ctDNA Sequencing Flags KEAP1, STK11 & NOTCH as Frequent Drivers of ICI Resistance in NSCLC

In a prospective two-cohort study (STING + COPE; n = 57) that collected plasma before therapy and at radiographic progression, investigators used an FDA-approved 500-gene ctDNA panel to profile resistance mechanisms after durable response to PD-1 inhibitors (n = 30) or EGFR TKIs (n = 13) in advanced NSCLC patients. At progression, 65% of patients carried ≥1 new mutation. Among these, 70% had ≥2 newly emergent alterations, demonstrating polyclonal escape. In the ICI arm, 57% showed new changes—most often NOTCH1/3, KEAP1, STK11, KMT2B or POLE; median PFS from ICI start was 7.0 months. In the post-TKI arm, 85% developed new ctDNA alterations (e.g., EGFR C797X, PIK3CA, MET amp) with mPFS 8.6 months. In both cohorts, TMB and circulating tumor fraction did not significantly change between baseline and progression. These findings parallel large tissue-based series that link KEAP1 and STK11 to primary ICI resistance, but here they emerge de novo, highlighting ctDNA’s ability to capture real-time evolutionary shifts that tissue samples miss.