Background: P-loop/C-helix compressing (PACC) mutations are a structurally distinct subset of uncommon EGFR mutations.The impact of single versus compound PACC genotypes on first-line (1L) outcomes remains unclear. Methods:We conducted an international retrospective multicentre cohort study across 12 centres and 1 platform in patients (pts) with aNSCLC harbouring EGFR PACC mutation who received 1L treatment.Compound status was classified as: single PACC, compound pure (PACC + PACC) or compound mixed (PACC + non-PACC).Primary endpoints were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results: Baseline characteristics are described in the table.1L therapy consisted mainly of EGFR TKIs: third generation (3rd gen) 40.6/28.6/32.4% and 2nd gen 34.0/ 37.4/35.2%across single/compound pure/compound mixed groups.Platinum doublet (+/-ICI) was uncommon (single 5.7% and 2.8%; compound pure 7.7% and 3.3%; compound mixed 2.8% and 1.4%).Pts with brain metastases (BM) more frequently received 3rd gen TKI (45.4% vs 33.2%).ORR (n=339 pts) was 51.6%, 65.1% and 71.4% for single, compound pure, and compound mixed, respectively.Median follow-up was 43.0 months (m) (95% CI 35.2-52.7).Median PFS was 9.0 m, 10.3 m, and 12.7 m (p=0.045), while median OS was 20.3m, 27.4 m, and 29.6 m, respectively (p=0.029).BM were associated with shorter PFS (8.7 vs 11.5 m; p=0.030) and OS (17.2 vs 27.4 m; p=0.012). Conclusions:In our series, outcomes differed by EGFR PACC genotype, favouring compound variants; confirmation in prospective cohorts is warranted.
Monaca et al. (2026) studied this question.