ctDNA Detection of Polyclonal KRAS Resistance in Adagrasib‐Treated NSCLC

Circulating tumor DNA (ctDNA) monitoring may detect resistance to KRAS G12C inhibitors earlier than conventional imaging. However, in the specific context of KRAS G12C inhibitors, the temporal relationship between molecular, radiologic, and clinical progression remains poorly characterized. A 66‐year‐old woman with KRAS G12C / STK11 / KEAP1 ‐mutant lung adenocarcinoma received second‐line adagrasib after progression on chemo‐immunotherapy. Serial ctDNA monitoring by droplet digital PCR and targeted next‐generation sequencing was performed. Baseline KRAS G12C ctDNA (6205.3 copies/mL) declined to 3.2 copies/mL after 7 weeks, indicating initial response. However, ctDNA levels rose to 21.1 copies/mL at month 4 and 315.2 copies/mL at month 6. Concurrent NGS revealed three emergent KRAS mutations (G12D, G13D, Q61H), confirming polyclonal resistance. Notably, CT and MRI imaging remained stable by RECIST criteria throughout this period. Significant clinical deterioration, requiring prolonged hospitalization, occurred approximately 8 weeks after initial ctDNA rise. The patient died 2 months after detection of resistance mutations. In this case, NGS ctDNA detected three acquired KRAS resistance mutations in addition to the original G12C, during a prolonged period of radiographic stability, illustrating polyclonal evolution under adagrasib pressure. These findings suggest that longitudinal liquid biopsy monitoring may provide early detection of resistance in KRAS G12C ‐mutant NSCLC.