MET-Driven Resistance to Sotorasib in KRAS G12C-Mutant NSCLC and Response to Combined KRAS and MET Inhibition.
[INTRODUCTION] mutations define a molecularly distinct subset of NSCLC for which targeted therapy with sotorasib has exhibited clinical efficacy.
APA
Riedel R, Ruge L, et al. (2026). MET-Driven Resistance to Sotorasib in KRAS G12C-Mutant NSCLC and Response to Combined KRAS and MET Inhibition.. JTO clinical and research reports, 7(3), 100925. https://doi.org/10.1016/j.jtocrr.2025.100925
MLA
Riedel R, et al.. "MET-Driven Resistance to Sotorasib in KRAS G12C-Mutant NSCLC and Response to Combined KRAS and MET Inhibition.." JTO clinical and research reports, vol. 7, no. 3, 2026, pp. 100925.
PMID
41815506
Abstract
[INTRODUCTION] mutations define a molecularly distinct subset of NSCLC for which targeted therapy with sotorasib has exhibited clinical efficacy. However, acquired resistance is inevitable. amplification has been described as a putative off-target resistance mechanism, although its clinical relevance remains incompletely understood.
[METHODS] We conducted a retrospective case series of patients with -mutant NSCLC treated with sotorasib at the University Hospital Cologne, Germany. Patients with available paired pre- and posttreatment biopsies were analyzed for resistance mechanisms using routine molecular diagnostics, including fluorescence in situ hybridization.
[RESULTS] Nine patients with paired pre and posttreatment biopsies were identified. High-level amplification was detected by fluorescence in situ hybridization in four cases and intermediate-level amplification in one case after progression on sotorasib. Notably, one patient with acquired amplification achieved a renewed partial response to the combination of sotorasib and tepotinib after progression on sotorasib monotherapy.
[CONCLUSION] This study provides real-world evidence that amplification is an acquired and potentially targetable resistance mechanism to KRAS G12C inhibition in NSCLC. Our findings support rebiopsy at progression on sotorasib. Further prospective trials are warranted to validate amplification as a resistance mechanism and to define optimal therapeutic thresholds for combined KRAS and MET inhibition.
[METHODS] We conducted a retrospective case series of patients with -mutant NSCLC treated with sotorasib at the University Hospital Cologne, Germany. Patients with available paired pre- and posttreatment biopsies were analyzed for resistance mechanisms using routine molecular diagnostics, including fluorescence in situ hybridization.
[RESULTS] Nine patients with paired pre and posttreatment biopsies were identified. High-level amplification was detected by fluorescence in situ hybridization in four cases and intermediate-level amplification in one case after progression on sotorasib. Notably, one patient with acquired amplification achieved a renewed partial response to the combination of sotorasib and tepotinib after progression on sotorasib monotherapy.
[CONCLUSION] This study provides real-world evidence that amplification is an acquired and potentially targetable resistance mechanism to KRAS G12C inhibition in NSCLC. Our findings support rebiopsy at progression on sotorasib. Further prospective trials are warranted to validate amplification as a resistance mechanism and to define optimal therapeutic thresholds for combined KRAS and MET inhibition.