Efficacy and Tolerability of Osimertinib and Sotorasib Combination Treatment for Osimertinib Resistance Caused by KRAS G12C Mutation: A Report of Two Cases

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is currently considered the standard first-line systemic treatment for patients with advanced EGFR-mutated non–small-cell lung cancer (NSCLC). Although osimertinib has significantly improved disease outcomes,1 resistance inevitably develops. The acquired resistance mechanisms can be highly heterogeneous, including on- and off-target mechanisms.2,3 Although aberrations in the RAS-MAPK pathway have been known to lead to osimertinib resistance, the emergence of KRAS G12C mutations in this setting has rarely been reported. Recently sotorasib, a first-in-class KRAS G12C inhibitor has been approved for patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, which provides an opportunity to directly target KRAS G12C.4 Here, we report two cases of resistance to first-line osimertinib caused by acquired KRAS G12C mutations. Both patients were treated with a combination of osimertinib and sotorasib.