS) (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 non-responders had inferior OS (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 pre-treatment 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.